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Ying L, Zhang L, Chen Y, Huang C, Zhou J, Xie J, Liu L. Predicting immunotherapy prognosis and targeted therapy sensitivity of colon cancer based on a CAF-related molecular signature. Sci Rep 2025; 15:6387. [PMID: 39984646 PMCID: PMC11845748 DOI: 10.1038/s41598-025-90899-z] [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: 11/12/2024] [Accepted: 02/17/2025] [Indexed: 02/23/2025] Open
Abstract
The role of cancer-associated fibroblasts (CAFs) in modulating the tumor microenvironment (TME) is gaining attention, yet their impact on prognosis and therapeutic response in colon cancer remains unclear. Here, we identified genes associated with CAF infiltration via weighted gene co-expression network analysis (WGCNA) utilizing data from The Cancer Genome Atlas (TCGA) and GSE39582 cohorts. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were used to construct CAF molecular signatures (CAFscore). Patients were categorized into high and low CAFscore groups to analyze clinicopathological traits, somatic mutations, immune evasion, and treatment responses. In this study, a total of 244 genes were correlated with CAF infiltration, with 11 linked to overall survival. Notably, FSTL3, CRIP2, and SLC2A3 were selected for the CAFscore. A higher CAFscore was associated with poorer prognoses, increased malignancy, and therapeutic resistance, particularly among patients with high tumor mutation burden and microsatellite instability. Furthermore, elevated FSTL3 expression was associated with reduced CD8+ T cell infiltration, indicating a suppressive TME. Mechanistically, CAFs may promote immune evasion via NAMPT ligand-receptor interactions based on single-cell RNA sequencing data. Thus, the CAFscore is crucial for personalizing treatment strategies and identifying patients who require more aggressive management.
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Affiliation(s)
- Leqian Ying
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
- School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
| | - Lu Zhang
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
- School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
| | - Yanping Chen
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
| | - Chunchun Huang
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
- School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
| | - Jingyi Zhou
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
- School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
| | - Jinbing Xie
- Department of Radiology, Nurturing Center of Jiangsu Province for the State Laboratory of AI Imaging and Interventional Radiology, Basic Medicine Research and Innovation Center of Ministry of Education, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China
| | - Lin Liu
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao, Nanjing, 210000, China.
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2
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Rochefort P, Desseigne F, Bonadona V, Dussart S, Coutzac C, Sarabi M, la Fouchardiere CD. Immune checkpoint inhibitor sensitivity of DNA repair deficient tumors. Immunotherapy 2021; 13:1205-1213. [PMID: 34494466 DOI: 10.2217/imt-2021-0024] [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: 11/21/2022] Open
Abstract
Faithful DNA replication is necessary to maintain genome stability and implicates a complex network with several pathways depending on DNA damage type: homologous repair, nonhomologous end joining, base excision repair, nucleotide excision repair and mismatch repair. Alteration in components of DNA repair machinery led to DNA damage accumulation and potentially carcinogenesis. Preclinical data suggest sensitivity to immune checkpoint inhibitors in tumors with DNA repair deficiency. Here, we review clinical studies that explored the use of immune checkpoint inhibitor in patient harboring tumor with DNA repair deficiency.
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Affiliation(s)
- Pauline Rochefort
- Department of Medical Oncology, Centre Léon Bérard, 69008, Lyon, France
| | | | - Valérie Bonadona
- Unit of Genetic Epidemiology & Prevention, Centre Léon Bérard, 69008, Lyon, France
| | - Sophie Dussart
- Unit of Genetic Epidemiology & Prevention, Centre Léon Bérard, 69008, Lyon, France
| | - Clélia Coutzac
- Department of Medical Oncology, Centre Léon Bérard, 69008, Lyon, France
| | - Matthieu Sarabi
- Department of Medical Oncology, Centre Léon Bérard, 69008, Lyon, France
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3
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McDermott FD, Newton K, Beggs AD, Clark SK. Implications for the colorectal surgeon following the 100 000 Genomes Project. Colorectal Dis 2021; 23:1049-1058. [PMID: 33471415 DOI: 10.1111/codi.15539] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 01/24/2021] [Accepted: 01/11/2021] [Indexed: 12/19/2022]
Abstract
AIM The 100 000 Genomes Project was completed in 2019 with the objective of integrating genomic medicine into routine National Health Service (NHS) clinical pathways. This project and genomic research will revolutionize the way we practice colorectal surgery in the 21st century. This paper aims to provide an overview of genomic medicine and its implications for the colorectal surgeon. RESULTS Within NHS England, consolidation has created seven regional Genomic Laboratory Hubs. DNA from solid tumours, including colorectal cancers, will be assessed using 500-gene panels, results will be fed back to Genome Tumour Advisory Boards. Identifying variants from biopsies earlier in the clinical pathway may alter surgical and other treatment options for patients. However, there is an important distinction between somatic variants within a tumour biopsy and germline variants that may suggest a heritable condition such as Lynch syndrome. Novel drugs, for example immunotherapy, will increase treatment options including downstaging cancers and changing the surgical approach. The use of circulating tumour DNA (liquid biopsies) will have applications in diagnosis, treatment and surveillance of cancer. There are many exciting potential future applications of this technology for offering personalized medicine that will require multidisciplinary working and the colorectal community. CONCLUSION There are many challenges but also exciting opportunities to embed new 'omic' technologies and innovation into 21st century colorectal surgery. The next phase for the colorectal community is how we engage with this change, with questions around training, identification of genomic multidisciplinary team (MDT) champions and how we collaborate with the core members of the MDT, clinical geneticists and national genomic testing.
