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Montano C, Timp W. Evolution of genome-wide methylation profiling technologies. Genome Res 2025; 35:572-582. [PMID: 40228903 PMCID: PMC12047278 DOI: 10.1101/gr.278407.123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/16/2025]
Abstract
In this mini-review, we explore the advancements in genome-wide DNA methylation profiling, tracing the evolution from traditional methods such as methylation arrays and whole-genome bisulfite sequencing to the cutting-edge single-molecule profiling enabled by long-read sequencing (LRS) technologies. We highlight how LRS is transforming clinical and translational research, particularly by its ability to simultaneously measure genetic and epigenetic information, providing a more comprehensive understanding of complex disease mechanisms. We discuss current challenges and future directions in the field, emphasizing the need for innovative computational tools and robust, reproducible approaches to fully harness the capabilities of LRS in molecular diagnostics.
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Affiliation(s)
- Carolina Montano
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA
- Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
| | - Winston Timp
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA;
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2
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Lønning PE, Nikolaienko O, Knappskog S. Constitutional Epimutations: From Rare Events Toward Major Cancer Risk Factors? JCO Precis Oncol 2025; 9:e2400746. [PMID: 40179326 PMCID: PMC11995855 DOI: 10.1200/po-24-00746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 01/09/2025] [Accepted: 01/14/2025] [Indexed: 04/05/2025] Open
Abstract
Constitutional epimutations are epigenetic aberrations that arise in normal cells prenatally. Two major forms exist: secondary constitutional epimutations (SCEs), associated with cis-acting genetic aberrations, and primary constitutional epimutations (PCEs), for which no associated genetic aberrations were identified. Some SCEs have been associated with risk of cancer (MLH1 and MSH2 with colon or endometrial cancers, BRCA1 with familial breast and ovarian cancers), although such epimutations are rare, with a total of <100 cases reported. This contrasts recent findings for PCE, where low-level mosaic BRCA1 epimutations are recorded in 5%-10% of healthy females across all age groups, including newborns. BRCA1 PCEs predict an elevated risk of high-grade serous ovarian cancer and triple-negative breast cancer (TNBC) and are estimated to account for about 20% of all TNBCs. A similarly high population frequency is observed for mosaic constitutional epimutations in MGMT, occurring as PCE or SCE, but not in MLH1. Contrasting BRCA1 and MLH1, a potential association with cancer risk for MGMT epimutations is yet unclear. In this review, we provide a summary of findings linking constitutional epimutations to cancer risk with emphasis on PCE. We also highlight challenges in detection of PCE exemplified by low-level mosaic epimutations in BRCA1 and indicate the need for further studies, hypothesizing that improved knowledge about PCE may add significantly to our understanding of cancer risk, carcinogenesis, and potentially development of other diseases as well.
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Affiliation(s)
| | - Oleksii Nikolaienko
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Stian Knappskog
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
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3
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Taryma-Leśniak O, Sokolowska KE, Liput M, Wojdacz TK. High-sensitivity Epimutations Testing with MS-HRM. Curr Protoc 2025; 5:e70094. [PMID: 39928292 DOI: 10.1002/cpz1.70094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2025]
Abstract
Epimutation is defined as any heritable change in gene activity that does not affect the actual sequence of DNA. One of the most researched epimutations is promoter methylation of breast cancer susceptibility gene BRCA1. This epimutation may arise de novo in somatic tissues, such as breast or ovarian cancer tissue, but has also been shown to be widely distributed throughout tissues. BRCA1 methylation detectable in peripheral blood has been associated with the risk of both breast and ovarian cancer in patients without a germline pathogenic variant status of this gene. The strength of this association suggests that diagnostic screening for the BRCA1 epimutation should be considered with potential implications in cancer risk assessment. However, the detection of BRCA1 epimutation may be challenging, as it is generally detectable at a very low level in blood. Methylation-sensitive high-resolution melting (MS-HRM) was shown to provide a high sensitivity of methylation detection, and as it is a PCR-based method, epimutation screening based on MS-HRM is labor- and cost-effective. Here we describe the MS-HRM protocol for BRCA1 epimutation screening. © 2025 Wiley Periodicals LLC. Basic Protocol: High sensitivity constitutional epimutations testing with MS-HRM.
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Affiliation(s)
- Olga Taryma-Leśniak
- Independent Clinical Epigenetics Laboratory, Pomeranian Medical University, Szczecin, Poland
- These authors contributed equally to this work
| | - Katarzyna E Sokolowska
- Independent Clinical Epigenetics Laboratory, Pomeranian Medical University, Szczecin, Poland
- These authors contributed equally to this work
| | - Magdalena Liput
- Independent Clinical Epigenetics Laboratory, Pomeranian Medical University, Szczecin, Poland
| | - Tomasz K Wojdacz
- Independent Clinical Epigenetics Laboratory, Pomeranian Medical University, Szczecin, Poland
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Cazzaniga L, Zanzottera C, Mannucci S, Fava F, Marabelli M, Calvello M, Feroce I, Risti M, Del Fiol Manna E, Bertario L, Serrano D, Bonanni B. MLH1 promoter hypermethylation and Lynch Syndrome: When to test for constitutional epimutations of MLH1 gene? TUMORI JOURNAL 2025:3008916241312530. [PMID: 39831439 DOI: 10.1177/03008916241312530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Lynch syndrome is a genetic condition predisposing to cancer, particularly colorectal cancer and endometrial cancer, due to germline mutations in MisMatch Repair genes. More rarely, Lynch syndrome is the result of a constitutional MLH1 promoter methylation. This review summarizes the current knowledge about the role of this epigenetic mechanism in the Lynch syndrome. Universal Tumor Screening, performed on tumoral specimens to identify features suggestive of Lynch syndrome, shows the same features both in the case of sporadic cancers and Lynch syndrome-cancers due to a constitutional MLH1 methylation: microsatellite instability, deficiency of MisMatch Repair proteins, and methylation of MLH1 gene. Over the last few years, identifying methylation of MLH1 promoter on tumors was used to discern sporadic tumors from Lynch syndrome tumors: the methylation of the MLH1 promoter was usually explained as a somatic event and this could lead to a missed diagnosis of some Lynch syndrome cases. Therefore, establishing criteria to decide when to test patients for constitutional MLH1 methylation is urgent. In the case of microsatellite instability/deficiency of MisMatch Repair tumors with MLH1 methylation, a germline genetic test could be requested for all colorectal cancer patients aged 55 years or younger and all endometrial cancer patients younger than 50 years old, independently from family history. The prevalence of germline MLH1 epimutations is not precisely known and possibly underestimated. The associated cancer risk could be similar to that due to a MLH1 sequence variant. MLH1 epimutations could be secondary to other genetic defects and follow an autosomal dominant inheritance. On the contrary, primary epimutations are often "de novo" events, and their transmission does not follow Mendelian rules.
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Affiliation(s)
- Laura Cazzaniga
- IEO, European Institute of Oncology IRCCS, Division of Cancer Prevention and Genetics, Milan, Italy
- Department of Health Sciences, Medical Genetics, University of Milan, Milan, Italy
| | - Cristina Zanzottera
- IEO, European Institute of Oncology IRCCS, Division of Cancer Prevention and Genetics, Milan, Italy
| | - Sara Mannucci
- IEO, European Institute of Oncology IRCCS, Division of Cancer Prevention and Genetics, Milan, Italy
| | - Francesca Fava
- IEO, European Institute of Oncology IRCCS, Division of Cancer Prevention and Genetics, Milan, Italy
| | - Monica Marabelli
- IEO, European Institute of Oncology IRCCS, Division of Cancer Prevention and Genetics, Milan, Italy
| | - Mariarosaria Calvello
- IEO, European Institute of Oncology IRCCS, Division of Cancer Prevention and Genetics, Milan, Italy
- Oncology Competence Center, Gruppo Ospedaliero Moncucco, Lugano, Switzerland
| | - Irene Feroce
- IEO, European Institute of Oncology IRCCS, Division of Cancer Prevention and Genetics, Milan, Italy
| | - Matilde Risti
- IEO, European Institute of Oncology IRCCS, Division of Cancer Prevention and Genetics, Milan, Italy
| | | | - Lucio Bertario
- IEO, European Institute of Oncology IRCCS, Division of Cancer Prevention and Genetics, Milan, Italy
| | - Davide Serrano
- IEO, European Institute of Oncology IRCCS, Division of Cancer Prevention and Genetics, Milan, Italy
| | - Bernardo Bonanni
- IEO, European Institute of Oncology IRCCS, Division of Cancer Prevention and Genetics, Milan, Italy
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Bozsik A, Butz H, Grolmusz VK, Pócza T, Patócs A, Papp J. Spectrum and genotyping strategies of "dark" genetic matter in germline susceptibility genes of tumor syndromes. Crit Rev Oncol Hematol 2025; 205:104549. [PMID: 39528122 DOI: 10.1016/j.critrevonc.2024.104549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 10/23/2024] [Accepted: 10/26/2024] [Indexed: 11/16/2024] Open
Abstract
PURPOSE Despite the widespread use of high-throughput genotyping strategies, certain mutation types remain understudied. We provide an overview of these often overlooked mutation types, with representative examples from common hereditary cancer syndromes. METHODS We conducted a comprehensive review of the literature and locus-specific variant databases to summarize the germline pathogenic variants discovered through non-routine genotyping methods. We evaluated appropriate detection and analysis methods tailored for these specific genetic aberrations. Additionally, we performed in silico splice predictions on deep intronic variants registered in the ClinVar database. RESULTS Our study suggests that, aside from founder mutations, most cases are sporadic. However, we anticipate a relatively high likelihood of splice effects for deep intronic variants. The findings underscore the significant clinical utility of genome sequencing techniques and the importance of applying relevant analysis methods.
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Affiliation(s)
- Anikó Bozsik
- Department of Molecular Genetics, The National Tumor Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Center, Ráth György út 7-9, Budapest H-1122, Hungary; Hereditary Tumours Research Group, Eötvös Loránd Research Network, Nagyvárad tér 4, Budapest H-1089, Hungary.
| | - Henriett Butz
- Department of Molecular Genetics, The National Tumor Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Center, Ráth György út 7-9, Budapest H-1122, Hungary; Hereditary Tumours Research Group, Eötvös Loránd Research Network, Nagyvárad tér 4, Budapest H-1089, Hungary; Department of Laboratory Medicine, Semmelweis University, Ráth György út 7-9, Budapest H-1122, Hungary; Department of Oncology Biobank, National Institute of Oncology, Budapest 1122, Hungary
| | - Vince Kornél Grolmusz
- Department of Molecular Genetics, The National Tumor Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Center, Ráth György út 7-9, Budapest H-1122, Hungary; Hereditary Tumours Research Group, Eötvös Loránd Research Network, Nagyvárad tér 4, Budapest H-1089, Hungary
| | - Tímea Pócza
- Department of Molecular Genetics, The National Tumor Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Center, Ráth György út 7-9, Budapest H-1122, Hungary
| | - Attila Patócs
- Department of Molecular Genetics, The National Tumor Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Center, Ráth György út 7-9, Budapest H-1122, Hungary; Hereditary Tumours Research Group, Eötvös Loránd Research Network, Nagyvárad tér 4, Budapest H-1089, Hungary; Department of Laboratory Medicine, Semmelweis University, Ráth György út 7-9, Budapest H-1122, Hungary
| | - János Papp
- Department of Molecular Genetics, The National Tumor Biology Laboratory, National Institute of Oncology, Comprehensive Cancer Center, Ráth György út 7-9, Budapest H-1122, Hungary; Hereditary Tumours Research Group, Eötvös Loránd Research Network, Nagyvárad tér 4, Budapest H-1089, Hungary
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O’Connor CA, Harrold E, Lin D, Walch H, Gazzo A, Ranganathan M, Kane S, Keane F, Schoenfeld J, Moss D, Thurtle-Schmidt DM, Suehnholz SP, Chakravarty D, Balogun F, Varghese A, Yu K, Kelsen D, Latham A, Weigelt B, Park W, Stadler Z, O’Reilly EM. Lynch Syndrome and Somatic Mismatch Repair Variants in Pancreas Cancer. JAMA Oncol 2024; 10:1511-1518. [PMID: 39235819 PMCID: PMC11378065 DOI: 10.1001/jamaoncol.2024.3651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 05/20/2024] [Indexed: 09/06/2024]
Abstract
Importance Microsatellite (MS) instability (MSI-H) occurs frequently in Lynch syndrome (LS)-associated tumors and is associated with response to immune checkpoint blockade (ICB) therapy. MSI-H is conferred by germline or somatic variants in mismatch repair genes. The contribution of somatic oncogenesis to MSI-H in pancreatic cancer (PC) is unknown. Objective To evaluate an LS-related PC cohort to define clinicogenomic features, describe somatic MSI-H cases (germline negative), characterize response to ICB, and guide preferred MS testing methods. Design, Setting, and Participants This single-institution, retrospective analysis was conducted from March 2012 to July 2023 at Memorial Sloan Kettering Cancer Center and included 55 patients with PC and either an LS germline pathogenic variant (gPV) or somatic mismatch repair (MMR) variant. Main Outcomes and Measures Composite MMR and MS status determined using orthogonal methods. An artificial intelligence classifier was used to account for low-cellularity specimens. Demographic and clinical data were abstracted from medical record. Zygosity status and somatic comutation landscape analyzed. Results Fifty-five patients (23 women [42%]) had PC and an MMR variant: 32 (58%) had LS (LS cohort) and 23 (42%) had a somatic MMR variant (no germline pathogenic variant, somatic MMR cohort). In the LS cohort, 10 (31%) had gMSH2, 9 (28%) gMSH6, 8 (25%) gPMS2, 4 (13%) gMLH1, 1 (3%) gEPCAM. The median age at diagnosis was 68 years (range, 45-88 years). For composite MS status, 17 (59%) were MSI-H, 12 (41%) MS stable, and 3 MS unknown. Five cases were reclassified as MSI-H by the artificial intelligence classifier. In the somatic MMR cohort, 11 (48%) had MSH6, 7 (30%) MLH1, 3 (13%) MSH2, and 2 (9%) PMS2. The median age at diagnosis was 72 years (range, 66-85 years). For composite MS status, 10 (43%) were MSI-H, 11 (48%) MS stable, and 2 (9%) MS indeterminate. Six cases were reclassified as MSI-H by the artificial intelligence classifier. For the LS and somatic MMR cohorts, 20 received ICB (n = 17 MSI-H). The median ICB duration was 27.7 months (95% CI, 11.5 to not reached); the disease control rate was 80%. Conclusion The results of this cross-sectional study suggest that MSI-H occurs due to LS or somatic oncogenesis in PC. Orthogonal MS testing is key in PC; the artificial intelligence classifier reclassified approximately 20% of cases, most of which were low cellularity. ICB for patients with LS or somatic MSI-H PC provided significant benefit.