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Affiliation(s)
- Frank D McDermott
- Royal Devon and Exeter Foundation Trust, University of Exeter, Exeter, UK
| | - Katy Newton
- Department of Surgery and Cancer, LNWUH NHS Trust, St Mark's Hospital, Imperial College, London, UK
| | - Andrew D Beggs
- Institute of Cancer and Genomic Sciences, University of Birmingham and Queen Elizabeth Hospital, Birmingham, UK
| | - Susan K Clark
- Department of Surgery and Cancer, LNWUH NHS Trust, St Mark's Hospital, Imperial College, London, UK
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4
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Hino H, Shiomi A, Kusuhara M, Kagawa H, Yamakawa Y, Hatakeyama K, Kawabata T, Oishi T, Urakami K, Nagashima T, Kinugasa Y, Yamaguchi K. Clinicopathological and mutational analyses of colorectal cancer with mutations in the POLE gene. Cancer Med 2019; 8:4587-4597. [PMID: 31240875 PMCID: PMC6712448 DOI: 10.1002/cam4.2344] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 05/28/2019] [Accepted: 05/31/2019] [Indexed: 01/03/2023] Open
Abstract
Here, we investigated the clinicopathological and mutation profiles of colorectal cancer (CRC) with POLE mutations. Whole‐exome sequencing was performed in 910 surgically resected primary CRCs. Tumors exceeding 500 counts of nonsynonymous single nucleotide variants (SNVs) were classified as hypermutators, whereas the remaining were classified as nonhypermutators. The hypermutators were subdivided into 2 groups. CRCs harboring more than 20% C‐to‐A and less than 3% C‐to‐G transversions were classified as POLE category tumors, whereas the remaining were classified as common‐hypermutators. Gene expression profiling (GEP) analysis was performed in 892 (98.0%) tumors. Fifty‐seven (6.3%) and 10 (1.1%) tumors were classified common‐hypermutators and POLE category tumors, respectively. POLE category tumors harbored a significantly higher SNV count than common‐hypermutators, and all POLE category tumors were associated with exonuclease domain mutations, such as P286R, F367C, V411L, and S297Y, in the POLE gene. Patients with POLE category tumors were significantly younger than those with nonhypermutators and common‐hypermutators. All POLE mutations in the early‐onset (age of onset ≤50 years old) POLE category (7 tumors) were P286R mutations. GEP analysis revealed that PD‐L1 and PD‐1 gene expression levels were significantly increased in both common‐hypermutators and POLE category tumors compared with those in nonhypermutators. CD8A expression was significantly upregulated in POLE category tumors compared with that in nonhypermutators. Thus, we concluded that CRCs with POLE proofreading deficiency had characteristics distinct from those of other CRCs. Analysis of POLE proofreading deficiency may be clinically significant for personalized management of CRCs.
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Affiliation(s)
- Hitoshi Hino
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Akio Shiomi
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Masatoshi Kusuhara
- Regional Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Hiroyasu Kagawa
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Yushi Yamakawa
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Keiichi Hatakeyama
- Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Takanori Kawabata
- Clinical Research Promotion Unit, Clinical Research Center, Shizuoka Cancer Center, Shizuoka, Japan
| | - Takuma Oishi
- Division of Pathology, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Kenichi Urakami
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | | | - Yusuke Kinugasa
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan.,Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ken Yamaguchi
- Shizuoka Cancer Center Hospital and Research Institute, Shizuoka, Japan
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5
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Development of an MSI-positive colon tumor with aberrant DNA methylation in a PPAP patient. J Hum Genet 2019; 64:729-740. [PMID: 31089268 DOI: 10.1038/s10038-019-0611-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 03/18/2019] [Accepted: 04/19/2019] [Indexed: 02/07/2023]
Abstract
Polymerase proofreading-associated polyposis (PPAP) is a disease caused by germline variations in the POLE and POLD1 genes that encode catalytic subunits of DNA polymerases. Studies of cancer genomes have identified somatic mutations in these genes, suggesting the importance of polymerase proofreading of DNA replication in suppressing tumorigenesis. Here, we identified a germline frameshift variation in the POLE gene (c.4191_4192delCT, p.Tyr1398*) in a case with multiple adenomatous polyps and three synchronous colon cancers. Interestingly, one of the colon cancers showed microsatellite instability-high (MSI-H) and another microsatellite stable. Immunohistochemical staining revealed that the MSI-H tumor cells lost the expression of MLH1 protein. Whole genome sequencing of the MSI-H tumor did not find pathogenic somatic mutations in mismatch repair genes but found frameshift mutations in the TET genes that catalyze 5-methylcytosine hydroxylation. Bisulfite sequencing of the tumor corroborated an increase in the number of hypermethylated regions including the MLH1 promoter. These data indicate that PPAP patients might develop MSI-positive tumors through epigenetic silencing of MLH1. These findings will contribute to comprehensive understanding of the molecular basis of tumors that involve deficiency of proofreading activity of DNA polymerases.
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6
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Tanakaya K. Current clinical topics of Lynch syndrome. Int J Clin Oncol 2018; 24:1013-1019. [DOI: 10.1007/s10147-018-1282-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 04/17/2018] [Indexed: 01/02/2023]
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Abstract
Genetic abnormalities are present in all tumor types, although the frequency and type can vary. Chromosome abnormalities include highly aberrant structures, particularly chromothriptic chromosomes. The generation of massive sequencing data has illuminated the scope of the mutational burden in cancer genomes, identifying patterns of mutations (mutation signatures), which have the potential to shed light on the relatedness and etiologies of cancers and impact therapy response. Some mutation patterns are clearly attributable to disruptions in pathways that maintain genomic integrity. Here we review recent advances in our understanding of genetic changes occurring in cancers and the roles of genome maintenance pathways.
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Affiliation(s)
- Elizabeth M Kass
- Developmental Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Mary Ellen Moynahan
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Maria Jasin
- Developmental Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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8
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Mertz TM, Baranovskiy AG, Wang J, Tahirov TH, Shcherbakova PV. Nucleotide selectivity defect and mutator phenotype conferred by a colon cancer-associated DNA polymerase δ mutation in human cells. Oncogene 2017; 36:4427-4433. [PMID: 28368425 PMCID: PMC5542868 DOI: 10.1038/onc.2017.22] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 12/17/2016] [Accepted: 12/30/2016] [Indexed: 12/14/2022]
Abstract
Mutations in the POLD1 and POLE genes encoding DNA polymerases δ (Polδ) and ɛ (Polɛ) cause hereditary colorectal cancer (CRC) and have been found in many sporadic colorectal and endometrial tumors. Much attention has been focused on POLE exonuclease domain mutations, which occur frequently in hypermutated DNA mismatch repair (MMR)-proficient tumors and appear to be responsible for the bulk of genomic instability in these tumors. In contrast, somatic POLD1 mutations are seen less frequently and typically occur in MMR-deficient tumors. Their functional significance is often unclear. Here we demonstrate that expression of the cancer-associated POLD1-R689W allele is strongly mutagenic in human cells. The mutation rate increased synergistically when the POLD1-R689W expression was combined with a MMR defect, indicating that the mutator effect of POLD1-R689W results from a high rate of replication errors. Purified human Polδ-R689W has normal exonuclease activity, but the nucleotide selectivity of the enzyme is severely impaired, providing a mechanistic explanation for the increased mutation rate in the POLD1-R689W-expressing cells. The vast majority of mutations induced by the POLD1-R689W are GC→︀TA transversions and GC→︀AT transitions, with transversions showing a strong strand bias and a remarkable preference for polypurine/polypyrimidine sequences. The mutational specificity of the Polδ variant matches that of the hypermutated CRC cell line, HCT15, in which this variant was first identified. The results provide compelling evidence for the pathogenic role of the POLD1-R689W mutation in the development of the human tumor and emphasize the need to experimentally determine the significance of Polδ variants present in sporadic tumors.