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Affiliation(s)
- Catherine A. O’Connor
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Biology, Davidson College, Davidson, North Carolina
| | - Emily Harrold
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Mater Misericordiae University Hospital Dublin, Dublin, Ireland
| | - David Lin
- Kravis Center for Molecular Oncology, Memorial Sloan Kettering, New York, New York
| | - Henry Walch
- Kravis Center for Molecular Oncology, Memorial Sloan Kettering, New York, New York
| | - Andrea Gazzo
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Megha Ranganathan
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sarah Kane
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Fergus Keane
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Joshua Schoenfeld
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Drew Moss
- Mount Sinai Morningside West, New York, New York
| | | | - Sarah P. Suehnholz
- Human Oncology Pathogenesis Program, Sloan Kettering Institute, New York, New York
| | - Debyani Chakravarty
- Human Oncology Pathogenesis Program, Sloan Kettering Institute, New York, New York
| | - Fiyinfolu Balogun
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- David M. Rubenstein Center for Pancreas Cancer Research, New York, New York
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Anna Varghese
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- David M. Rubenstein Center for Pancreas Cancer Research, New York, New York
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Kenneth Yu
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- David M. Rubenstein Center for Pancreas Cancer Research, New York, New York
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - David Kelsen
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- David M. Rubenstein Center for Pancreas Cancer Research, New York, New York
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Alicia Latham
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- David M. Rubenstein Center for Pancreas Cancer Research, New York, New York
| | - Britta Weigelt
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Wungki Park
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- David M. Rubenstein Center for Pancreas Cancer Research, New York, New York
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Zsofia Stadler
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Eileen M. O’Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
- David M. Rubenstein Center for Pancreas Cancer Research, New York, New York
- Department of Medicine, Weill Cornell Medical College, New York, New York
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Li Y, Bai H, Liu W, Zhou W, Gu H, Zhao P, Zhu M, Li Y, Yan X, Zhao N, Huang X. Intergenerational epigenetic inheritance mediated by MYS-2/MOF in the pathogenesis of Alzheimer's disease. iScience 2024; 27:110588. [PMID: 39220410 PMCID: PMC11363564 DOI: 10.1016/j.isci.2024.110588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 02/08/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Although autosomal-dominant inheritance is believed an important cause of familial clustering Alzheimer's disease (FAD), it covers only a small proportion of FAD incidence, and so we investigated epigenetic memory as an alternative mechanism to contribute for intergenerational AD pathogenesis. Our data in vivo showed that mys-2 of Caenorhabditis elegans that encodes a putative MYST acetyltransferase responsible for H4K16 acetylation modulated AD occurrence. The phenotypic improvements in the parent generation caused by mys-2 disfunction were passed to their progeny due to epigenetic memory, which resulted in similar H4K16ac levels among the candidate target genes of MYS-2 and similar gene expression patterns of the AD-related pathways. Furthermore, the ROS/CDK-5/ATM pathway functioned as an upstream activator of MYS-2. Our study indicated that MYS-2/MOF could be inherited intergenerationally via epigenetic mechanisms in C. elegans and mammalian cell of AD model, providing a new insight into our understanding of the etiology and inheritance of FAD.
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Affiliation(s)
- Yuhong Li
- School of Medicine, State Key Lab for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming 650091, China
- College of Biological Resources and Food Engineering, Qujing Normal University, Qujing 655000, China
| | - Hua Bai
- School of Medicine, State Key Lab for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming 650091, China
- School of Public Health, Kunming Medical University, Kunming 650500, China
| | - Wenwen Liu
- School of Medicine, State Key Lab for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming 650091, China
| | - Wenhui Zhou
- School of Medicine, State Key Lab for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming 650091, China
| | - Huan Gu
- School of Medicine, State Key Lab for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming 650091, China
| | - Peiji Zhao
- School of Medicine, State Key Lab for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming 650091, China
| | - Man Zhu
- School of Medicine, State Key Lab for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming 650091, China
- College of Biological Resources and Food Engineering, Qujing Normal University, Qujing 655000, China
| | - Yixin Li
- School of Medicine, State Key Lab for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming 650091, China
| | - Xinyi Yan
- School of Medicine, State Key Lab for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming 650091, China
| | - Ninghui Zhao
- Neurosurgery of the Second Hospital Affiliated with Kunming Medical University, Kunming 650101, China
| | - Xiaowei Huang
- School of Medicine, State Key Lab for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming 650091, China
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Heriyanto DS, Yoshuantari N, Akbariani G, Lau V, Hanini H, Hidayati Z, Arief MZ, Gunawan AN, Ridwanuloh AM, Kusharyoto W, Handaya AY, Ilyas M, Kurnianda J, Hutajulu SH, Susanti S. High Probability of Lynch Syndrome Among Colorectal Cancer Patients Is Associated With Higher Occurrence of KRAS and PIK3CA Mutations. World J Oncol 2024; 15:612-624. [PMID: 38993255 PMCID: PMC11236368 DOI: 10.14740/wjon1843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 05/25/2024] [Indexed: 07/13/2024] Open
Abstract
Background In Indonesia, early-onset colorectal cancer (EOCRC) rates are higher in patients < 50 years old compared to Western populations, possibly due to a higher frequency of Lynch syndrome (LS) in CRC patients. We aimed to examine the association of KRAS and PIK3CA mutations with LS. Methods In this retrospective cross-sectional single-center study, the PCR-HRM-based test was used for screening of microsatellite instability (MSI) mononucleotide markers (BAT25, BAT26, BCAT25, MYB, EWSR1), MLH1 promoter methylation, and oncogene mutations of BRAF (V600E), KRAS (exon 2 and 3), and PIK3CA (exon 9 and 20) in FFPE DNA samples. Results All the samples (n = 244) were from Dr. Sardjito General Hospital Yogyakarta, Indonesia. KRAS and PIK3CA mutations were found in 151/244 (61.88%) and 107/244 (43.85%) of samples, respectively. KRAS and PIK3CA mutations were significantly associated with MSI status in 32/42 (76.19%) and 25/42 (59.52%) of samples, respectively. KRAS mutation was significantly associated with LS status in 26/32 (81.25%) of samples. The PIK3CA mutation was present in a higher proportion in LS samples of 19/32 (59.38%), but not statistically significant. Clinicopathology showed that KRAS mutation was significantly associated with right-sided CRC and higher histology grade in 39/151 (25.83%) and 24/151 (16.44%) samples, respectively. PIK3CA mutation was significantly associated with female sex and lower levels of tumor-infiltrating lymphocytes in 62/107 (57.94%) and 26/107 (30.23%) samples, respectively. KRAS and PIK3CA mutations did not significantly affect overall survival (120 months) in LS and non-LS patients. Conclusions The high probability of LS in Indonesian CRC patients is associated with KRAS and PIK3CA mutations.
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Affiliation(s)
- Didik Setyo Heriyanto
- Department of Anatomical Pathology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr Sardjito General Hospital Yogyakarta, Indonesia
- Collaboration Research Center for Precision Oncology based Omics - PKR PrOmics, Yogyakarta, Indonesia
| | - Naomi Yoshuantari
- Department of Anatomical Pathology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr Sardjito General Hospital Yogyakarta, Indonesia
| | - Gilang Akbariani
- Pathgen Diagnostik Teknologi, Ir. Soekarno Science and Technology Park, National Research and Innovation Agency Republic of Indonesia, Bogor, Indonesia
| | - Vincent Lau
- Department of Anatomical Pathology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr Sardjito General Hospital Yogyakarta, Indonesia
| | - Hanifa Hanini
- Pathgen Diagnostik Teknologi, Ir. Soekarno Science and Technology Park, National Research and Innovation Agency Republic of Indonesia, Bogor, Indonesia
| | - Zulfa Hidayati
- Pathgen Diagnostik Teknologi, Ir. Soekarno Science and Technology Park, National Research and Innovation Agency Republic of Indonesia, Bogor, Indonesia
| | - Muhammad Zulfikar Arief
- Pathgen Diagnostik Teknologi, Ir. Soekarno Science and Technology Park, National Research and Innovation Agency Republic of Indonesia, Bogor, Indonesia
| | - Andrew Nobiantoro Gunawan
- Department of Anatomical Pathology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr Sardjito General Hospital Yogyakarta, Indonesia
| | - Asep Muhamad Ridwanuloh
- Research Center for Genetic Engineering, Research Organization for Life Sciences and Environment, National Research and Innovation Agency Republic of Indonesia, Ir. Soekarno Science and Technology Park, Bogor, Indonesia
| | - Wien Kusharyoto
- Research Center for Genetic Engineering, Research Organization for Life Sciences and Environment, National Research and Innovation Agency Republic of Indonesia, Ir. Soekarno Science and Technology Park, Bogor, Indonesia
| | - Adeodatus Yuda Handaya
- Division of Digestive Surgeon, Department of Surgery, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr Sardjito General Hospital Yogyakarta, Indonesia
| | - Mohammad Ilyas
- Molecular Pathology Research Group, Academic Unit of Translational Medical Science, Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, UK
| | - Johan Kurnianda
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr Sardjito General Hospital, Yogyakarta, Indonesia
| | - Susanna Hilda Hutajulu
- Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr Sardjito General Hospital, Yogyakarta, Indonesia
| | - Susanti Susanti
- Pathgen Diagnostik Teknologi, Ir. Soekarno Science and Technology Park, National Research and Innovation Agency Republic of Indonesia, Bogor, Indonesia
- Molecular Pathology Research Group, Academic Unit of Translational Medical Science, Biodiscovery Institute, School of Medicine, University of Nottingham, Nottingham, UK
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Muhammadiyah Purwokerto, Indonesia
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9
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Ibrahim MB, Flanagan J, Ibrahim T, Rouleau E. Unraveling noncoding DNA variants and epimutations: a paradigm shift in hereditary cancer research. Future Oncol 2024; 20:1289-1298. [PMID: 38722139 PMCID: PMC11318707 DOI: 10.2217/fon-2023-0665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 03/11/2024] [Indexed: 06/12/2024] Open
Abstract
Exhaustive efforts have been dedicated to uncovering genomic aberrations linked to cancer susceptibility. Noncoding sequence variants and epigenetic alterations significantly influence gene regulation and could contribute to cancer development. However, exploring noncoding regions in hereditary cancer susceptibility demands cutting-edge methodologies for functionally characterizing genomic discoveries. Additionally, comprehending the impact on cancer development of variants in noncoding DNA and the epigenome necessitates integrating diverse data through bioinformatic analyses. As novel technologies and analytical methods continue to advance, this realm of research is rapidly gaining traction. Within this mini-review, we delve into future research domains concerning aberrations in noncoding DNA regions, such as pseudoexons, promoter variants and cis-epimutations.
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Affiliation(s)
- Maria Baz Ibrahim
- Department of Oncogenetics & Tumor Biology, Paul Brousse Hospital, Villejuif, France
| | - James Flanagan
- Department of Surgery & Cancer, Ovarian Cancer Action Research Centre, Imperial College London, London, W12 8EE, UK
| | - Tony Ibrahim
- International Department of Medical Oncology, Gustave Roussy, 94805, Villejuif, France
| | - Etienne Rouleau
- Department of Biology & Pathology-Cancer Genetics Laboratory, Gustave Roussy, 94805, Villejuif, France
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10
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Saito S, Saito Y, Sato S, Aoki S, Fujita H, Ito Y, Ono N, Funakoshi T, Kawai T, Suzuki H, Sasaki T, Tanaka T, Inoie M, Hata K, Kataoka K, Kosaki K, Amagai M, Nakabayashi K, Kubo A. Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis. Am J Hum Genet 2024; 111:896-912. [PMID: 38653249 PMCID: PMC11080608 DOI: 10.1016/j.ajhg.2024.03.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 03/12/2024] [Accepted: 03/28/2024] [Indexed: 04/25/2024] Open
Abstract
Porokeratosis is a clonal keratinization disorder characterized by solitary, linearly arranged, or generally distributed multiple skin lesions. Previous studies showed that genetic alterations in MVK, PMVK, MVD, or FDPS-genes in the mevalonate pathway-cause hereditary porokeratosis, with skin lesions harboring germline and lesion-specific somatic variants on opposite alleles. Here, we identified non-hereditary porokeratosis associated with epigenetic silencing of FDFT1, another gene in the mevalonate pathway. Skin lesions of the generalized form had germline and lesion-specific somatic variants on opposite alleles in FDFT1, representing FDFT1-associated hereditary porokeratosis identified in this study. Conversely, lesions of the solitary or linearly arranged localized form had somatic bi-allelic promoter hypermethylation or mono-allelic promoter hypermethylation with somatic genetic alterations on opposite alleles in FDFT1, indicating non-hereditary porokeratosis. FDFT1 localization was uniformly diminished within the lesions, and lesion-derived keratinocytes showed cholesterol dependence for cell growth and altered expression of genes related to cell-cycle and epidermal development, confirming that lesions form by clonal expansion of FDFT1-deficient keratinocytes. In some individuals with the localized form, gene-specific promoter hypermethylation of FDFT1 was detected in morphologically normal epidermis adjacent to methylation-related lesions but not distal to these lesions, suggesting that asymptomatic somatic epigenetic mosaicism of FDFT1 predisposes certain skin areas to the disease. Finally, consistent with its genetic etiology, topical statin treatment ameliorated lesions in FDFT1-deficient porokeratosis. In conclusion, we identified bi-allelic genetic and/or epigenetic alterations of FDFT1 as a cause of porokeratosis and shed light on the pathogenesis of skin mosaicism involving clonal expansion of epigenetically altered cells.
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Affiliation(s)
- Sonoko Saito
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yuki Saito
- Department of Gastroenterology, Keio University School of Medicine, Tokyo 160-8582, Japan; Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Showbu Sato
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Satomi Aoki
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Harumi Fujita
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yoshihiro Ito
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Noriko Ono
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Takeru Funakoshi
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Tomoko Kawai
- Department of Maternal-Fetal Biology, National Center for Child Health and Development, Tokyo 157-8535, Japan
| | - Hisato Suzuki
- Center for Medical Genetics, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Takashi Sasaki
- Center for Supercentenarian Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Tomoyo Tanaka
- R&D department, Japan Tissue Engineering Co., Ltd., Aichi 443-0022, Japan
| | - Masukazu Inoie
- R&D department, Japan Tissue Engineering Co., Ltd., Aichi 443-0022, Japan
| | - Kenichiro Hata
- Department of Maternal-Fetal Biology, National Center for Child Health and Development, Tokyo 157-8535, Japan; Department of Human Molecular Genetics, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan
| | - Keisuke Kataoka
- Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Kenjiro Kosaki
- Center for Medical Genetics, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Masayuki Amagai
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Kazuhiko Nakabayashi
- Department of Maternal-Fetal Biology, National Center for Child Health and Development, Tokyo 157-8535, Japan.
| | - Akiharu Kubo
- Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan; Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Hyogo 650-0017, Japan.
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11
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Helderman NC, Andini KD, van Leerdam ME, van Hest LP, Hoekman DR, Ahadova A, Bajwa-Ten Broeke SW, Bosse T, van der Logt EMJ, Imhann F, Kloor M, Langers AMJ, Smit VTHBM, Terlouw D, van Wezel T, Morreau H, Nielsen M. MLH1 Promotor Hypermethylation in Colorectal and Endometrial Carcinomas from Patients with Lynch Syndrome. J Mol Diagn 2024; 26:106-114. [PMID: 38061582 DOI: 10.1016/j.jmoldx.2023.10.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 07/19/2023] [Accepted: 10/17/2023] [Indexed: 01/26/2024] Open
Abstract
Screening for Lynch syndrome (LS) in colorectal cancer (CRC) and endometrial cancer patients generally involves immunohistochemical staining of the mismatch repair (MMR) proteins. In case of MLH1 protein loss, MLH1 promotor hypermethylation (MLH1-PM) testing is performed to indirectly distinguish the constitutional MLH1 variants from somatic epimutations. Recently, multiple studies have reported that MLH1-PM and pathogenic constitutional MMR variants are not mutually exclusive. This study describes 6 new and 86 previously reported MLH1-PM CRCs or endometrial cancers in LS patients. Of these, methylation of the MLH1 gene promotor C region was reported in 30 MLH1, 6 MSH2, 6 MSH6, and 3 PMS2 variant carriers at a median age at diagnosis of 48.5 years [interquartile range (IQR), 39-56.75 years], 39 years (IQR, 29-51 years), 58 years (IQR, 53.5-67 years), and 68 years (IQR, 65.6-68.5 years), respectively. For 31 MLH1-PM CRCs in LS patients from the literature, only the B region of the MLH1 gene promotor was tested, whereas for 13 cases in the literature the tested region was not specified. Collectively, these data indicate that a diagnosis of LS should not be excluded when MLH1-PM is detected. Clinicians should carefully consider whether follow-up genetic MMR gene testing should be offered, with age <60 to 70 years and/or a positive family history among other factors being suggestive for a potential constitutional MMR gene defect.