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Affiliation(s)
- T M Mertz
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - A G Baranovskiy
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - J Wang
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - T H Tahirov
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - P V Shcherbakova
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
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9
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Replicative DNA polymerase defects in human cancers: Consequences, mechanisms, and implications for therapy. DNA Repair (Amst) 2017; 56:16-25. [PMID: 28687338 DOI: 10.1016/j.dnarep.2017.06.003] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The fidelity of DNA replication relies on three error avoidance mechanisms acting in series: nucleotide selectivity of replicative DNA polymerases, exonucleolytic proofreading, and post-replicative DNA mismatch repair (MMR). MMR defects are well known to be associated with increased cancer incidence. Due to advances in DNA sequencing technologies, the past several years have witnessed a long-predicted discovery of replicative DNA polymerase defects in sporadic and hereditary human cancers. The polymerase mutations preferentially affect conserved amino acid residues in the exonuclease domain and occur in tumors with an extremely high mutation load. Thus, a concept has formed that defective proofreading of replication errors triggers the development of these tumors. Recent studies of the most common DNA polymerase variants, however, suggested that their pathogenicity may be determined by functional alterations other than loss of proofreading. In this review, we summarize our current understanding of the consequences of DNA polymerase mutations in cancers and the mechanisms of their mutator effects. We also discuss likely explanations for a high recurrence of some but not other polymerase variants and new ideas for therapeutic interventions emerging from the mechanistic studies.
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10
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Risks at the DNA Replication Fork: Effects upon Carcinogenesis and Tumor Heterogeneity. Genes (Basel) 2017; 8:genes8010046. [PMID: 28117753 PMCID: PMC5295039 DOI: 10.3390/genes8010046] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 01/09/2017] [Accepted: 01/17/2017] [Indexed: 12/27/2022] Open
Abstract
The ability of all organisms to copy their genetic information via DNA replication is a prerequisite for cell division and a biological imperative of life. In multicellular organisms, however, mutations arising from DNA replication errors in the germline and somatic cells are the basis of genetic diseases and cancer, respectively. Within human tumors, replication errors additionally contribute to mutator phenotypes and tumor heterogeneity, which are major confounding factors for cancer therapeutics. Successful DNA replication involves the coordination of many large-scale, complex cellular processes. In this review, we focus on the roles that defects in enzymes that normally act at the replication fork and dysregulation of enzymes that inappropriately damage single-stranded DNA at the fork play in causing mutations that contribute to carcinogenesis. We focus on tumor data and experimental evidence that error-prone variants of replicative polymerases promote carcinogenesis and on research indicating that the primary target mutated by APOBEC (apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like) cytidine deaminases is ssDNA present at the replication fork. Furthermore, we discuss evidence from model systems that indicate replication stress and other cancer-associated metabolic changes may modulate mutagenic enzymatic activities at the replication fork.
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11
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Katoh H, Ishikawa S. Genomic pathobiology of gastric carcinoma. Pathol Int 2016; 67:63-71. [DOI: 10.1111/pin.12493] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 11/24/2016] [Indexed: 12/26/2022]
Affiliation(s)
- Hiroto Katoh
- Department of Genomic Pathology; Medical Research Institute; Tokyo Medical and Dental University; Tokyo Japan
| | - Shumpei Ishikawa
- Department of Genomic Pathology; Medical Research Institute; Tokyo Medical and Dental University; Tokyo Japan
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12
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Suhaimi SS, Ab Mutalib NS, Jamal R. Understanding Molecular Landscape of Endometrial Cancer through Next Generation Sequencing: What We Have Learned so Far? Front Pharmacol 2016; 7:409. [PMID: 27847479 PMCID: PMC5088199 DOI: 10.3389/fphar.2016.00409] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 10/14/2016] [Indexed: 01/06/2023] Open
Abstract
Endometrial cancer (EC) is among the most common gynecological cancers affecting women worldwide. Despite the early detection and rather high overall survival rate, around 20% of the cases recur with poor prognosis. The Next Generation Sequencing (NGS) technology, also known as massively parallel sequencing, symbolizes a high-throughput, fast, sensitive and accurate way to study the molecular landscape of a cancer and this has indeed revolutionized endometrial cancer research. Understanding the potential, advantages, and limitations of NGS will be crucial for the healthcare providers and scientists in providing the genome-driven care in this era of precision medicine and pharmacogenomics. This mini review aimed to compile and critically summarize the recent findings contributed by NGS technology pertaining to EC. Importantly, we also discussed the potential of this technology for fundamental discovery research, individualized therapy, screening of at-risk individual and early diagnosis.
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Affiliation(s)
- Siti-Syazani Suhaimi
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia Cheras, Malaysia
| | | | - Rahman Jamal
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia Cheras, Malaysia
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13
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Abstract
Colorectal cancer (CRC) is a complex disease that develops as a consequence of both genetic and environmental risk factors. A small proportion (3-5%) of cases arise from hereditary syndromes predisposing to early onset CRC as a result of mutations in over a dozen well defined genes. In contrast, CRC is predominantly a late onset 'sporadic' disease, developing in individuals with no obvious hereditary syndrome. In recent years, genome wide association studies have discovered that over 40 genetic regions are associated with weak effects on sporadic CRC, and it has been estimated that increasingly large genome wide scans will identify many additional novel genetic regions. Subsequent experimental validations have identified the causally related variant(s) in a limited number of these genetic regions. Further biological insight could be obtained through ethnically diverse study populations, larger genetic sequencing studies and development of higher throughput functional experiments. Along with inherited variation, integration of the tumour genome may shed light on the carcinogenic processes in CRC. In addition to summarising the genetic architecture of CRC, this review discusses genetic factors that modify environmental predictors of CRC, as well as examples of how genetic insight has improved clinical surveillance, prevention and treatment strategies. In summary, substantial progress has been made in uncovering the genetic architecture of CRC, and continued research efforts are expected to identify additional genetic risk factors that further our biological understanding of this disease. Subsequently these new insights will lead to improved treatment and prevention of colorectal cancer.
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Affiliation(s)
- Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington School of Public Health, Seattle, WA, USA
| | - Stephanie Bien
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Niha Zubair
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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14
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Colon cancer-associated mutator DNA polymerase δ variant causes expansion of dNTP pools increasing its own infidelity. Proc Natl Acad Sci U S A 2015; 112:E2467-76. [PMID: 25827231 DOI: 10.1073/pnas.1422934112] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Defects in DNA polymerases δ (Polδ) and ε (Polε) cause hereditary colorectal cancer and have been implicated in the etiology of some sporadic colorectal and endometrial tumors. We previously reported that the yeast pol3-R696W allele mimicking a human cancer-associated variant, POLD1-R689W, causes a catastrophic increase in spontaneous mutagenesis. Here, we describe the mechanism of this extraordinary mutator effect. We found that the mutation rate increased synergistically when the R696W mutation was combined with defects in Polδ proofreading or mismatch repair, indicating that pathways correcting DNA replication errors are not compromised in pol3-R696W mutants. DNA synthesis by purified Polδ-R696W was error-prone, but not to the extent that could account for the unprecedented mutator phenotype of pol3-R696W strains. In a search for cellular factors that augment the mutagenic potential of Polδ-R696W, we discovered that pol3-R696W causes S-phase checkpoint-dependent elevation of dNTP pools. Abrogating this elevation by strategic mutations in dNTP metabolism genes eliminated the mutator effect of pol3-R696W, whereas restoration of high intracellular dNTP levels restored the mutator phenotype. Further, the use of dNTP concentrations present in pol3-R696W cells for in vitro DNA synthesis greatly decreased the fidelity of Polδ-R696W and produced a mutation spectrum strikingly similar to the spectrum observed in vivo. The results support a model in which (i) faulty synthesis by Polδ-R696W leads to a checkpoint-dependent increase in dNTP levels and (ii) this increase mediates the hypermutator effect of Polδ-R696W by facilitating the extension of mismatched primer termini it creates and by promoting further errors that continue to fuel the mutagenic pathway.