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Affiliation(s)
- Noah C Helderman
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
| | - Katarina D Andini
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Monique E van Leerdam
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands; Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Liselotte P van Hest
- Department of Human Genetics, Amsterdam University Medical Center, Vrije Universiteit Amsterdam and University of Amsterdam, Amsterdam, the Netherlands
| | - Daniël R Hoekman
- Department of Human Genetics, Amsterdam University Medical Center, Vrije Universiteit Amsterdam and University of Amsterdam, Amsterdam, the Netherlands
| | - Aysel Ahadova
- Department of Applied Tumor Biology, Heidelberg University Hospital, Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Centre, Heidelberg, Germany
| | - Sanne W Bajwa-Ten Broeke
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Tjalling Bosse
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
| | | | - Floris Imhann
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Matthias Kloor
- Department of Applied Tumor Biology, Heidelberg University Hospital, Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Centre, Heidelberg, Germany
| | - Alexandra M J Langers
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Vincent T H B M Smit
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
| | - Diantha Terlouw
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands; Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
| | - Tom van Wezel
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
| | - Hans Morreau
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands
| | - Maartje Nielsen
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
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12
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Nikolaienko O, Eikesdal HP, Ognedal E, Gilje B, Lundgren S, Blix ES, Espelid H, Geisler J, Geisler S, Janssen EAM, Yndestad S, Minsaas L, Leirvaag B, Lillestøl R, Knappskog S, Lønning PE. Prenatal BRCA1 epimutations contribute significantly to triple-negative breast cancer development. Genome Med 2023; 15:104. [PMID: 38053165 PMCID: PMC10698991 DOI: 10.1186/s13073-023-01262-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 11/16/2023] [Indexed: 12/07/2023] Open
Abstract
BACKGROUND Normal cell BRCA1 epimutations have been associated with increased risk of triple-negative breast cancer (TNBC). However, the fraction of TNBCs that may have BRCA1 epimutations as their underlying cause is unknown. Neither are the time of occurrence and the potential inheritance patterns of BRCA1 epimutations established. METHODS To address these questions, we analyzed BRCA1 methylation status in breast cancer tissue and matched white blood cells (WBC) from 408 patients with 411 primary breast cancers, including 66 TNBCs, applying a highly sensitive sequencing assay, allowing allele-resolved methylation assessment. Furthermore, to assess the time of origin and the characteristics of normal cell BRCA1 methylation, we analyzed umbilical cord blood of 1260 newborn girls and 200 newborn boys. Finally, we assessed BRCA1 methylation status among 575 mothers and 531 fathers of girls with (n = 102) and without (n = 473) BRCA1 methylation. RESULTS We found concordant tumor and mosaic WBC BRCA1 epimutations in 10 out of 66 patients with TNBC and in four out of six patients with estrogen receptor (ER)-low expression (< 10%) tumors (combined: 14 out of 72; 19.4%; 95% CI 11.1-30.5). In contrast, we found concordant WBC and tumor methylation in only three out of 220 patients with 221 ER ≥ 10% tumors and zero out of 114 patients with 116 HER2-positive tumors. Intraindividually, BRCA1 epimutations affected the same allele in normal and tumor cells. Assessing BRCA1 methylation in umbilical WBCs from girls, we found mosaic, predominantly monoallelic BRCA1 epimutations, with qualitative features similar to those in adults, in 113/1260 (9.0%) of individuals, but no correlation to BRCA1 methylation status either in mothers or fathers. A significantly lower fraction of newborn boys carried BRCA1 methylation (9/200; 4.5%) as compared to girls (p = 0.038). Similarly, WBC BRCA1 methylation was found less common among fathers (16/531; 3.0%), as compared to mothers (46/575; 8.0%; p = 0.0003). CONCLUSIONS Our findings suggest prenatal BRCA1 epimutations might be the underlying cause of around 20% of TNBC and low-ER expression breast cancers. Such constitutional mosaic BRCA1 methylation likely arise through gender-related mechanisms in utero, independent of Mendelian inheritance.
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Affiliation(s)
- Oleksii Nikolaienko
- K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Jonas Lies Vei 65, N5021, Bergen, Norway
| | - Hans P Eikesdal
- K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Jonas Lies Vei 65, N5021, Bergen, Norway
| | - Elisabet Ognedal
- K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Jonas Lies Vei 65, N5021, Bergen, Norway
| | - Bjørnar Gilje
- Department of Hematology and Oncology, Stavanger University Hospital, Stavanger, Norway
| | - Steinar Lundgren
- Cancer Clinic, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Egil S Blix
- Department of Oncology, University Hospital of North Norway, Tromsø, Norway
| | - Helge Espelid
- Department of Surgery, Haugesund Hospital, Haugesund, Norway
| | - Jürgen Geisler
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Stephanie Geisler
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
| | - Emiel A M Janssen
- Department of Pathology, Stavanger University Hospital, Stavanger, Norway
- Department of Chemistry, Bioscience and Environmental Engineering, Stavanger University, Stavanger, Norway
| | - Synnøve Yndestad
- K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Jonas Lies Vei 65, N5021, Bergen, Norway
| | - Laura Minsaas
- K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Jonas Lies Vei 65, N5021, Bergen, Norway
| | - Beryl Leirvaag
- K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Jonas Lies Vei 65, N5021, Bergen, Norway
| | - Reidun Lillestøl
- K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Jonas Lies Vei 65, N5021, Bergen, Norway
| | - Stian Knappskog
- K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Jonas Lies Vei 65, N5021, Bergen, Norway
| | - Per E Lønning
- K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.
- Department of Oncology, Haukeland University Hospital, Jonas Lies Vei 65, N5021, Bergen, Norway.
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13
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Bond DM, Ortega-Recalde O, Laird MK, Hayakawa T, Richardson KS, Reese FCB, Kyle B, McIsaac-Williams BE, Robertson BC, van Heezik Y, Adams AL, Chang WS, Haase B, Mountcastle J, Driller M, Collins J, Howe K, Go Y, Thibaud-Nissen F, Lister NC, Waters PD, Fedrigo O, Jarvis ED, Gemmell NJ, Alexander A, Hore TA. The admixed brushtail possum genome reveals invasion history in New Zealand and novel imprinted genes. Nat Commun 2023; 14:6364. [PMID: 37848431 PMCID: PMC10582058 DOI: 10.1038/s41467-023-41784-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 09/13/2023] [Indexed: 10/19/2023] Open
Abstract
Combining genome assembly with population and functional genomics can provide valuable insights to development and evolution, as well as tools for species management. Here, we present a chromosome-level genome assembly of the common brushtail possum (Trichosurus vulpecula), a model marsupial threatened in parts of their native range in Australia, but also a major introduced pest in New Zealand. Functional genomics reveals post-natal activation of chemosensory and metabolic genes, reflecting unique adaptations to altricial birth and delayed weaning, a hallmark of marsupial development. Nuclear and mitochondrial analyses trace New Zealand possums to distinct Australian subspecies, which have subsequently hybridised. This admixture allowed phasing of parental alleles genome-wide, ultimately revealing at least four genes with imprinted, parent-specific expression not yet detected in other species (MLH1, EPM2AIP1, UBP1 and GPX7). We find that reprogramming of possum germline imprints, and the wider epigenome, is similar to eutherian mammals except onset occurs after birth. Together, this work is useful for genetic-based control and conservation of possums, and contributes to understanding of the evolution of novel mammalian epigenetic traits.
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Affiliation(s)
- Donna M Bond
- Department of Anatomy, University of Otago, Dunedin, New Zealand
| | | | - Melanie K Laird
- Department of Anatomy, University of Otago, Dunedin, New Zealand
| | - Takashi Hayakawa
- Faculty of Environmental Earth Science, Hokkaido University, Sapporo, Hokkaido, 060-0808, Japan
| | - Kyle S Richardson
- Department of Anatomy, University of Otago, Dunedin, New Zealand
- Biology Department, University of Montana Western, Dillon, MT, 59725, USA
| | - Finlay C B Reese
- Department of Anatomy, University of Otago, Dunedin, New Zealand
| | - Bruce Kyle
- Department of Anatomy, University of Otago, Dunedin, New Zealand
| | | | | | | | - Amy L Adams
- Department of Zoology, University of Otago, Dunedin, New Zealand
| | - Wei-Shan Chang
- School of Life and Environmental Science, Faculty of Science, The University of Sydney, Sydney, NSW, Australia
- Health and Biosecurity, CSIRO, Canberra, ACT, Australia
| | - Bettina Haase
- Vertebrate Genome Laboratory, The Rockefeller University, New York, NY, USA
| | | | | | - Joanna Collins
- Tree of Life, Wellcome Sanger Institute, Hinxton, Cambridge, UK
| | - Kerstin Howe
- Tree of Life, Wellcome Sanger Institute, Hinxton, Cambridge, UK
| | - Yasuhiro Go
- Graduate School of Information Science, Hyogo University, Hyogo, Japan
- Cognitive Genomics Research Group, Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Aichi, Japan
- Department of System Neuroscience, National Institute for Physiological Sciences, Aichi, Japan
| | - Francoise Thibaud-Nissen
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA
| | - Nicholas C Lister
- School of Biotechnology and Biomolecular Science, Faculty of Science, UNSW Sydney, Sydney, NSW, 2052, Australia
| | - Paul D Waters
- School of Biotechnology and Biomolecular Science, Faculty of Science, UNSW Sydney, Sydney, NSW, 2052, Australia
| | - Olivier Fedrigo
- Vertebrate Genome Laboratory, The Rockefeller University, New York, NY, USA
| | - Erich D Jarvis
- Vertebrate Genome Laboratory, The Rockefeller University, New York, NY, USA
- Laboratory of Neurogenetics of Language, The Rockefeller University, New York, NY, 10065, USA
- Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA
| | - Neil J Gemmell
- Department of Anatomy, University of Otago, Dunedin, New Zealand
| | - Alana Alexander
- Department of Anatomy, University of Otago, Dunedin, New Zealand
| | - Timothy A Hore
- Department of Anatomy, University of Otago, Dunedin, New Zealand.
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14
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de Jong VMT, Pruntel R, Steenbruggen TG, Bleeker FE, Nederlof P, Hogervorst FBL, Linn SC. Identifying the BRCA1 c.-107A > T variant in Dutch patients with a tumor BRCA1 promoter hypermethylation. Fam Cancer 2023; 22:151-154. [PMID: 36112334 PMCID: PMC10020283 DOI: 10.1007/s10689-022-00314-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 06/02/2022] [Indexed: 11/26/2022]
Abstract
An inherited single nucleotide variant (SNV) in the 5'UTR of the BRCA1 gene c.-107A > T was identified to be related to BRCA1 promoter hypermethylation and a hereditary breast and ovarian cancer phenotype in two UK families. We investigated whether this BRCA1 variant was also present in a Dutch cohort of breast and ovarian cancer patients with tumor BRCA1 promoter hypermethylation. We selected all breast and ovarian cancer cases that tested positive for tumor BRCA1 promoter hypermethylation at the Netherlands Cancer Institute and Sanger sequenced the specific mutation in the tumor DNA. In total, we identified 193 tumors with BRCA1 promoter hypermethylation in 178 unique patients. The wild-type allele was identified in 100% (193/193) of sequenced tumor samples. In a large cohort of 178 patients, none had tumors harboring the previously identified c.-107A > T SNV in BRCA1. We therefore can conclude that the germline SNV is not pervasive in patients with tumor BRCA1 promoter hypermethylation.
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Affiliation(s)
- Vincent M T de Jong
- Department of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, Netherlands
| | - Roelof Pruntel
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Tessa G Steenbruggen
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Fonnet E Bleeker
- Department of Clinical Genetics, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Petra Nederlof
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Frans B L Hogervorst
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Sabine C Linn
- Department of Molecular Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, Netherlands.
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands.
- Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands.
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15
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Hitchins MP, Alvarez R, Zhou L, Aguirre F, Dámaso E, Pineda M, Capella G, Wong JJL, Yuan X, Ryan SR, Sathe DS, Baxter MD, Cannon T, Biswas R, DeMarco T, Grzelak D, Hampel H, Pearlman R. MLH1-methylated endometrial cancer under 60 years of age as the "sentinel" cancer in female carriers of high-risk constitutional MLH1 epimutation. Gynecol Oncol 2023; 171:129-140. [PMID: 36893489 PMCID: PMC10153467 DOI: 10.1016/j.ygyno.2023.02.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 02/22/2023] [Accepted: 02/26/2023] [Indexed: 03/11/2023]
Abstract
OBJECTIVE Universal screening of endometrial carcinoma (EC) for mismatch repair deficiency (MMRd) and Lynch syndrome uses presence of MLH1 methylation to omit common sporadic cases from follow-up germline testing. However, this overlooks rare cases with high-risk constitutional MLH1 methylation (epimutation), a poorly-recognized mechanism that predisposes to Lynch-type cancers with MLH1 methylation. We aimed to determine the role and frequency of constitutional MLH1 methylation among EC cases with MMRd, MLH1-methylated tumors. METHODS We screened blood for constitutional MLH1 methylation using pyrosequencing and real-time methylation-specific PCR in patients with MMRd, MLH1-methylated EC ascertained from (i) cancer clinics (n = 4, <60 years), and (ii) two population-based cohorts; "Columbus-area" (n = 68, all ages) and "Ohio Colorectal Cancer Prevention Initiative (OCCPI)" (n = 24, <60 years). RESULTS Constitutional MLH1 methylation was identified in three out of four patients diagnosed between 36 and 59 years from cancer clinics. Two had mono-/hemiallelic epimutation (∼50% alleles methylated). One with multiple primaries had low-level mosaicism in normal tissues and somatic "second-hits" affecting the unmethylated allele in all tumors, demonstrating causation. In the population-based cohorts, all 68 cases from the Columbus-area cohort were negative and low-level mosaic constitutional MLH1 methylation was identified in one patient aged 36 years out of 24 from the OCCPI cohort, representing one of six (∼17%) patients <50 years and one of 45 patients (∼2%) <60 years in the combined cohorts. EC was the first/dual-first cancer in three patients with underlying constitutional MLH1 methylation. CONCLUSIONS A correct diagnosis at first presentation of cancer is important as it will significantly alter clinical management. Screening for constitutional MLH1 methylation is warranted in patients with early-onset EC or synchronous/metachronous tumors (any age) displaying MLH1 methylation.
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Affiliation(s)
- Megan P Hitchins
- Department of Biomedical Sciences, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Medicine (Oncology), Stanford University, Stanford, CA, USA.
| | - Rocio Alvarez
- Department of Biomedical Sciences, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Lisa Zhou
- Department of Biomedical Sciences, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Francesca Aguirre
- Department of Biomedical Sciences, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Estela Dámaso
- Department of Medicine (Oncology), Stanford University, Stanford, CA, USA; Hereditary Cancer Program, Catalan Institute of Oncology, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, Av. Gran Via de l'Hospitalet, 199-203, 08908 L' Hospitalet de Llobregat, Barcelona, Spain; Molecular Genetics Unit, Elche University Hospital, Elche, Alicante. Foundation for the Promotion of Health and Biomedical Research of Valencia Region (FISABIO), FISABIO- Elche Health Department, Spain
| | - Marta Pineda
- Molecular Genetics Unit, Elche University Hospital, Elche, Alicante. Foundation for the Promotion of Health and Biomedical Research of Valencia Region (FISABIO), FISABIO- Elche Health Department, Spain; Consortium for Biomedical Research in Cancer - CIBERONC, Carlos III Institute of Health, Av. De Monforte de Lemos 5, 28029 Madrid, Spain
| | - Gabriel Capella
- Molecular Genetics Unit, Elche University Hospital, Elche, Alicante. Foundation for the Promotion of Health and Biomedical Research of Valencia Region (FISABIO), FISABIO- Elche Health Department, Spain; Consortium for Biomedical Research in Cancer - CIBERONC, Carlos III Institute of Health, Av. De Monforte de Lemos 5, 28029 Madrid, Spain
| | - Justin J-L Wong
- Epigenetics and RNA Biology Program Centenary Institute, and Faculty of Medicine and Health, The University of Sydney, Camperdown, New South Wales 2050, Australia
| | - Xiaopu Yuan
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Shawnia R Ryan
- Hereditary Cancer Assessment Program, University of New Mexico Comprehensive Cancer Center, NM, USA
| | - Devika S Sathe
- Precision Medicine and Genetics, Frederick Health, MD, USA
| | | | - Timothy Cannon
- Cancer Genetics Program, Inova Schar Cancer Institute, Inova Fairfax Hospital, VA, USA
| | - Rakesh Biswas
- Cancer Genetics Program, Inova Schar Cancer Institute, Inova Fairfax Hospital, VA, USA
| | - Tiffani DeMarco
- Cancer Genetics Program, Inova Schar Cancer Institute, Inova Fairfax Hospital, VA, USA
| | | | - Heather Hampel
- Department of Internal Medicine and the Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA; Division of Clinical Cancer Genomics, Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA
| | - Rachel Pearlman
- Department of Internal Medicine and the Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA
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16
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Takahashi Y, Morales Valencia M, Yu Y, Ouchi Y, Takahashi K, Shokhirev MN, Lande K, Williams AE, Fresia C, Kurita M, Hishida T, Shojima K, Hatanaka F, Nuñez-Delicado E, Esteban CR, Izpisua Belmonte JC. Transgenerational inheritance of acquired epigenetic signatures at CpG islands in mice. Cell 2023; 186:715-731.e19. [PMID: 36754048 DOI: 10.1016/j.cell.2022.12.047] [Citation(s) in RCA: 99] [Impact Index Per Article: 49.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 08/19/2022] [Accepted: 12/29/2022] [Indexed: 02/10/2023]
Abstract
Transgenerational epigenetic inheritance in mammals remains a debated subject. Here, we demonstrate that DNA methylation of promoter-associated CpG islands (CGIs) can be transmitted from parents to their offspring in mice. We generated DNA methylation-edited mouse embryonic stem cells (ESCs), in which CGIs of two metabolism-related genes, the Ankyrin repeat domain 26 and the low-density lipoprotein receptor, were specifically methylated and silenced. DNA methylation-edited mice generated by microinjection of the methylated ESCs exhibited abnormal metabolic phenotypes. Acquired methylation of the targeted CGI and the phenotypic traits were maintained and transmitted across multiple generations. The heritable CGI methylation was subjected to reprogramming in parental PGCs and subsequently reestablished in the next generation at post-implantation stages. These observations provide a concrete step toward demonstrating transgenerational epigenetic inheritance in mammals, which may have implications in our understanding of evolutionary biology as well as the etiology, diagnosis, and prevention of non-genetically inherited human diseases.
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Affiliation(s)
- Yuta Takahashi
- Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Altos Labs, 5510 Morehouse Drive, Suite 300, San Diego, CA 92121, USA
| | - Mariana Morales Valencia
- Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Altos Labs, 5510 Morehouse Drive, Suite 300, San Diego, CA 92121, USA
| | - Yang Yu
- Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction, Ministry of Education, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China; Stem Cell Research Center, Peking University Third Hospital, Beijing 100191, China
| | - Yasuo Ouchi
- Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Altos Labs, 5510 Morehouse Drive, Suite 300, San Diego, CA 92121, USA; Department of Regenerative Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba 260-8670, Japan
| | - Kazuki Takahashi
- Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Altos Labs, 5510 Morehouse Drive, Suite 300, San Diego, CA 92121, USA
| | - Maxim Nikolaievich Shokhirev
- Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Kathryn Lande
- Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - April E Williams
- Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Chiara Fresia
- Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Masakazu Kurita
- Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Department of Plastic, Reconstructive and Aesthetic Surgery, The University of Tokyo Hospital, Tokyo, Japan
| | - Tomoaki Hishida
- Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Laboratory of Biological Chemistry, School of Pharmaceutical Sciences, Wakayama Medical University, 25-1 Shitibancho, Wakayama, Wakayama, Japan
| | - Kensaku Shojima
- Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Fumiyuki Hatanaka
- Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Altos Labs, 5510 Morehouse Drive, Suite 300, San Diego, CA 92121, USA
| | - Estrella Nuñez-Delicado
- Universidad Católica San Antonio de Murcia (UCAM), Campus de los Jerónimos, no. 135 Guadalupe 30107, Murcia, Spain
| | - Concepcion Rodriguez Esteban
- Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Altos Labs, 5510 Morehouse Drive, Suite 300, San Diego, CA 92121, USA
| | - Juan Carlos Izpisua Belmonte
- Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Altos Labs, 5510 Morehouse Drive, Suite 300, San Diego, CA 92121, USA.
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17
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Peltomäki P, Nyström M, Mecklin JP, Seppälä TT. Lynch Syndrome Genetics and Clinical Implications. Gastroenterology 2023; 164:783-799. [PMID: 36706841 DOI: 10.1053/j.gastro.2022.08.058] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 08/29/2022] [Accepted: 08/30/2022] [Indexed: 01/29/2023]
Abstract
Lynch syndrome (LS) is one of the most prevalent hereditary cancer syndromes in humans and accounts for some 3% of unselected patients with colorectal or endometrial cancer and 10%-15% of those with DNA mismatch repair-deficient tumors. Previous studies have established the genetic basis of LS predisposition, but there have been significant advances recently in the understanding of the molecular pathogenesis of LS tumors, which has important implications in clinical management. At the same time, immunotherapy has revolutionized the treatment of advanced cancers with DNA mismatch repair defects. We aim to review the recent progress in the LS field and discuss how the accumulating epidemiologic, clinical, and molecular information has contributed to a more accurate and complete picture of LS, resulting in genotype- and immunologic subtype-specific strategies for surveillance, cancer prevention, and treatment.
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Affiliation(s)
- Päivi Peltomäki
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.
| | - Minna Nyström
- Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Jukka-Pekka Mecklin
- Department of Education and Science, Nova Hospital, Central Finland Health Care District, Jyväskylä, Finland; Faculty of Sports and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - Toni T Seppälä
- Department of Surgery, Helsinki University Hospital, Helsinki, Finland; Applied Tumor Genomics Research Programs Unit, University of Helsinki, Helsinki, Finland; Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Tampere, Finland
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18
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Mighton C, Lerner‐Ellis J. Principles of molecular testing for hereditary cancer. Genes Chromosomes Cancer 2022; 61:356-381. [DOI: 10.1002/gcc.23048] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 04/03/2022] [Accepted: 04/06/2022] [Indexed: 11/10/2022] Open
Affiliation(s)
- Chloe Mighton
- Laboratory Medicine and Pathology, Mount Sinai Hospital, Sinai Health Toronto ON Canada
- Lunenfeld Tanenbaum Research Institute, Sinai Health Toronto ON Canada
- Genomics Health Services Research Program Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto Toronto ON Canada
- Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health University of Toronto Toronto ON Canada
| | - Jordan Lerner‐Ellis
- Laboratory Medicine and Pathology, Mount Sinai Hospital, Sinai Health Toronto ON Canada
- Lunenfeld Tanenbaum Research Institute, Sinai Health Toronto ON Canada
- Department of Laboratory Medicine and Pathobiology University of Toronto Toronto ON Canada
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19
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Curtius K, Gupta S, Boland CR. Review article: Lynch Syndrome-a mechanistic and clinical management update. Aliment Pharmacol Ther 2022; 55:960-977. [PMID: 35315099 DOI: 10.1111/apt.16826] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/02/2021] [Accepted: 02/02/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Lynch syndrome (LS) is an autosomal dominant familial condition caused by a pathogenic variant (PV) in a DNA mismatch repair gene, which then predisposes carriers to various cancers. AIM To review the pathogenesis, clinical presentation, differential diagnosis and clinical strategies for detection and management of LS. METHODS A narrative review synthesising knowledge from published literature, as well as current National Comprehensive Cancer Network guidelines for management of LS was conducted. RESULTS LS tumours are characterised by unique pathogenesis, ultimately resulting in hypermutation, microsatellite instability and high immunogenicity that has significant implications for cancer risk, clinical presentation, treatment and surveillance. LS is one of the most common hereditary causes of cancer, and about 1 in 279 individuals carry a PV in an LS gene that predisposes to associated cancers. Individuals with LS have increased risks for colorectal, endometrial and other cancers, with significant variation in lifetime risk by LS-associated gene. CONCLUSIONS As genetic testing becomes more widespread, the number of individuals identified with LS is expected to increase in the population. Understanding the pathogenesis of LS informs current strategies for detection and clinical management, and also guides future areas for clinical innovation. Unravelling the mechanisms by which these tumours evolve may help to more precisely tailor management by the gene involved.
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Affiliation(s)
- Kit Curtius
- Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Samir Gupta
- Section of Gastroenterology, San Diego Veterans Affairs Healthcare System, San Diego, CA, USA.,Division of Gastroenterology, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - C Richard Boland
- Division of Gastroenterology, School of Medicine, University of California San Diego, La Jolla, CA, USA
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20
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Lynch-like Syndrome: Potential Mechanisms and Management. Cancers (Basel) 2022; 14:cancers14051115. [PMID: 35267422 PMCID: PMC8909420 DOI: 10.3390/cancers14051115] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/20/2022] [Accepted: 02/21/2022] [Indexed: 02/05/2023] Open
Abstract
Simple Summary Lynch-like syndrome (LLS) is defined as colorectal cancer cases with microsatellite instability (MSI) and loss of expression of MLH1, MSH2, MSH6, or PMS2 by immunohistochemistry (IHC) in the absence of a germline mutation in these genes that cannot be explained by BRAF mutation or MLH1 hypermethylation. The application of the universal strategy for the diagnosis of Lynch syndrome (LS) in all CRCs is leading to an increase in the incidence of cases of LLS. It has been described that risk of cancer in relatives of LLS patients is in between of that found in Lynch syndrome families and sporadic cases. That makes LLS patients and their families a challenging group for which the origin of CRC is unknown, being a mixture between unidentified hereditary CRC and sporadic cases. The potential causes of LLS are discussed in this review, as well as methods for identification of truly hereditary cases. Abstract Lynch syndrome is an autosomal dominant disorder caused by germline mutations in DNA mismatch repair (MMR) system genes, such as MLH1, MSH2, MSH6, or PMS2. It is the most common hereditary colorectal cancer syndrome. Screening is regularly performed by using microsatellite instability (MSI) or immunohistochemistry for the MMR proteins in tumor samples. However, in a proportion of cases, MSI is found or MMR immunohistochemistry is impaired in the absence of a germline mutation in MMR genes, BRAF mutation, or MLH1 hypermethylation. These cases are defined as Lynch-like syndrome. Patients with Lynch-like syndrome represent a mixture of truly hereditary and sporadic cases, with a risk of colorectal cancer in first-degree relatives that is between the risk of Lynch syndrome in families and relatives of sporadic colon cancer cases. Although multiple approaches have been suggested to distinguish between hereditary and sporadic cases, a homogeneous testing protocol and consensus on the adequate classification of these patients is still lacking. For this reason, management of Lynch-like syndrome and prevention of cancer in these families is clinically challenging. This review explains the concept of Lynch-like syndrome, potential mechanisms for its development, and methods for adequately distinguishing between sporadic and hereditary cases of this entity.
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21
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Epimutation in inherited metabolic disorders: the influence of aberrant transcription in adjacent genes. Hum Genet 2022; 141:1309-1325. [PMID: 35190856 DOI: 10.1007/s00439-021-02414-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 12/08/2021] [Indexed: 12/12/2022]
Abstract
Epigenetic diseases can be produced by a stable alteration, called an epimutation, in DNA methylation, in which epigenome alterations are directly involved in the underlying molecular mechanisms of the disease. This review focuses on the epigenetics of two inherited metabolic diseases, epi-cblC, an inherited metabolic disorder of cobalamin (vitamin B12) metabolism, and alpha-thalassemia type α-ZF, an inherited disorder of α2-globin synthesis, with a particular interest in the role of aberrant antisense transcription of flanking genes in the generation of epimutations in CpG islands of gene promoters. In both disorders, the epimutation is triggered by an aberrant antisense transcription through the promoter, which produces an H3K36me3 histone mark involved in the recruitment of DNA methyltransferases. It results from diverse genetic alterations. In alpha-thalassemia type α-ZF, a deletion removes HBA1 and HBQ1 genes and juxtaposes the antisense LUC7L gene to the HBA2 gene. In epi-cblC, the epimutation in the MMACHC promoter is produced by mutations in the antisense flanking gene PRDX1, which induces a prolonged antisense transcription through the MMACHC promoter. The presence of the epimutation in sperm, its transgenerational inheritance via the mutated PRDX1, and the high expression of PRDX1 in spermatogonia but its nearly undetectable transcription in spermatids and spermatocytes, suggest that the epimutation could be maintained during germline reprogramming and despite removal of aberrant transcription. The epivariation seen in the MMACHC promoter (0.95 × 10-3) is highly frequent compared to epivariations affecting other genes of the Online Catalog of Human Genes and Genetic Disorders in an epigenome-wide dataset of 23,116 individuals. This and the comparison of epigrams of two monozygotic twins suggest that the aberrant transcription could also be influenced by post-zygotic environmental exposures.
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22
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Holter S, Hall MJ, Hampel H, Jasperson K, Kupfer SS, Larsen Haidle J, Mork ME, Palaniapppan S, Senter L, Stoffel EM, Weissman SM, Yurgelun MB. Risk assessment and genetic counseling for Lynch syndrome - Practice resource of the National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer. J Genet Couns 2022; 31:568-583. [PMID: 35001450 DOI: 10.1002/jgc4.1546] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 12/17/2021] [Accepted: 12/18/2021] [Indexed: 12/13/2022]
Abstract
Identifying individuals who have Lynch syndrome involves a complex diagnostic workup that includes taking a detailed family history and a combination of various tests such as immunohistochemistry and/or molecular which may be germline and/or somatic. The National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer have come together to publish this practice resource for the evaluation of Lynch syndrome. The purpose of this practice resource was to provide guidance and a testing algorithm for Lynch syndrome as well as recommendations on when to offer testing. This practice resource does not replace a consultation with a genetics professional. This practice resource includes explanations in support of this and a summary of background data. While this practice resource is not intended to serve as a review of Lynch syndrome, it includes a discussion of background information and cites a number of key publications which should be reviewed for a more in-depth understanding. This practice resource is intended for genetic counselors, geneticists, gastroenterologists, surgeons, medical oncologists, obstetricians and gynecologists, nurses, and other healthcare providers who evaluate patients for Lynch syndrome.
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Affiliation(s)
- Spring Holter
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Michael J Hall
- Department of Clinical Genetics, Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Heather Hampel
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | | | - Sonia S Kupfer
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois, USA
| | | | - Maureen E Mork
- Department of Clinical Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | | - Leigha Senter
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Elena M Stoffel
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Scott M Weissman
- Chicago Genetic Consultants, LLC, Northbrook, Illinois, USA
- Genome Medical, South San Francisco, California, USA
| | - Matthew B Yurgelun
- Dana-Farber Cancer Institute, Harvard Medical School, and Brigham and Women's Hospital, Boston, Massachusetts, USA
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23
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Mukherjee S, Dasgupta S, Mishra PK, Chaudhury K. Air pollution-induced epigenetic changes: disease development and a possible link with hypersensitivity pneumonitis. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:55981-56002. [PMID: 34498177 PMCID: PMC8425320 DOI: 10.1007/s11356-021-16056-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/16/2021] [Indexed: 05/16/2023]
Abstract
Air pollution is a serious threat to our health and has become one of the major causes of many diseases including cardiovascular disease, respiratory disease, and cancer. The association between air pollution and various diseases has long been a topic of research interest. However, it remains unclear how air pollution actually impacts health by modulating several important cellular functions. Recently, some evidence has emerged about air pollution-induced epigenetic changes, which are linked with the etiology of various human diseases. Among several epigenetic modifications, DNA methylation represents the most prominent epigenetic alteration underlying the air pollution-induced pathogenic mechanism. Several other types of epigenetic changes, such as histone modifications, miRNA, and non-coding RNA expression, have also been found to have been linked with air pollution. Hypersensitivity pneumonitis (HP), one of the most prevalent forms of interstitial lung diseases (ILDs), is triggered by the inhalation of certain organic and inorganic substances. HP is characterized by inflammation in the tissues around the lungs' airways and may lead to irreversible lung scarring over time. This review, in addition to other diseases, attempts to understand whether certain pollutants influence HP development through such epigenetic modifications.