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15
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Stenzinger A, Pfarr N, Endris V, Penzel R, Jansen L, Wolf T, Herpel E, Warth A, Klauschen F, Kloor M, Roth W, Bläker H, Chang-Claude J, Brenner H, Hoffmeister M, Weichert W. Mutations in POLE and survival of colorectal cancer patients--link to disease stage and treatment. Cancer Med 2014; 3:1527-38. [PMID: 25124163 PMCID: PMC4298379 DOI: 10.1002/cam4.305] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Revised: 06/10/2014] [Accepted: 06/24/2014] [Indexed: 12/14/2022] Open
Abstract
Recent molecular profiling studies reported a new class of ultramutated colorectal cancers (CRCs), which are caused by exonuclease domain mutations (EDMs) in DNA polymerase ϵ (POLE). Data on the clinical implications of these findings as to whether these mutations define a unique CRC entity with distinct clinical outcome are lacking. We performed Sanger sequencing of the POLE exonuclease domain in 431 well-characterized patients with microsatellite stable (MSS) CRCs of a population-based patient cohort. Mutation data were analyzed for associations with major epidemiological, clinical, genetic, and pathological parameters including overall survival (OS) and disease-specific survival (DSS). In 373 of 431 MSS CRC, all exons of the exonuclease domain were analyzable. Fifty-four mutations were identified in 46 of these samples (12.3%). Besides already reported EDMs, we detected many new mutations in exons 13 and 14 (corresponding to amino acids 410-491) as well as in exon 9 and exon 11 (corresponding to aa 268-303 and aa 341-369). However, we did not see any significant associations of EDMs with clinicopathological parameters, including sex, age, tumor location and tumor stage, CIMP, KRAS, and BRAF mutations. While with a median follow-up time of 5.0 years, survival analysis of the whole cohort revealed nonsignificantly different adjusted hazard ratios (HRs) of 1.35 (95% CI: 0.82-2.25) and 1.44 (0.81-2.58) for OS and DSS indicating slightly impaired survival of patients with EDMs, subgroup analysis for patients with stage III/IV disease receiving chemotherapy revealed a statistically significantly increased adjusted HR (1.87; 95%CI: 1.02-3.44). In conclusion, POLE EDMs do not appear to define an entirely new clinically distinct disease entity in CRC but may have prognostic or predictive implications in CRC subgroups, whose significance remains to be investigated in future studies.
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Affiliation(s)
| | - Nicole Pfarr
- Institute of Pathology, Heidelberg University HospitalGermany
| | - Volker Endris
- Institute of Pathology, Heidelberg University HospitalGermany
| | - Roland Penzel
- Institute of Pathology, Heidelberg University HospitalGermany
| | - Lina Jansen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ)Heidelberg, Germany
| | - Thomas Wolf
- Institute of Pathology, Heidelberg University HospitalGermany
- German Consortium for Translational Cancer Research (DKTK)Germany
| | - Esther Herpel
- Institute of Pathology, Heidelberg University HospitalGermany
| | - Arne Warth
- Institute of Pathology, Heidelberg University HospitalGermany
| | | | - Matthias Kloor
- Department of Applied Tumor Biology, Institute of Pathology, University of HeidelbergHeidelberg, Germany
| | - Wilfried Roth
- Institute of Pathology, Heidelberg University HospitalGermany
| | - Hendrik Bläker
- Institute of Pathology, Charité University MedicineBerlin, Germany
| | - Jenny Chang-Claude
- Unit of Genetic Epidemiology, German Cancer Research Center (DKFZ)Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ)Heidelberg, Germany
- German Consortium for Translational Cancer Research (DKTK)Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ)Heidelberg, Germany
| | - Wilko Weichert
- Institute of Pathology, Heidelberg University HospitalGermany
- German Consortium for Translational Cancer Research (DKTK)Germany
- National Center for Tumor Diseases (NCT)Heidelberg, Germany
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16
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Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer. Eur J Hum Genet 2014; 23:1080-4. [PMID: 25370038 DOI: 10.1038/ejhg.2014.242] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 09/11/2014] [Accepted: 09/19/2014] [Indexed: 12/17/2022] Open
Abstract
Germline variants affecting the exonuclease domains of POLE and POLD1 predispose to multiple colorectal adenomas and/or colorectal cancer (CRC). The aim of this study was to estimate the prevalence of previously described heterozygous germline variants POLE c.1270C>G, p.(Leu424Val) and POLD1 c.1433G>A, p.(Ser478Asn) in a Dutch series of unexplained familial, early onset CRC and polyposis index cases. We examined 1188 familial CRC and polyposis index patients for POLE p.(Leu424Val) and POLD1 p.(Ser478Asn) variants using competitive allele-specific PCR. In addition, protein expression of the POLE and DNA mismatch repair genes was studied by immunohistochemistry in tumours from POLE carriers. Somatic mutations were screened using semiconductor sequencing. We detected three index patients (0.25%) with a POLE p.(Leu424Val) variant. In one patient, the variant was found to be de-novo. Tumours from three patients from two families were microsatellite instable, and immunohistochemistry showed MSH6/MSH2 deficiency suggestive of Lynch syndrome. Somatic mutations but no germline MSH6 and MSH2 variants were subsequently found, and one tumour displayed a hypermutator phenotype. None of the 1188 patients carried the POLD1 p.(Ser478Asn) variant. POLE germline variant carriers are also associated with a microsatellite instable CRC. POLE DNA analysis now seems warranted in microsatellite instable CRC, especially in the absence of a causative DNA mismatch repair gene germline variant.