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Affiliation(s)
- Suranjana Mukherjee
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, 721302, India.
| | - Sanjukta Dasgupta
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, 721302, India
| | - Pradyumna K Mishra
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Bhopal, Madhya Pradesh, 462030, India
| | - Koel Chaudhury
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, 721302, India
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24
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Ruiz de la Cruz M, de la Cruz Montoya AH, Rojas Jiménez EA, Martínez Gregorio H, Díaz Velásquez CE, Paredes de la Vega J, de la Cruz Hernández-Hernández F, Vaca Paniagua F. Cis-Acting Factors Causing Secondary Epimutations: Impact on the Risk for Cancer and Other Diseases. Cancers (Basel) 2021; 13:cancers13194807. [PMID: 34638292 PMCID: PMC8508567 DOI: 10.3390/cancers13194807] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 08/09/2021] [Accepted: 08/15/2021] [Indexed: 12/25/2022] Open
Abstract
Epigenetics affects gene expression and contributes to disease development by alterations known as epimutations. Hypermethylation that results in transcriptional silencing of tumor suppressor genes has been described in patients with hereditary cancers and without pathogenic variants in the coding region of cancer susceptibility genes. Although somatic promoter hypermethylation of these genes can occur in later stages of the carcinogenic process, constitutional methylation can be a crucial event during the first steps of tumorigenesis, accelerating tumor development. Primary epimutations originate independently of changes in the DNA sequence, while secondary epimutations are a consequence of a mutation in a cis or trans-acting factor. Secondary epimutations have a genetic basis in cis of the promoter regions of genes involved in familial cancers. This highlights epimutations as a novel carcinogenic mechanism whose contribution to human diseases is underestimated by the scarcity of the variants described. In this review, we provide an overview of secondary epimutations and present evidence of their impact on cancer. We propose the necessity for genetic screening of loci associated with secondary epimutations in familial cancer as part of prevention programs to improve molecular diagnosis, secondary prevention, and reduce the mortality of these diseases.
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Affiliation(s)
- Miguel Ruiz de la Cruz
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla 54090, Mexico; (M.R.d.l.C.); (E.A.R.J.); (H.M.G.); (C.E.D.V.); (J.P.d.l.V.)
- Avenida Instituto Politécnico Nacional # 2508, Colonia San Pedro Zacatenco, Delegación Gustavo A. Madero, C.P. Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico;
| | | | - Ernesto Arturo Rojas Jiménez
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla 54090, Mexico; (M.R.d.l.C.); (E.A.R.J.); (H.M.G.); (C.E.D.V.); (J.P.d.l.V.)
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla 54090, Mexico;
| | - Héctor Martínez Gregorio
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla 54090, Mexico; (M.R.d.l.C.); (E.A.R.J.); (H.M.G.); (C.E.D.V.); (J.P.d.l.V.)
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla 54090, Mexico;
| | - Clara Estela Díaz Velásquez
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla 54090, Mexico; (M.R.d.l.C.); (E.A.R.J.); (H.M.G.); (C.E.D.V.); (J.P.d.l.V.)
| | - Jimena Paredes de la Vega
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla 54090, Mexico; (M.R.d.l.C.); (E.A.R.J.); (H.M.G.); (C.E.D.V.); (J.P.d.l.V.)
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla 54090, Mexico;
| | - Fidel de la Cruz Hernández-Hernández
- Avenida Instituto Politécnico Nacional # 2508, Colonia San Pedro Zacatenco, Delegación Gustavo A. Madero, C.P. Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico;
| | - Felipe Vaca Paniagua
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Tlalnepantla 54090, Mexico; (M.R.d.l.C.); (E.A.R.J.); (H.M.G.); (C.E.D.V.); (J.P.d.l.V.)
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla 54090, Mexico;
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Ciudad de México 14080, Mexico
- Correspondence: ; Tel.: +52-55-5623-1333 (ext. 39788)
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Kaneko E, Sato N, Sugawara T, Noto A, Takahashi K, Makino K, Terada Y. MLH1 promoter hypermethylation predicts poorer prognosis in mismatch repair deficiency endometrial carcinomas. J Gynecol Oncol 2021; 32:e79. [PMID: 34431253 PMCID: PMC8550932 DOI: 10.3802/jgo.2021.32.e79] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 05/01/2021] [Accepted: 06/15/2021] [Indexed: 11/30/2022] Open
Abstract
Objective The antitumor effects of anti-PD-1 antibody against mismatch repair deficiency (MMR-D)-associated cancers have been reported. MMR-D is found in approximately 20%–30% of endometrial carcinomas (ECs) and frequently occurs due to MLH1 promoter hypermethylation (MLH1-PHM). ECs with MLH1-PHM are classified according to the molecular screening of Lynch syndrome (LS), but few detailed reports are available. The purpose of this study was to clarify the clinical features of EC with MLH1-PHM. Methods Immunohistochemistry of MMR proteins (MLH1, MSH2, MSH6, and PMS2) was performed on specimens from 527 ECs treated at our university hospital from 2003 to 2018. MLH1 methylation analysis was added to cases with MLH1/PMS2 loss. ECs were classified as follows: cases that retained MMR proteins as “MMR-proficient;” cases with MLH1/PMS2 loss and MLH1-PHM as “met-EC;” and cases with other MMR protein loss and MLH1/PMS2 loss without MLH1-PHM as “suspected-LS.” The clinical features, including long-term prognosis, of each group, were analyzed. Results Accordingly, 419 (79.5%), 65 (12.3%), and 43 (8.2%) cases were categorized as “MMR-proficient,” “suspected-LS,” and “met-EC,” respectively. Significantly, “met-EC” had a lower proportion of grade 1 tumors (37.5%) and a higher proportion of stage III/IV tumors (37.2%) than the other groups. The overall and progression-free survival of “met-EC” were significantly worse than those of “suspected-LS” in all cases. Conclusion In ECs with MMR-D, “met-ECs” were a subgroup with a poorer prognosis than “suspected-LS.” “Met-ECs” would be the main target for anti-PD-1 antibody treatment, and its clinical susceptibility should be verified individually.
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Affiliation(s)
- Enami Kaneko
- Department of Obstetrics and Gynecology, Akita University Graduate School of Medicine, Akita, Japan.
| | - Naoki Sato
- Department of Obstetrics and Gynecology, Akita University Graduate School of Medicine, Akita, Japan
| | - Tae Sugawara
- Department of Obstetrics and Gynecology, Akita University Graduate School of Medicine, Akita, Japan
| | - Aya Noto
- Department of Obstetrics and Gynecology, Akita Kousei Medical Center, Akita, Japan
| | - Kazue Takahashi
- Department of Obstetrics and Gynecology, Hiraka General Hospital, Akita, Japan
| | - Kenichi Makino
- Department of Obstetrics and Gynecology, Akita University Graduate School of Medicine, Akita, Japan
| | - Yukihiro Terada
- Department of Obstetrics and Gynecology, Akita University Graduate School of Medicine, Akita, Japan
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Nikolaienko O, Lønning PE, Knappskog S. ramr: an R/Bioconductor package for detection of rare aberrantly methylated regions. Bioinformatics 2021; 38:133-140. [PMID: 34383893 PMCID: PMC8696093 DOI: 10.1093/bioinformatics/btab586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 06/26/2021] [Accepted: 08/11/2021] [Indexed: 02/03/2023] Open
Abstract
MOTIVATION With recent advances in the field of epigenetics, the focus is widening from large and frequent disease- or phenotype-related methylation signatures to rare alterations transmitted mitotically or transgenerationally (constitutional epimutations). Merging evidence indicate that such constitutional alterations, albeit occurring at a low mosaic level, may confer risk of disease later in life. Given their inherently low incidence rate and mosaic nature, there is a need for bioinformatic tools specifically designed to analyze such events. RESULTS We have developed a method (ramr) to identify aberrantly methylated DNA regions (AMRs). ramr can be applied to methylation data obtained by array or next-generation sequencing techniques to discover AMRs being associated with elevated risk of cancer as well as other diseases. We assessed accuracy and performance metrics of ramr and confirmed its applicability for analysis of large public datasets. Using ramr we identified aberrantly methylated regions that are known or may potentially be associated with development of colorectal cancer and provided functional annotation of AMRs that arise at early developmental stages. AVAILABILITY AND IMPLEMENTATION The R package is freely available at https://github.com/BBCG/ramr and https://bioconductor.org/packages/ramr. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Affiliation(s)
| | - Per Eystein Lønning
- K. G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway,Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Stian Knappskog
- K. G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway,Department of Oncology, Haukeland University Hospital, Bergen, Norway
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27
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Shrestha KS, Aska EM, Tuominen MM, Kauppi L. Tissue-specific reduction in MLH1 expression induces microsatellite instability in intestine of Mlh1 +/- mice. DNA Repair (Amst) 2021; 106:103178. [PMID: 34311271 DOI: 10.1016/j.dnarep.2021.103178] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 11/28/2022]
Abstract
Tumors of Lynch syndrome (LS) patients display high levels of microsatellite instability (MSI), which results from complete loss of DNA mismatch repair (MMR), in line with Knudson's two-hit hypothesis. Why some organs, in particular those of the gastrointestinal (GI) tract, are prone to tumorigenesis in LS remains unknown. We hypothesized that MMR is haploinsufficient in certain tissues, compromising microsatellite stability in a tissue-specific manner before tumorigenesis. Using mouse genetics, we tested how levels of MLH1, a central MMR protein, affect age- and tissue-specific microsatellite stability in vivo and whether elevated MSI is detectable prior to loss of MMR function and to neoplastic growth. To assess putative tissue-specific MMR haploinsufficiency, we determined relevant molecular phenotypes (MSI, Mlh1 promoter methylation status, MLH1 protein and RNA levels) in jejuna of Mlh1+/- mice and compared them to those in spleen, as well as to MMR-proficient and -deficient controls (Mlh1+/+ and Mlh1-/- mice). While spleen MLH1 levels of Mlh1+/- mice were, as expected, approximately 50 % compared to wildtype mice, MLH1 levels in jejunum varied substantially between individual Mlh1+/- mice and moreover, decreased with age. Mlh1+/- mice with soma-wide Mlh1 promoter methylation often displayed severe MLH1 depletion in jejunum. Reduced (but still detectable) MLH1 levels correlated with elevated MSI in Mlh1+/- jejunum. MSI in jejunum increased with age, while in spleens of the same mice, MLH1 levels and microsatellites remained stable. Thus, MLH1 expression levels are particularly labile in intestine of Mlh1+/- mice, giving rise to tissue-specific MSI long before neoplasia. A similar mechanism likely also operates also in the human GI epithelium and could explain the wide range in age-of-onset of LS-associated tumorigenesis.
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Affiliation(s)
- Kul S Shrestha
- Systems Oncology (ONCOSYS) Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Doctoral Program in Integrative Life Sciences, University of Helsinki, Helsinki, Finland; Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Elli-Mari Aska
- Systems Oncology (ONCOSYS) Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Doctoral Program in Integrative Life Sciences, University of Helsinki, Helsinki, Finland; Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Minna M Tuominen
- Systems Oncology (ONCOSYS) Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Liisa Kauppi
- Systems Oncology (ONCOSYS) Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
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28
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Zyla R, Graham T, Aronson M, Velsher L, Mrkonjic M, Turashvili G. MLH1 epimutation is a rare mechanism for Lynch syndrome: A case report and review of the literature. Genes Chromosomes Cancer 2021; 60:635-639. [PMID: 33934415 DOI: 10.1002/gcc.22957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/24/2021] [Accepted: 04/27/2021] [Indexed: 11/10/2022] Open
Abstract
Endometrial carcinoma is one of the prototypical malignancies associated with Lynch syndrome, an inherited cancer syndrome most commonly caused by germline mutations in DNA mismatch repair (MMR) genes, although rare alternative mechanisms also exist. In this report, we describe a patient first diagnosed with colorectal cancer at age 33, then vulvar squamous cell carcinoma, facial sebaceous adenoma/sebaceoma, and finally endometrial carcinoma at age 52. All tumors were MLH1/PMS2-deficient by immunohistochemistry, and MLH1 promoter methylation was identified in the endometrial cancer. Germline MLH1 testing was negative for pathogenic variants, but she was subsequently diagnosed with Lynch syndrome secondary to a germline monoallelic constitutional epimutation of the MLH1 promoter. Identification of patients displaying a Lynch syndrome phenotype but lacking germline MMR mutations is important to avoid delays in the diagnosis of Lynch syndrome as well as the initiation of appropriate cancer screening and genetic counseling.
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Affiliation(s)
- Roman Zyla
- Department of Pathology and Laboratory Medicine, Sinai Health System and University of Toronto, Toronto, Ontario, Canada
| | - Tracy Graham
- Cancer Genetics and High Risk Program, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Melyssa Aronson
- Zane Cohen Centre, Sinai Health System and University of Toronto, Toronto, Ontario, Canada
| | - Lea Velsher
- Cancer Genetics and High Risk Program, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Miralem Mrkonjic
- Department of Pathology and Laboratory Medicine, Sinai Health System and University of Toronto, Toronto, Ontario, Canada
| | - Gulisa Turashvili
- Department of Pathology and Laboratory Medicine, Sinai Health System and University of Toronto, Toronto, Ontario, Canada
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Do Transgenerational Epigenetic Inheritance and Immune System Development Share Common Epigenetic Processes? J Dev Biol 2021; 9:jdb9020020. [PMID: 34065783 PMCID: PMC8162332 DOI: 10.3390/jdb9020020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/02/2021] [Accepted: 05/06/2021] [Indexed: 12/14/2022] Open
Abstract
Epigenetic modifications regulate gene expression for development, immune response, disease, and other processes. A major role of epigenetics is to control the dynamics of chromatin structure, i.e., the condensed packaging of DNA around histone proteins in eukaryotic nuclei. Key epigenetic factors include enzymes for histone modifications and DNA methylation, non-coding RNAs, and prions. Epigenetic modifications are heritable but during embryonic development, most parental epigenetic marks are erased and reset. Interestingly, some epigenetic modifications, that may be resulting from immune response to stimuli, can escape remodeling and transmit to subsequent generations who are not exposed to those stimuli. This phenomenon is called transgenerational epigenetic inheritance if the epigenetic phenotype persists beyond the third generation in female germlines and second generation in male germlines. Although its primary function is likely immune response for survival, its role in the development and functioning of the immune system is not extensively explored, despite studies reporting transgenerational inheritance of stress-induced epigenetic modifications resulting in immune disorders. Hence, this review draws from studies on transgenerational epigenetic inheritance, immune system development and function, high-throughput epigenetics tools to study those phenomena, and relevant clinical trials, to focus on their significance and deeper understanding for future research, therapeutic developments, and various applications.
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30
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Shrestha KS, Tuominen MM, Kauppi L. Mlh1 heterozygosity and promoter methylation associates with microsatellite instability in mouse sperm. Mutagenesis 2021; 36:237-244. [PMID: 33740045 PMCID: PMC8262379 DOI: 10.1093/mutage/geab010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 03/17/2021] [Indexed: 11/13/2022] Open
Abstract
DNA mismatch repair (MMR) proteins play an important role in maintaining genome stability, both in somatic and in germline cells. Loss of MLH1, a central MMR protein, leads to infertility and to microsatellite instability (MSI) in spermatocytes, however, the effect of Mlh1 heterozygosity on germline genome stability remains unexplored. To test the effect of Mlh1 heterozygosity on MSI in mature sperm, we combined mouse genetics with single-molecule PCR that detects allelic changes at unstable microsatellites. We discovered 4.5% and 5.9% MSI in sperm of 4- and 12-month-old Mlh1+/− mice, respectively, and that Mlh1 promoter methylation in Mlh1+/− sperm correlated with higher MSI. No such elevated MSI was seen in non-proliferating somatic cells. Additionally, we show contrasting dynamics of deletions versus insertions at unstable microsatellites (mononucleotide repeats) in sperm.