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Kim ER, Kim YH. Clinical application of genetics in management of colorectal cancer. Intest Res 2014; 12:184-93. [PMID: 25349592 PMCID: PMC4204714 DOI: 10.5217/ir.2014.12.3.184] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 06/27/2014] [Accepted: 06/29/2014] [Indexed: 12/22/2022] Open
Abstract
The extensive study of genetic alterations in colorectal cancer (CRC) has led to molecular diagnostics playing an increasingly important role in CRC diagnosis and treatment. Currently, it is believed that CRC is a consequence of the accumulation of both genetic and epigenetic genomic alterations. It is known that there are at least 3 major pathways that lead to colorectal carcinogenesis: (1) the chromosomal instability pathway, (2) the microsatellite instability pathway, and (3) the cytosine-phospho-guanine island methylator phenotype pathway. With recent advances in CRC genetics, the identification of specific molecular alterations responsible for CRC pathogenesis has directly influences clinical care. Patients at high risk for developing CRC can be identified by genetic testing for specific molecular alterations, and the use of molecular biomarkers for predictive and prognostic purposes is also increasing. This is clearly supported by the recent advances in genetic testing for CRC whereby specific molecular alterations are identified for the purpose of guiding treatment with targeting therapies such as anti-endothelial growth factor receptor monoclonal antibodies.
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Affiliation(s)
- Eun Ran Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young-Ho Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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18
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Ling L, Zhao P, Yan G, Chen M, Zhang T, Wang L, Jiang Y. The frequency of Th17 and Th22 cells in patients with colorectal cancer at pre-operation and post-operation. Immunol Invest 2014; 44:56-69. [PMID: 25026244 DOI: 10.3109/08820139.2014.936445] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
T helper 17 (Th17) and Th22 cells regulate the development of tumors. However, their roles in the development of colorectal cancer (CRC) are still unclear. A total of 49 patients with CRC and 18 healthy controls (HC) were evaluated for the percentages of circulating Th17 and Th22 cells by flow cytometry. The concentrations of serum interleukin-17A (IL-17A), IL-22 and carcinoembryonic antigen (CEA) were examined. The levels of IL-17A and IL-22 in tumors were determined by real-time PCR. We found that the percentages of Th17 and Th22 cells in the CRC patients were significantly lower than that in the HC and were associated negatively with the pathological stages of CRC. The levels of IL-17A and IL-22 mRNA transcripts were lower in the tumor tissues, particularly in the advanced CRC. After the tumor resection, the percentages of circulating Th17 and Th22 cells increased. These data suggest that decreased Th17 and Th22 responses may be associated with the development of CRC.
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Affiliation(s)
- Limian Ling
- Department of Colorectal & Anal Surgery, the First Hospital, Jilin University , Changchun , China and
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19
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Esteban-Jurado C, Garre P, Vila M, Lozano JJ, Pristoupilova A, Beltrán S, Abulí A, Muñoz J, Balaguer F, Ocaña T, Castells A, Piqué JM, Carracedo A, Ruiz-Ponte C, Bessa X, Andreu M, Bujanda L, Caldés T, Castellví-Bel S. New genes emerging for colorectal cancer predisposition. World J Gastroenterol 2014; 20:1961-1971. [PMID: 24587672 PMCID: PMC3934466 DOI: 10.3748/wjg.v20.i8.1961] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 12/20/2013] [Accepted: 01/15/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most frequent neoplasms and an important cause of mortality in the developed world. This cancer is caused by both genetic and environmental factors although 35% of the variation in CRC susceptibility involves inherited genetic differences. Mendelian syndromes account for about 5% of the total burden of CRC, with Lynch syndrome and familial adenomatous polyposis the most common forms. Excluding hereditary forms, there is an important fraction of CRC cases that present familial aggregation for the disease with an unknown germline genetic cause. CRC can be also considered as a complex disease taking into account the common disease-commom variant hypothesis with a polygenic model of inheritance where the genetic components of common complex diseases correspond mostly to variants of low/moderate effect. So far, 30 common, low-penetrance susceptibility variants have been identified for CRC. Recently, new sequencing technologies including exome- and whole-genome sequencing have permitted to add a new approach to facilitate the identification of new genes responsible for human disease predisposition. By using whole-genome sequencing, germline mutations in the POLE and POLD1 genes have been found to be responsible for a new form of CRC genetic predisposition called polymerase proofreading-associated polyposis.