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Affiliation(s)
- Kul S Shrestha
- Systems Oncology (ONCOSYS) Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8 (PO Box 63), FI-00014 Helsinki, Finland.,Doctoral Program in Integrative Life Sciences, University of Helsinki, Viikinkaari 1 (PO Box 65), FI-00014 Helsinki, Finland
| | - Minna M Tuominen
- Systems Oncology (ONCOSYS) Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8 (PO Box 63), FI-00014 Helsinki, Finland
| | - Liisa Kauppi
- Systems Oncology (ONCOSYS) Research Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8 (PO Box 63), FI-00014 Helsinki, Finland.,Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8 (PO Box 63), FI-00014 Helsinki, Finland
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31
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Durán M, Faull I, Lastra E, Laes JF, Rodrigo AB, Sánchez-Escribano R. ARID1A genomic alterations driving microsatellite instability through somatic MLH1 methylation with response to immunotherapy in metastatic lung adenocarcinoma: a case report. J Med Case Rep 2021; 15:89. [PMID: 33608032 PMCID: PMC7896399 DOI: 10.1186/s13256-020-02589-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 11/17/2020] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Tumor molecular screening allows categorization of molecular alterations to select the best therapeutic strategy. AT-rich interactive domain-containing 1A (ARID1A) gene mutations are present in gastric, endometrial, and clear cell ovarian tumors. Inactivation of this gene impairs mismatch repair (MMR) machinery leading to an increased mutation burden that correlates with microsatellite instability (MSI), associated with tumor-infiltrating lymphocytes and programmed death ligand 1 (PD-L1) expression. This is the first case report in lung adenocarcinoma of ARID1A gene alterations leading to sporadic MSI, through somatic mutL homolog 1 (MLH1) promoter methylation, with an MLH1 gene mutation as the second somatic hit. CASE PRESENTATION A 50-year-old never-smoker Bulgarian woman, with no comorbidities and no family history of cancer, was diagnosed with metastatic lung adenocarcinoma. PD-L1 immunohistochemistry (IHC) of tissue biopsies on right groin adenopathies resulted in 30% positivity. Liquid biopsy test reported actionable alterations in ARID1A gene, rearranged during transfection (RET) gene fusions, epidermal growth factor receptor (EGFR) gene R776H mutation, breast cancer (BRCA) genes 1/2, and cyclin-dependent kinase inhibitor 2A (CDKN2A) gene mutations. The patient was treated with immunotherapy, and showed a treatment response lasting for 19 months until a new metastasis appeared at the right deltoid muscle. Genomic analysis of a sample of this metastasis confirmed PD-L1 positivity of greater than 50% with CD8+ T cells expression and showed MSI with a deleterious c.298C>T (p.R100*) MLH1 gene mutation. Multiplex ligation-dependent probe amplification (MLPA) of this sample unveiled MLH1 gene promoter methylation. The MLH1 gene mutation and the MLH1 gene methylation were not present at the germline setting. CONCLUSIONS In this particular case, we show that ARID1A gene mutations with sporadic MSI due to somatic MLH1 gene promoter methylation and MLH1 gene mutation could change the prognosis and define the response to immunotherapy in a patient with lung adenocarcinoma. Comprehensive solid and liquid biopsy tests are useful to find out resistance mechanisms to immune checkpoint inhibitors. Our data encourages the development of new therapies against ARID1A mutations and epigenomic methylation when involved in MSI neoplasms.
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Affiliation(s)
- Mercedes Durán
- Instituto de Biología Y Genética Molecular, IBGM University of Valladolid, Sanz Y Fores Street, 3, 47003, Valladolid, Spain
| | - Iris Faull
- Guardant Health, 505 Penobscot Dr, Redwood, CA, 94063, USA
| | - Enrique Lastra
- Molecular Tumor Board, Genetic Counselling Unit, Medical Oncology Department, Hospital Universitario de Burgos, Av. Islas Baleares, 3, 09006, Burgos, Spain.
| | | | | | - Ricardo Sánchez-Escribano
- Medical Oncology Department, Hospital Clínico Universitario De Valladolid, Av. Ramón Y Cajal, 3, 47003, Valladolid, Spain
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32
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Oleksiewicz U, Machnik M. Causes, effects, and clinical implications of perturbed patterns within the cancer epigenome. Semin Cancer Biol 2020; 83:15-35. [PMID: 33359485 DOI: 10.1016/j.semcancer.2020.12.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 12/18/2020] [Accepted: 12/18/2020] [Indexed: 02/06/2023]
Abstract
Somatic mutations accumulating over a patient's lifetime are well-defined causative factors that fuel carcinogenesis. It is now clear, however, that epigenomic signature is also largely perturbed in many malignancies. These alterations support the transcriptional program crucial for the acquisition and maintenance of cancer hallmarks. Epigenetic instability may arise due to the genetic mutations or transcriptional deregulation of the proteins implicated in epigenetic signaling. Moreover, external stimulation and physiological aging may also participate in this phenomenon. The epigenomic signature is frequently associated with a cell of origin, as well as with tumor stage and differentiation, which all reflect its high heterogeneity across and within various tumors. Here, we will overview the current understanding of the causes and effects of the altered and heterogeneous epigenomic landscape in cancer. We will focus mainly on DNA methylation and post-translational histone modifications as the key regulatory epigenetic signaling marks. In addition, we will describe how this knowledge is translated into the clinic. We will particularly concentrate on the applicability of epigenetic alterations as biomarkers for improved diagnosis, prognosis, and prediction. Finally, we will also review current developments regarding epi-drug usage in clinical and experimental settings.
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Affiliation(s)
- Urszula Oleksiewicz
- Department of Cancer Immunology, Poznan University of Medical Sciences, Poznan, Poland; Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Centre, Poznan, Poland.
| | - Marta Machnik
- Department of Cancer Immunology, Poznan University of Medical Sciences, Poznan, Poland; Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Centre, Poznan, Poland
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33
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Poduval DB, Ognedal E, Sichmanova Z, Valen E, Iversen GT, Minsaas L, Lønning PE, Knappskog S. Assessment of tumor suppressor promoter methylation in healthy individuals. Clin Epigenetics 2020; 12:131. [PMID: 32859265 PMCID: PMC7455917 DOI: 10.1186/s13148-020-00920-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 08/17/2020] [Indexed: 12/21/2022] Open
Abstract
Background The number of tumor suppressor genes for which germline mutations have been linked to cancer risk is steadily increasing. However, while recent reports have linked constitutional normal tissue promoter methylation of BRCA1 and MLH1 to ovarian and colon cancer risk, the role of epigenetic alterations as cancer risk factors remains largely unknown, presenting an important area for future research. Currently, we lack fast and sensitive methods for assessment of promoter methylation status across known tumor suppressor genes. Results In this paper, we present a novel NGS-based approach assessing promoter methylation status across a large panel of defined tumor suppressor genes to base-pair resolution. The method omits the limitations related to commonly used array-approaches. Our panel includes 565 target regions covering the promoters of 283 defined tumor suppressors, selected by pre-specified criteria, and was applied for rapid targeted methylation-specific NGS. The feasibility of the method was assessed by analyzing normal tissue DNA (white blood cells, WBC) samples from 34 healthy postmenopausal women and by performing preliminary assessment of the methylation landscape of tumor suppressors in these individuals. The mean target coverage was 189.6x providing a sensitivity of 0.53%, sufficient for promoter methylation assessment of low-level methylated genes like BRCA1. Within this limited test-set, we detected 206 regions located in the promoters of 149 genes to be differentially methylated (hyper- or hypo-) at > 99% confidence level. Seven target regions in gene promoters (CIITA, RASSF1, CHN1, PDCD1LG2, GSTP1, XPA, and ZNF668) were found to be hyper-methylated in a minority of individuals, with a > 20 percent point difference in mean methylation across the region between individuals. In an exploratory hierarchical clustering analysis, we found that the individuals analyzed may be grouped into two main groups based on their WBC methylation profile across the 283 tumor suppressor gene promoters. Conclusions Methylation-specific NGS of our tumor suppressor panel, with detailed assessment of differential methylation in healthy individuals, presents a feasible method for identification of novel epigenetic risk factors for cancer.
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Affiliation(s)
- Deepak B Poduval
- K.G. Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Elisabet Ognedal
- K.G. Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Oncology, Haukeland University Hospital, Bergen, Norway.,Present address: Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
| | - Zuzana Sichmanova
- K.G. Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Eivind Valen
- Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway.,Sars International Centre for Marine Molecular Biology, University of Bergen, Bergen, Norway
| | - Gjertrud T Iversen
- K.G. Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Laura Minsaas
- K.G. Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Per E Lønning
- K.G. Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Stian Knappskog
- K.G. Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway. .,Department of Oncology, Haukeland University Hospital, Bergen, Norway.
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Peltomäki P, Olkinuora A, Nieminen TT. Updates in the field of hereditary nonpolyposis colorectal cancer. Expert Rev Gastroenterol Hepatol 2020; 14:707-720. [PMID: 32755332 DOI: 10.1080/17474124.2020.1782187] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Up to one third of colorectal cancers show familial clustering and 5% are hereditary single-gene disorders. Hereditary non-polyposis colorectal cancer comprises DNA mismatch repair-deficient and -proficient subsets, represented by Lynch syndrome (LS) and familial colorectal cancer type X (FCCTX), respectively. Accurate knowledge of molecular etiology and genotype-phenotype correlations are critical for tailored cancer prevention and treatment. AREAS COVERED The authors highlight advances in the molecular dissection of hereditary non-polyposis colorectal cancer, based on recent literature retrieved from PubMed. Future possibilities for novel gene discoveries are discussed. EXPERT COMMENTARY LS is molecularly well established, but new information is accumulating of the associated clinical and tumor phenotypes. FCCTX remains poorly defined, but several promising candidate genes have been discovered and share some preferential biological pathways. Multi-level characterization of specimens from large patient cohorts representing multiple populations, combined with proper bioinformatic and functional analyses, will be necessary to resolve the outstanding questions.
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Affiliation(s)
- Paivi Peltomäki
- Department of Medical and Clinical Genetics, University of Helsinki , Helsinki, Finland
| | - Alisa Olkinuora
- Department of Medical and Clinical Genetics, University of Helsinki , Helsinki, Finland
| | - Taina T Nieminen
- Department of Medical and Clinical Genetics, University of Helsinki , Helsinki, Finland
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35
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Fiala EM, Ortiz MV, Kennedy JA, Glodzik D, Fleischut MH, Duffy KA, Hathaway ER, Heaton T, Gerstle JT, Steinherz P, Shukla N, McNeer N, Tkachuk K, Bouvier N, Cadoo K, Carlo MI, Latham A, Dubard Gault M, Joseph V, Kemel Y, Kentsis A, Stadler Z, La Quaglia M, Papaemmanuil E, Friedman D, Ganguly A, Kung A, Offit K, Kalish JM, Walsh MF. 11p15.5 epimutations in children with Wilms tumor and hepatoblastoma detected in peripheral blood. Cancer 2020; 126:3114-3121. [PMID: 32320050 PMCID: PMC7383476 DOI: 10.1002/cncr.32907] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 02/18/2020] [Accepted: 03/17/2020] [Indexed: 01/14/2023]
Abstract
Background Constitutional or somatic mosaic epimutations are increasingly recognized as a mechanism of gene dysregulation resulting in cancer susceptibility. Beckwith‐Wiedemann syndrome is the cancer predisposition syndrome most commonly associated with epimutation and is extremely variable in its phenotypic presentation, which can include isolated tumors. Because to the authors' knowledge large‐scale germline DNA sequencing studies have not included methylation analysis, the percentage of pediatric cancer predisposition that is due to epimutations is unknown. Methods Germline methylation testing at the 11p15.5 locus was performed in blood for 24 consecutive patients presenting with hepatoblastoma (3 patients) or Wilms tumor (21 patients). Results Six individuals with Wilms tumor and 1 patient with hepatoblastoma were found to have low‐level gain of methylation at imprinting control 1, and a child with hepatoblastoma was found to have loss of methylation at imprinting control 2. The loss of methylation at imprinting control 2 was found to be maternally inherited, despite not being associated with any detectable genomic alteration. Conclusions Overall, 33% of patients (8 of 24 patients) with Wilms tumor or hepatoblastoma were found to have an epigenetic susceptibility that was detectable in the blood. It is interesting to note that low‐level gain of methylation at imprinting control 1 predominantly was detected in females with bilateral Wilms tumors. Further studies in larger cohorts are needed to determine the efficacy of testing all patients with Wilms tumor or hepatoblastoma for 11p15.5 epimutations in the blood as part of DNA analysis because this hallmark of predisposition will not be detected by sequencing‐based approaches and detecting a cancer predisposition may modify treatment. In the current study, all patients presenting with Wilms tumor or hepatoblastoma undergo 11p15.5 methylation analysis. Approximately one‐third are found to have an epimutation at this locus that is detectable in peripheral blood.
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Affiliation(s)
- Elise M Fiala
- Division of Clinical Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael V Ortiz
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York
| | - Jennifer A Kennedy
- Division of Clinical Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Dominik Glodzik
- Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Megan Harlan Fleischut
- Division of Clinical Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Kelly A Duffy
- Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Evan R Hathaway
- Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Todd Heaton
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York.,Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Justin T Gerstle
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York.,Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Peter Steinherz
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York
| | - Neerav Shukla
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York
| | - Nicole McNeer
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Kaitlyn Tkachuk
- Division of Clinical Genetics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nancy Bouvier
- Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Karen Cadoo
- Division of Clinical Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York.,Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Maria I Carlo
- Division of Clinical Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York.,Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Alicia Latham
- Division of Clinical Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York.,Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.,Division of Long Term Follow-Up, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Marianne Dubard Gault
- Division of Clinical Genetics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Vijai Joseph
- Division of Clinical Genetics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Yelena Kemel
- Division of Clinical Genetics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Alex Kentsis
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York.,Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Zsofia Stadler
- Division of Clinical Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York.,Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael La Quaglia
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York.,Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Elli Papaemmanuil
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Danielle Friedman
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York.,Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.,Division of Long Term Follow-Up, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Arupa Ganguly
- Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Andrew Kung
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York
| | - Kenneth Offit
- Division of Clinical Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York.,Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jennifer M Kalish
- Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Michael F Walsh
- Division of Clinical Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York.,Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
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Machnik M, Oleksiewicz U. Dynamic Signatures of the Epigenome: Friend or Foe? Cells 2020; 9:cells9030653. [PMID: 32156057 PMCID: PMC7140607 DOI: 10.3390/cells9030653] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 02/24/2020] [Accepted: 03/04/2020] [Indexed: 12/12/2022] Open
Abstract
Highly dynamic epigenetic signaling is influenced mainly by (micro)environmental stimuli and genetic factors. The exact mechanisms affecting particular epigenomic patterns differ dependently on the context. In the current review, we focus on the causes and effects of the dynamic signatures of the human epigenome as evaluated with the high-throughput profiling data and single-gene approaches. We will discuss three different aspects of phenotypic outcomes occurring as a consequence of epigenetics interplaying with genotype and environment. The first issue is related to the cases of environmental impacts on epigenetic profile, and its adverse and advantageous effects related to human health and evolutionary adaptation. The next topic will present a model of the interwoven co-evolution of genetic and epigenetic patterns exemplified with transposable elements (TEs) and their epigenetic repressors Krüppel-associated box zinc finger proteins (KRAB–ZNFs). The third aspect concentrates on the mitosis-based microevolution that takes place during carcinogenesis, leading to clonal diversity and expansion of tumor cells. The whole picture of epigenome plasticity and its role in distinct biological processes is still incomplete. However, accumulating data define epigenomic dynamics as an essential co-factor driving adaptation at the cellular and inter-species levels with a benefit or disadvantage to the host.
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Affiliation(s)
- Marta Machnik
- Department of Cancer Immunology, Poznan University of Medical Sciences, 60-806 Poznan, Poland;
- Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland
| | - Urszula Oleksiewicz
- Department of Cancer Immunology, Poznan University of Medical Sciences, 60-806 Poznan, Poland;
- Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland
- Correspondence:
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Salgado C, Gruis N, Heijmans BT, Oosting J, van Doorn R. Genome-wide analysis of constitutional DNA methylation in familial melanoma. Clin Epigenetics 2020; 12:43. [PMID: 32143689 PMCID: PMC7060565 DOI: 10.1186/s13148-020-00831-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 02/20/2020] [Indexed: 12/26/2022] Open
Abstract
Background Heritable epigenetic alterations have been proposed as an explanation for familial clustering of melanoma. Here we performed genome-wide DNA methylation analysis on affected family members not carrying pathogenic variants in established melanoma susceptibility genes, compared with healthy volunteers. Results All melanoma susceptibility genes showed the absence of epimutations in familial melanoma patients, and no loss of imprinting was detected. Unbiased genome-wide DNA methylation analysis revealed significantly different levels of methylation in single CpG sites. The methylation level differences were small and did not affect reported tumour predisposition genes. Conclusion Our results provide no support for heritable epimutations as a cause of familial melanoma.
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Affiliation(s)
- Catarina Salgado
- Department of Dermatology, Leiden University Medical Center, Leiden, PO Box 9600, 2300 RC, Leiden, The Netherlands
| | - Nelleke Gruis
- Department of Dermatology, Leiden University Medical Center, Leiden, PO Box 9600, 2300 RC, Leiden, The Netherlands
| | | | - Bastiaan T Heijmans
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | - Jan Oosting
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Remco van Doorn
- Department of Dermatology, Leiden University Medical Center, Leiden, PO Box 9600, 2300 RC, Leiden, The Netherlands.