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20
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Heitzer E, Tomlinson I. Replicative DNA polymerase mutations in cancer. Curr Opin Genet Dev 2014; 24:107-13. [PMID: 24583393 PMCID: PMC4003352 DOI: 10.1016/j.gde.2013.12.005] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 12/20/2013] [Indexed: 12/18/2022]
Abstract
Three DNA polymerases - Pol α, Pol δ and Pol ɛ - are essential for DNA replication. After initiation of DNA synthesis by Pol α, Pol δ or Pol ɛ take over on the lagging and leading strand respectively. Pol δ and Pol ɛ perform the bulk of replication with very high fidelity, which is ensured by Watson-Crick base pairing and 3'exonuclease (proofreading) activity. Yeast models have shown that mutations in the exonuclease domain of Pol δ and Pol ɛ homologues can cause a mutator phenotype. Recently, we identified germline exonuclease domain mutations (EDMs) in human POLD1 and POLE that predispose to 'polymerase proofreading associated polyposis' (PPAP), a disease characterised by multiple colorectal adenomas and carcinoma, with high penetrance and dominant inheritance. Moreover, somatic EDMs in POLE have also been found in sporadic colorectal and endometrial cancers. Tumors with EDMs are microsatellite stable and show an 'ultramutator' phenotype, with a dramatic increase in base substitutions.
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Affiliation(s)
- Ellen Heitzer
- Institute of Human Genetics, Medical University of Graz, Harrachgasse 21/8, A-8010 Graz, Austria.
| | - Ian Tomlinson
- Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK; Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.
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21
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García-Barros M, Coant N, Truman JP, Snider AJ, Hannun YA. Sphingolipids in colon cancer. Biochim Biophys Acta Mol Cell Biol Lipids 2013; 1841:773-82. [PMID: 24060581 DOI: 10.1016/j.bbalip.2013.09.007] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Revised: 09/12/2013] [Accepted: 09/16/2013] [Indexed: 01/28/2023]
Abstract
Colorectal cancer is one of the major causes of death in the western world. Despite increasing knowledge of the molecular signaling pathways implicated in colon cancer, therapeutic outcomes are still only moderately successful. Sphingolipids, a family of N-acyl linked lipids, have not only structural functions but are also implicated in important biological functions. Ceramide, sphingosine and sphingosine-1-phosphate are the most important bioactive lipids, and they regulate several key cellular functions. Accumulating evidence suggests that many cancers present alterations in sphingolipids and their metabolizing enzymes. The aim of this review is to discuss the emerging roles of sphingolipids, both endogenous and dietary, in colon cancer and the interaction of sphingolipids with WNT/β-catenin pathway, one of the most important signaling cascades that regulate development and homeostasis in intestine. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.
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Affiliation(s)
- Mónica García-Barros
- Department of Medicine and the Stony Brook Cancer Center, Health Science Center, Stony Brook University, 101 Nicolls Road, T15, 023, 11794, Stony Brook, NY, USA.
| | - Nicolas Coant
- Department of Medicine and the Stony Brook Cancer Center, Health Science Center, Stony Brook University, 101 Nicolls Road, T15, 023, 11794, Stony Brook, NY, USA.
| | - Jean-Philip Truman
- Department of Medicine and the Stony Brook Cancer Center, Health Science Center, Stony Brook University, 101 Nicolls Road, T15, 023, 11794, Stony Brook, NY, USA.
| | - Ashley J Snider
- VAMC Northport, 79 Middleville Road, Northport, NY, USA, Health Science Center, Stony Brook University, Stony Brook, NY, USA.
| | - Yusuf A Hannun
- Department of Medicine and the Stony Brook Cancer Center, Health Science Center, Stony Brook University, 101 Nicolls Road, T15, 023, 11794, Stony Brook, NY, USA.
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