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38
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Julian CG. An Aptitude for Altitude: Are Epigenomic Processes Involved? Front Physiol 2019; 10:1397. [PMID: 31824328 PMCID: PMC6883803 DOI: 10.3389/fphys.2019.01397] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 10/29/2019] [Indexed: 12/30/2022] Open
Abstract
In recent years, high-throughput genomic technologies and computational advancements have invigorated efforts to identify the molecular mechanisms regulating human adaptation to high altitude. Although exceptional progress regarding the identification of genomic regions showing evidence of recent positive selection has been made, many of the key “hypoxia tolerant” phenotypes of highland populations have not yet been linked to putative adaptive genetic variants. As a result, fundamental questions regarding the biological processes by which such adaptations are acquired remain unanswered. This Mini Review discusses the hypothesis that the epigenome works in coordination with underlying genomic sequence to govern adaptation to the chronic hypoxia of high altitude by influencing adaptive capacity and phenotypic variation under conditions of environmental hypoxia. Efforts to unravel the complex interactions between the genome, epigenome, and environmental exposures are essential to more fully appreciate the mechanisms underlying human adaptation to hypoxia.
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Affiliation(s)
- Colleen G Julian
- Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
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Abstract
The idea that epigenetic determinants such as DNA methylation, histone modifications or RNA can be passed to the next generation through meiotic products (gametes) is long standing. Such meiotic epigenetic inheritance (MEI) is fairly common in yeast, plants and nematodes, but its extent in mammals has been much debated. Advances in genomics techniques are now driving the profiling of germline and zygotic epigenomes, thereby improving our understanding of MEI in diverse species. Whereas the role of DNA methylation in MEI remains unclear, insights from genome-wide studies suggest that a previously underappreciated fraction of mammalian genomes bypass epigenetic reprogramming during development. Notably, intergenerational inheritance of histone modifications, tRNA fragments and microRNAs can affect gene regulation in the offspring. It is important to note that MEI in mammals rarely constitutes transgenerational epigenetic inheritance (TEI), which spans multiple generations. In this Review, we discuss the examples of MEI in mammals, including mammalian epigenome reprogramming, and the molecular mechanisms of MEI in vertebrates in general. We also discuss the implications of the inheritance of histone modifications and small RNA for embryogenesis in metazoans, with a particular focus on insights gained from genome-wide studies.
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40
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Xavier MJ, Roman SD, Aitken RJ, Nixon B. Transgenerational inheritance: how impacts to the epigenetic and genetic information of parents affect offspring health. Hum Reprod Update 2019; 25:518-540. [DOI: 10.1093/humupd/dmz017] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 03/19/2019] [Accepted: 04/04/2019] [Indexed: 12/18/2022] Open
Abstract
Abstract
BACKGROUND
A defining feature of sexual reproduction is the transmission of genomic information from both parents to the offspring. There is now compelling evidence that the inheritance of such genetic information is accompanied by additional epigenetic marks, or stable heritable information that is not accounted for by variations in DNA sequence. The reversible nature of epigenetic marks coupled with multiple rounds of epigenetic reprogramming that erase the majority of existing patterns have made the investigation of this phenomenon challenging. However, continual advances in molecular methods are allowing closer examination of the dynamic alterations to histone composition and DNA methylation patterns that accompany development and, in particular, how these modifications can occur in an individual’s germline and be transmitted to the following generation. While the underlying mechanisms that permit this form of transgenerational inheritance remain unclear, it is increasingly apparent that a combination of genetic and epigenetic modifications plays major roles in determining the phenotypes of individuals and their offspring.
OBJECTIVE AND RATIONALE
Information pertaining to transgenerational inheritance was systematically reviewed focusing primarily on mammalian cells to the exclusion of inheritance in plants, due to inherent differences in the means by which information is transmitted between generations. The effects of environmental factors and biological processes on both epigenetic and genetic information were reviewed to determine their contribution to modulating inheritable phenotypes.
SEARCH METHODS
Articles indexed in PubMed were searched using keywords related to transgenerational inheritance, epigenetic modifications, paternal and maternal inheritable traits and environmental and biological factors influencing transgenerational modifications. We sought to clarify the role of epigenetic reprogramming events during the life cycle of mammals and provide a comprehensive review of how the genomic and epigenomic make-up of progenitors may determine the phenotype of its descendants.
OUTCOMES
We found strong evidence supporting the role of DNA methylation patterns, histone modifications and even non-protein-coding RNA in altering the epigenetic composition of individuals and producing stable epigenetic effects that were transmitted from parents to offspring, in both humans and rodent species. Multiple genomic domains and several histone modification sites were found to resist demethylation and endure genome-wide reprogramming events. Epigenetic modifications integrated into the genome of individuals were shown to modulate gene expression and activity at enhancer and promoter domains, while genetic mutations were shown to alter sequence availability for methylation and histone binding. Fundamentally, alterations to the nuclear composition of the germline in response to environmental factors, ageing, diet and toxicant exposure have the potential to become hereditably transmitted.
WIDER IMPLICATIONS
The environment influences the health and well-being of progeny by working through the germline to introduce spontaneous genetic mutations as well as a variety of epigenetic changes, including alterations in DNA methylation status and the post-translational modification of histones. In evolutionary terms, these changes create the phenotypic diversity that fuels the fires of natural selection. However, rather than being adaptive, such variation may also generate a plethora of pathological disease states ranging from dominant genetic disorders to neurological conditions, including spontaneous schizophrenia and autism.
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Affiliation(s)
- Miguel João Xavier
- Reproductive Science Group, Faculty of Science, The University of Newcastle, Callaghan, NSW 2308, Australia
- Priority Research Centre for Reproductive Science, The University of Newcastle, Callaghan, NSW 2308, Australia
| | - Shaun D Roman
- Reproductive Science Group, Faculty of Science, The University of Newcastle, Callaghan, NSW 2308, Australia
- Priority Research Centre for Reproductive Science, The University of Newcastle, Callaghan, NSW 2308, Australia
- Priority Research Centre for Chemical Biology and Clinical Pharmacology, The University of Newcastle, Callaghan, NSW 2308, Australia
| | - R John Aitken
- Reproductive Science Group, Faculty of Science, The University of Newcastle, Callaghan, NSW 2308, Australia
- Priority Research Centre for Reproductive Science, The University of Newcastle, Callaghan, NSW 2308, Australia
- Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW 2308, Australia
| | - Brett Nixon
- Reproductive Science Group, Faculty of Science, The University of Newcastle, Callaghan, NSW 2308, Australia
- Priority Research Centre for Reproductive Science, The University of Newcastle, Callaghan, NSW 2308, Australia
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Chen J, Haanpää MK, Gruber JJ, Jäger N, Ford JM, Snyder MP. High-Resolution Bisulfite-Sequencing of Peripheral Blood DNA Methylation in Early-Onset and Familial Risk Breast Cancer Patients. Clin Cancer Res 2019; 25:5301-5314. [PMID: 31175093 DOI: 10.1158/1078-0432.ccr-18-2423] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 04/11/2019] [Accepted: 06/05/2019] [Indexed: 12/14/2022]
Abstract
PURPOSE Understanding and explaining hereditary predisposition to cancer has focused on the genetic etiology of the disease. However, mutations in known genes associated with breast cancer, such as BRCA1 and BRCA2, account for less than 25% of familial cases of breast cancer. Recently, specific epigenetic modifications at BRCA1 have been shown to promote hereditary breast cancer, but the broader potential for epigenetic contribution to hereditary breast cancer is not yet well understood. EXPERIMENTAL DESIGN We examined DNA methylation through deep bisulfite sequencing of CpG islands and known promoter or regulatory regions in peripheral blood DNA from 99 patients with familial or early-onset breast or ovarian cancer, 6 unaffected BRCA mutation carriers, and 49 unaffected controls. RESULTS In 9% of patients, we observed altered methylation in the promoter regions of genes known to be involved in cancer, including hypermethylation at the tumor suppressor PTEN and hypomethylation at the proto-oncogene TEX14. These alterations occur in the form of allelic methylation that span up to hundreds of base pairs in length. CONCLUSIONS Our observations suggest a broader role for DNA methylation in early-onset, familial risk breast cancer. Further studies are warranted to clarify these mechanisms and the benefits of DNA methylation screening for early risk prediction of familial cancers.
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Affiliation(s)
- Justin Chen
- Department of Genetics, Stanford University, Stanford, California
| | - Maria K Haanpää
- Department of Medicine, Oncology Division, Stanford University, Stanford, California
| | - Joshua J Gruber
- Department of Genetics, Stanford University, Stanford, California.,Department of Medicine, Oncology Division, Stanford University, Stanford, California
| | - Natalie Jäger
- Department of Genetics, Stanford University, Stanford, California
| | - James M Ford
- Department of Genetics, Stanford University, Stanford, California. .,Department of Medicine, Oncology Division, Stanford University, Stanford, California
| | - Michael P Snyder
- Department of Genetics, Stanford University, Stanford, California.
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Martínez-Ramírez OC, Pérez-Morales R, Castro-Hernández C, Gonsebatt ME, Casas-Ávila L, Valdés-Flores M, Petrosyan P, de León-Suárez VP, Rubio J. Association of the Promoter Methylation and the rs12917 Polymorphism of MGMT with Formation of DNA Bulky Adducts and the Risk of Lung Cancer in Mexican Mestizo Population. DNA Cell Biol 2019; 38:307-313. [DOI: 10.1089/dna.2018.4526] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Affiliation(s)
| | - Rebeca Pérez-Morales
- Departamento de Biología Molecular, Facultad de Ciencias Químicas, Universidad Juárez del Estado de Durango, Durango, Mexico
| | - Clementina Castro-Hernández
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Maria Eugenia Gonsebatt
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Leonora Casas-Ávila
- Departamento de Genética, Instituto Nacional de Rehabilitación, Ciudad de México, Mexico
| | | | - Pavel Petrosyan
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | | | - Julieta Rubio
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
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Lønning PE, Eikesdal HP, Løes IM, Knappskog S. Constitutional Mosaic Epimutations - a hidden cause of cancer? Cell Stress 2019; 3:118-135. [PMID: 31225507 PMCID: PMC6551830 DOI: 10.15698/cst2019.04.183] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 03/04/2019] [Accepted: 03/05/2019] [Indexed: 12/11/2022] Open
Abstract
Silencing of tumor suppressor genes by promoter hypermethylation is a key mechanism to facilitate cancer progression in many malignancies. While promoter hypermethylation can occur at later stages of the carcinogenesis process, constitutional methylation of key tumor suppressors may be an initiating event whereby cancer is started. Constitutional BRCA1 methylation due to cis-acting germline genetic variants is associated with a high risk of breast and ovarian cancer. However, this seems to be a rare event, restricted to a very limited number of families. In contrast, mosaic constitutional BRCA1 methylation is detected in 4-7% of newborn females without germline BRCA1 mutations. While the cause of such methylation is poorly understood, mosaic normal tissue BRCA1 methylation is associated with a 2-3 fold increased risk of high-grade serous ovarian cancer (HGSOC). As such, BRCA1 methylation may be the cause of a significant number of ovarian cancers. Given the molecular similarities between HGSOC and basal-like breast cancer, the findings with respect to HGSOC suggest that constitutional BRCA1 methylation could be a risk factor for basal-like breast cancer as well. Similar to BRCA1, some specific germline variants in MLH1 and MSH2 are associated with promoter methylation and a high risk of colorectal cancers in rare hereditary cases of the disease. However, as many as 15% of all colorectal cancers are of the microsatellite instability (MSI) "high" subtype, in which commonly the tumors harbor MLH1 hypermethylation. Constitutional mosaic methylation of MLH1 in normal tissues has been detected but not formally evaluated as a potential risk factor for incidental colorectal cancers. However, the findings with respect to BRCA1 in breast and ovarian cancer raises the question whether mosaic MLH1 methylation is a risk factor for MSI positive colorectal cancer as well. As for MGMT, a promoter variant is associated with elevated methylation across a panel of solid cancers, and MGMT promoter methylation may contribute to an elevated cancer risk in several of these malignancies. We hypothesize that constitutional mosaic promoter methylation of crucial tumor suppressors may trigger certain types of cancer, similar to germline mutations inactivating the same particular genes. Such constitutional methylation events may be a spark to ignite cancer development, and if associated with a significant cancer risk, screening for such epigenetic alterations could be part of cancer prevention programs to reduce cancer mortality in the future.
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Affiliation(s)
- Per E. Lønning
- K.G.Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Hans P. Eikesdal
- K.G.Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Inger M. Løes
- K.G.Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Stian Knappskog
- K.G.Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
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Azzollini J, Pesenti C, Pizzamiglio S, Fontana L, Guarino C, Peissel B, Plebani M, Tabano S, Sirchia SM, Colapietro P, Villa R, Paolini B, Verderio P, Miozzo M, Manoukian S. Constitutive BRCA1 Promoter Hypermethylation Can Be a Predisposing Event in Isolated Early-Onset Breast Cancer. Cancers (Basel) 2019; 11:cancers11010058. [PMID: 30634417 PMCID: PMC6356733 DOI: 10.3390/cancers11010058] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 01/03/2019] [Indexed: 12/14/2022] Open
Abstract
Early age at onset of breast cancer (eoBC) is suggestive of an increased genetic risk. Although genetic testing is offered to all eoBC-affected women, in isolated cases the detection rate of pathogenic variants is <10%. This study aimed at assessing the role of constitutive promoter methylation at BC-associated loci as an underlying predisposing event in women with eoBC and negative family history. Promoter methylation at 12 loci was assessed by the MassARRAY technology in blood from 154 BRCA1/2 negative patients with eoBC and negative family history, and 60 healthy controls. Hypermethylation was determined, within each promoter, by comparing the patient’s mean methylation value with thresholds based on one-sided 95% bootstrap confidence interval of the controls’ mean. Three patients had hypermethylated results, two at BRCA1 and one at RAD51C. Analyses on tumor tissue from the patient exceeding the highest threshold at BRCA1 revealed a mean methylation >60% and loss of heterozygosity at chromosome 17q. The patient hypermethylated at RAD51C showed low methylation in the tumor sample, ruling out a role for methylation-induced silencing in tumor development. In isolated eoBC patients, BRCA1 constitutive promoter methylation may be a predisposing event. Further studies are required to define the impact of methylation changes occurring at BC-predisposing genes and their role in tumorigenesis.
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Affiliation(s)
- Jacopo Azzollini
- Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
| | - Chiara Pesenti
- Department of Pathophysiology & Transplantation, Università degli Studi di Milano; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy.
| | - Sara Pizzamiglio
- Unit of Bioinformatics and Biostatistics, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
| | - Laura Fontana
- Department of Pathophysiology & Transplantation, Università degli Studi di Milano; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy.
| | - Carmela Guarino
- Immunohematology & Transfusion Medicine Service, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy.
| | - Bernard Peissel
- Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
| | - Maddalena Plebani
- Unit of Bioinformatics and Biostatistics, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
| | - Silvia Tabano
- Department of Pathophysiology & Transplantation, Università degli Studi di Milano; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy.
| | - Silvia Maria Sirchia
- Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, 20142 Milano, Italy.
| | - Patrizia Colapietro
- Department of Pathophysiology & Transplantation, Università degli Studi di Milano; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy.
| | - Roberta Villa
- Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
| | - Biagio Paolini
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
| | - Paolo Verderio
- Unit of Bioinformatics and Biostatistics, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
| | - Monica Miozzo
- Department of Pathophysiology & Transplantation, Università degli Studi di Milano; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milano, Italy.
| | - Siranoush Manoukian
- Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
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45
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The Clinical Utility of Epigenetics: A Case Study. Clin Epigenetics 2019. [DOI: 10.1007/978-981-13-8958-0_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
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Abstract
BACKGROUND The methylator pathway of colorectal carcinogenesis, characterized by CpG island hypermethylation and BRAF mutations, accounts for ≈25% of colorectal cancers. Because these cancers tend to be right sided and because DNA methylation in the right colon increases with age, we expect an increasing proportion of right-sided cancer over time. Conversely, we expect young patients (age <50 y) to have less methylated and fewer right-sided cancers OBJECTIVE:: The purpose of this study was to analyze the distribution and genetic traits of colorectal cancer from different age groups. DESIGN This was a retrospective cohort study. SETTING The study was conducted at a high-volume tertiary referral center. PATIENTS Patient samples included those from our colorectal cancer biobank of resected colorectal cancer specimens. MAIN OUTCOME MEASURES Tumor CpG island hypermethylation, microsatellite instability, and mutations in KRAS and BRAF oncogenes were analyzed in resected specimens and stratified by age and tumor location. Comparisons included age >50 or <50 years and decade of diagnosis (≤50, 51-60, 61-70, 71-80, and >81 y). Patients with IBD or hereditary syndromes were excluded. RESULTS A total of 497 colorectal cancers were analyzed (266 men and 231 women); 57 patients (11.5%) were ≤50 years of age. No young cancers (0/57) were hypermethylated compared with 97 (22%) of 440 cancers of patients aged >50 years (p < 0.001). An increasing percentage of tumors were CpG island phenotype high with each decade of age at diagnosis. No cancers in patients <50 years of age were microsatellite unstable compared with 91 (23.6%) of 346 for those >50 years of age. No young cancers contained a BRAF mutation compared with 46 (10.6%) of 434 in older cancers (p < 0.001). KRAS mutations were less common in young cancers compared with older cancers (13/57 (22.8%) vs 126/410 (30.7%); p < 0.01). Eleven (19.3%) of 57 young cancers were proximal compared with 228 (51.8%) of 440 (p < 0.001) older cancers. LIMITATIONS This study was limited by its retrospective design. CONCLUSIONS The lack of CpG island methylator phenotype tumors in young patients is consistent with the dominant left-sided cancer distribution seen in the young and focuses efforts to understand and prevent cancer in this age group on causes of chromosomal instability. See Video Abstract at http://links.lww.com/DCR/A709.
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Stenz L, Schechter DS, Serpa SR, Paoloni-Giacobino A. Intergenerational Transmission of DNA Methylation Signatures Associated with Early Life Stress. Curr Genomics 2018; 19:665-675. [PMID: 30532646 PMCID: PMC6225454 DOI: 10.2174/1389202919666171229145656] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 04/25/2017] [Accepted: 12/17/2017] [Indexed: 02/07/2023] Open
Abstract
Early life stress in humans (i.e. maltreatment, violence exposure, loss of a loved one) and in rodents (i.e. disrupted attachment or nesting, electric shock, restraint, predator odor) occurs during critical steps of neural circuit formation. ELS in humans is associated with increased risk for developmental psychopathology, including anxious and depressive phenotypes. The biological mechanisms underlying these potentially persistent maladaptive changes involve long-term epigenetic modifications, which have been suggested to be potentially transmissible to subsequent generations. DNA methylation is an epigenetic mechanism that modifies gene expression patterns in response to environmental challenges and influences mutation rates. It remains to be seen whether a functionally relevant fraction of DNA methylation marks can escape genome-wide erasures that occur in primordial germ cells and after fertilization within the zygote. Early life-stress-triggered changes in epigenetic mediated transmission of acquired behavioral traits among humans have been assessed mainly by targeting genes involved in the hypothalamic-pituitary-adrenal (HPA) axis, such as NR3C1 and FKBP5. Recently, researchers examining epigenetic transmission have begun to apply genome-wide approaches. In humans, reduced representation bisulfite sequencing (RRBS) was performed on peripheral samples that were obtained from individuals who were prenatally exposed to the "Dutch Hunger Winter", resulting in two Differentially Methylated Regions (DMRs) in INSR and CPTIA genes that were functionally, biologically and technically validated, and significantly associated with birth weights and LDL cholesterol levels in offspring. In rodents, non-genomic intergenerational transmission of anxiety which was associated with differentially methylated enhancers that were putatively involved in lipid signaling and synaptic/neurotransmission in hippocampal granule cells, was discovered also using RRBS. Finally, transgenerational transmission of altered behaviors was associated with sperm-derived microRNAs produced by ELS male mice. The field of epigenetic transmission is just beginning to enter the epigenomic era by using genome-wide analyses. Such approaches remain of strong interest to human studies, first in order to help to assess the relevance of the previous targeted studies, and second to discover new important epigenetic modifications of potential clinical importance. New discoveries may help to assess how transmittable the negative impact of stress may be to offspring. The latter may open doors for future treatments and resilience-promoting interventions, as well as new approaches to treat the effects of childhood trauma before the onset of psychiatric disorder.
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Affiliation(s)
| | - Daniel S. Schechter
- Address correspondence to this author at the Department of Child & Adolescent Psychiatry, University of Geneva Hospitals and Faculty of Medicine, Geneva, Switzerland; Tel: +41 (022) 372 5067; Fax: +91 (022) 372 5077; E-mail:
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Non-Coding Variants in BRCA1 and BRCA2 Genes: Potential Impact on Breast and Ovarian Cancer Predisposition. Cancers (Basel) 2018; 10:cancers10110453. [PMID: 30453575 PMCID: PMC6266896 DOI: 10.3390/cancers10110453] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 11/04/2018] [Accepted: 11/12/2018] [Indexed: 12/21/2022] Open
Abstract
BRCA1 and BRCA2 are major breast cancer susceptibility genes whose pathogenic variants are associated with a significant increase in the risk of breast and ovarian cancers. Current genetic screening is generally limited to BRCA1/2 exons and intron/exon boundaries. Most identified pathogenic variants cause the partial or complete loss of function of the protein. However, it is becoming increasingly clear that variants in these regions only account for a small proportion of cancer risk. The role of variants in non-coding regions beyond splice donor and acceptor sites, including those that have no qualitative effect on the protein, has not been thoroughly investigated. The key transcriptional regulatory elements of BRCA1 and BRCA2 are housed in gene promoters, untranslated regions, introns, and long-range elements. Within these sequences, germline and somatic variants have been described, but the clinical significance of the majority is currently unknown and it remains a significant clinical challenge. This review summarizes the available data on the impact of variants on non-coding regions of BRCA1/2 genes and their role on breast and ovarian cancer predisposition.
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Dámaso E, Castillejo A, Arias MDM, Canet-Hermida J, Navarro M, Del Valle J, Campos O, Fernández A, Marín F, Turchetti D, García-Díaz JDD, Lázaro C, Genuardi M, Rueda D, Alonso Á, Soto JL, Hitchins M, Pineda M, Capellá G. Primary constitutional MLH1 epimutations: a focal epigenetic event. Br J Cancer 2018; 119:978-987. [PMID: 30283143 PMCID: PMC6203851 DOI: 10.1038/s41416-018-0019-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 11/20/2017] [Accepted: 11/27/2017] [Indexed: 12/15/2022] Open
Abstract
Background Constitutional MLH1 epimutations are characterised by monoallelic methylation of the MLH1 promoter throughout normal tissues, accompanied by allele-specific silencing. The mechanism underlying primary MLH1 epimutations is currently unknown. The aim of this study was to perform an in-depth characterisation of constitutional MLH1 epimutations targeting the aberrantly methylated region around MLH1 and other genomic loci. Methods Twelve MLH1 epimutation carriers, 61 Lynch syndrome patients, and 41 healthy controls, were analysed by Infinium 450 K array. Targeted molecular techniques were used to characterise the MLH1 epimutation carriers and their inheritance pattern. Results No nucleotide or structural variants were identified in-cis on the epimutated allele in 10 carriers, in which inter-generational methylation erasure was demonstrated in two, suggesting primary type of epimutation. CNVs outside the MLH1 locus were found in two cases. EPM2AIP1-MLH1 CpG island was identified as the sole differentially methylated region in MLH1 epimutation carriers compared to controls. Conclusion Primary constitutional MLH1 epimutations arise as a focal epigenetic event at the EPM2AIP1-MLH1 CpG island in the absence of cis-acting genetic variants. Further molecular characterisation is needed to elucidate the mechanistic basis of MLH1 epimutations and their heritability/reversibility.
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Affiliation(s)
- Estela Dámaso
- Hereditary Cancer Program, Catalan Institute of Oncology-Bellvitge Biomedical Research Institute (ICO-IDIBELL),ONCOBELL, CIBERONC, Av.Gran Via de l'Hospitalet 199-203, L'Hospitalet de Llobregat, 08908, Barcelona, Spain
| | - Adela Castillejo
- Hereditary Cancer Program Valencian Region, Molecular Genetics Laboratory, Elche University Hospital, Camino de la Almazara 11, Elche, 03203, Alicante, Spain
| | - María Del Mar Arias
- Genetics Service, Complejo Hospitalario de Navarra, Calle de Irunlarrea 3, Pamplona, 31008, Navarra, Spain
| | - Julia Canet-Hermida
- Hereditary Cancer Program, Catalan Institute of Oncology-Bellvitge Biomedical Research Institute (ICO-IDIBELL),ONCOBELL, CIBERONC, Av.Gran Via de l'Hospitalet 199-203, L'Hospitalet de Llobregat, 08908, Barcelona, Spain
| | - Matilde Navarro
- Hereditary Cancer Program, Catalan Institute of Oncology-Bellvitge Biomedical Research Institute (ICO-IDIBELL),ONCOBELL, CIBERONC, Av.Gran Via de l'Hospitalet 199-203, L'Hospitalet de Llobregat, 08908, Barcelona, Spain
| | - Jesús Del Valle
- Hereditary Cancer Program, Catalan Institute of Oncology-Bellvitge Biomedical Research Institute (ICO-IDIBELL),ONCOBELL, CIBERONC, Av.Gran Via de l'Hospitalet 199-203, L'Hospitalet de Llobregat, 08908, Barcelona, Spain
| | - Olga Campos
- Hereditary Cancer Program, Catalan Institute of Oncology-Bellvitge Biomedical Research Institute (ICO-IDIBELL),ONCOBELL, CIBERONC, Av.Gran Via de l'Hospitalet 199-203, L'Hospitalet de Llobregat, 08908, Barcelona, Spain
| | - Anna Fernández
- Hereditary Cancer Program, Catalan Institute of Oncology-Bellvitge Biomedical Research Institute (ICO-IDIBELL),ONCOBELL, CIBERONC, Av.Gran Via de l'Hospitalet 199-203, L'Hospitalet de Llobregat, 08908, Barcelona, Spain
| | - Fátima Marín
- Hereditary Cancer Program, Catalan Institute of Oncology-Bellvitge Biomedical Research Institute (ICO-IDIBELL),ONCOBELL, CIBERONC, Av.Gran Via de l'Hospitalet 199-203, L'Hospitalet de Llobregat, 08908, Barcelona, Spain
| | - Daniela Turchetti
- Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum - Università di Bologna, Via Massarenti 11, Bologna, 40138, Italy
| | - Juan de Dios García-Díaz
- Unidad de Genética Clínica, Servicio de Medicina Interna, Hospital Universitario Príncipe de Asturias, Carretera Alcalá-Meco, Alcalá de Henares, 28805, Madrid, Spain
| | - Conxi Lázaro
- Hereditary Cancer Program, Catalan Institute of Oncology-Bellvitge Biomedical Research Institute (ICO-IDIBELL),ONCOBELL, CIBERONC, Av.Gran Via de l'Hospitalet 199-203, L'Hospitalet de Llobregat, 08908, Barcelona, Spain
| | - Maurizio Genuardi
- Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore - Fondazione Policlinico Universitario Agostino Gemelli, Largo Agostino Gemelli 8, Rome, 00168, Italy
| | - Daniel Rueda
- Hereditary Cancer Genetic Diagnostic Laboratory, Doce de Octubre University Hospital, Avenida de Córdoba, Madrid, Madrid, 28041, Spain
| | - Ángel Alonso
- Genetics Service, Complejo Hospitalario de Navarra, Calle de Irunlarrea 3, Pamplona, 31008, Navarra, Spain
| | - Jose Luis Soto
- Hereditary Cancer Program Valencian Region, Molecular Genetics Laboratory, Elche University Hospital, Camino de la Almazara 11, Elche, 03203, Alicante, Spain.,Alicante Institute for Health and Biomedical Research (ISABIAL-FISABIO Foundation), Alicante, Spain
| | - Megan Hitchins
- Department of Medicine, Division of Oncology, Stanford University, 1291 Welch Road, Stanford, 94305, California, USA
| | - Marta Pineda
- Hereditary Cancer Program, Catalan Institute of Oncology-Bellvitge Biomedical Research Institute (ICO-IDIBELL),ONCOBELL, CIBERONC, Av.Gran Via de l'Hospitalet 199-203, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.
| | - Gabriel Capellá
- Hereditary Cancer Program, Catalan Institute of Oncology-Bellvitge Biomedical Research Institute (ICO-IDIBELL),ONCOBELL, CIBERONC, Av.Gran Via de l'Hospitalet 199-203, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.
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Xiong JX, Wang YS, Sheng J, Xiang D, Huang TX, Tan BB, Zeng CM, Li HH, Yang J, Meltzer SJ, Mori Y, Qin YR, Guan XY, Fu L. Epigenetic alterations of a novel antioxidant gene SLC22A3 predispose susceptible individuals to increased risk of esophageal cancer. Int J Biol Sci 2018; 14:1658-1668. [PMID: 30416380 PMCID: PMC6216027 DOI: 10.7150/ijbs.28482] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 08/24/2018] [Indexed: 01/29/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) occurs with the highest frequency in China, especially in the high-risk Northern Chinese. Recent studies have reported that SLC22A3 is significantly downregulated in non-tumor (NT) esophageal tissues from familial ESCC patients compared with those from sporadic ESCC. However, the mechanism of how SLC22A3 regulates familial ESCC remains unknown. In this study, post hoc genome-wide association studies (GWAS) in 496 cases with a family history of upper gastrointestinal tract cancers and 1056 controls were performed and the results revealed that SLC22A3 is a novel susceptibility gene for familial ESCC. Reduced expression of SLC22A3 in NT esophageal tissues from familial ESCC patients significantly correlates with its promoter hypermethylation. Moreover, case-control study of Chinese descendants from different risk areas of China revealed that the methylation of the SLC22A3 gene in peripheral blood leukocyte (PBL) DNA samples could be a risk factor for developing ESCC in this high-risk population. Functional studies showed that SLC22A3 is a novel antioxidant gene, and deregulation of SLC22A3 facilitates heat stress-induced oxidative DNA damage and formation of γ-H2AX foci in normal esophageal epithelial cells. Collectively, we show that epigenetic alterations of SLC22A3 predispose susceptible individuals to increased risk of esophageal cancer.
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Affiliation(s)
- Ji-Xian Xiong
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pharmacology and Carson International Cancer Center, Shenzhen University School of Medicine, Shenzhen 518039, China
| | - Yan-Song Wang
- Department of Stomatology, Shenzhen Hospital of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
| | - Jingyi Sheng
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong
- Shenzhen Huarui Translational Research Institute, Shenzhen, China
| | - Di Xiang
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pharmacology and Carson International Cancer Center, Shenzhen University School of Medicine, Shenzhen 518039, China
| | - Tu-Xiong Huang
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pharmacology and Carson International Cancer Center, Shenzhen University School of Medicine, Shenzhen 518039, China
| | - Bin-Bin Tan
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pharmacology and Carson International Cancer Center, Shenzhen University School of Medicine, Shenzhen 518039, China
| | - Cui-Mian Zeng
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pharmacology and Carson International Cancer Center, Shenzhen University School of Medicine, Shenzhen 518039, China
| | - Hua-Hui Li
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pharmacology and Carson International Cancer Center, Shenzhen University School of Medicine, Shenzhen 518039, China
| | - Jiao Yang
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pharmacology and Carson International Cancer Center, Shenzhen University School of Medicine, Shenzhen 518039, China
| | - Stephen J. Meltzer
- Department of Medicine and Oncology, The Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
| | - Yuriko Mori
- Department of Medicine and Oncology, The Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
| | - Yan-Ru Qin
- Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Xin-Yuan Guan
- Department of Clinical Oncology, University of Hong Kong, Hong Kong
| | - Li Fu
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pharmacology and Carson International Cancer Center, Shenzhen University School of Medicine, Shenzhen 518039, China
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