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Sheth H, Sadhwani J, Jain A, Thenral SG, Ramprasad V, Bishop DT. Haplotype analysis detects MLH1 founder variant in Indian Lynch syndrome patient cohort. Fam Cancer 2024; 24:13. [PMID: 39702679 DOI: 10.1007/s10689-024-00436-6] [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: 10/11/2024] [Accepted: 12/09/2024] [Indexed: 12/21/2024]
Abstract
Lynch syndrome (LS) is an autosomal dominant hereditary cancer predisposition syndrome whereby the lifetime risk of developing gastrointestinal and genitourinary cancers rises by to over 50%. It is caused by heterozygous variants in the DNA mismatch repair genes- MLH1, MSH2, MSH6 and PMS2, with the majority detected in MLH1 and MSH2. Recurrently observed LS-associated variants in apparently unrelated individuals have either arisen de novo in different families due to mutation hotspots or are inherited from a common ancestor (founder) that lived several generations back. Testing for founder variants can facilitate molecular diagnosis of LS more efficiently and cost effectively than screening for all possible variants in the MMR genes. Here, we report a study of the missense variant c.306G > T in the MLH1 gene, the first potential founder variant identified in LS patients of Indian ethnicity. Haplotype analysis consisting of 25 LS carriers with the MLH1 c.306G > T variant and 100 healthy controls confirmed a shared haplotype in cases spanning a 27.8 kb region encompassing the c.306G > T variant (𝝌2 = 96.418; p = < 0.0001). Age of variant analysis suggests the variant to have arisen in the population approximately 800 years (95% CI: 670-934 years) ago. Furthermore, it is estimated that c.306G > T variant is likely to be observed in 6.4% of all LS patients of Indian ethnicity. These findings have important implications for genetic counselling and molecular diagnosis of Lynch syndrome.
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Affiliation(s)
- Harsh Sheth
- FRIGE Institute of Human Genetics, Ahmedabad, India.
| | | | | | | | | | - D Timothy Bishop
- Leeds Institute of Medical Research, University of Leeds, Leeds, UK
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Sipilä LJ, Aavikko M, Ravantti J, Martin S, Kuopio T, Lahtinen L, FinnGen, Peltomäki P, Mecklin JP, Aaltonen LA, Seppälä TT. Detection of a major Lynch Syndrome-causing MLH1 founder variant in a large-scale genotyped cohort. Fam Cancer 2024; 23:647-652. [PMID: 38847920 PMCID: PMC11512911 DOI: 10.1007/s10689-024-00400-4] [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: 01/19/2024] [Accepted: 05/12/2024] [Indexed: 10/27/2024]
Abstract
Some 50% of Finnish Lynch Syndrome (LS) cases are caused by a founder variant in MLH1, in which the entire exon 16 has been lost due to an Alu-mediated recombination event. We piloted detecting the variant in FinnGen, a large genotyped cohort comprising approximately 10% of the current Finnish population, and validated the MLH1 founder variant status of identified individuals residing in the Central Finland Biobank catchment area. A consensus sequence flanking the deletion was identified in whole genome sequences of six LS individuals with the founder variant. Genotype data of 212,196 individuals was queried for regional matches to the consensus sequence. Enrichment of cancer and age at cancer onset was compared between matching and non-matching individuals. Variant status was validated for a subset of the identified individuals using a polymerase chain reaction assay. Allelic matches in a chosen target region was detected in 348 individuals, with 89 having a cancer diagnosis (Bonferroni-adjusted p-value = 1), 20 a familial cancer history (p-adj. < .001), with mean age of onset of cancer being 53.6 years (p-adj. = .002). Eighteen of potential variant carriers had been sampled by the Central Finland Biobank, of which four (22%) were validated as true variant carriers. The workflow we have employed identifies MLH1 exon 16 deletion variant carriers from population-wide SNP genotyping data. An alternative design will be sought to limit false positive findings. Large genotyped cohorts provide a potential resource for identification and prevention of hereditary cancer.
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Affiliation(s)
- Lauri J Sipilä
- Department of Medical and Clinical Genetics, University of Helsinki, Biomedicum Helsinki Haartmaninkatu 8), PO Box 63, 00014, Helsinki, Finland
- Applied Tumor Genomics, Research Programs Unit, University of Helsinki, Biomedicum Helsinki Haartmaninkatu 8), PO Box 63, 00014, Helsinki, Finland
- Finnish Cancer Registry, Unioninkatu 22, 00130, Helsinki, Finland
| | - Mervi Aavikko
- Department of Medical and Clinical Genetics, University of Helsinki, Biomedicum Helsinki Haartmaninkatu 8), PO Box 63, 00014, Helsinki, Finland
- Applied Tumor Genomics, Research Programs Unit, University of Helsinki, Biomedicum Helsinki Haartmaninkatu 8), PO Box 63, 00014, Helsinki, Finland
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
| | - Janne Ravantti
- Department of Medical and Clinical Genetics, University of Helsinki, Biomedicum Helsinki Haartmaninkatu 8), PO Box 63, 00014, Helsinki, Finland
- Applied Tumor Genomics, Research Programs Unit, University of Helsinki, Biomedicum Helsinki Haartmaninkatu 8), PO Box 63, 00014, Helsinki, Finland
- Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, FI-00014, Helsinki, Finland
| | - Samantha Martin
- Department of Medical and Clinical Genetics, University of Helsinki, Biomedicum Helsinki Haartmaninkatu 8), PO Box 63, 00014, Helsinki, Finland
- Applied Tumor Genomics, Research Programs Unit, University of Helsinki, Biomedicum Helsinki Haartmaninkatu 8), PO Box 63, 00014, Helsinki, Finland
| | - Teijo Kuopio
- Central Finland Biobank, Wellbeing Services County of Central Finland and University of Jyväskylä, Jyväskylä, Finland
| | - Laura Lahtinen
- Department of Pathology, Wellbeing Services County of Central Finland, Jyväskylä, Finland
| | - FinnGen
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
| | - Päivi Peltomäki
- Department of Medical and Clinical Genetics, University of Helsinki, Biomedicum Helsinki Haartmaninkatu 8), PO Box 63, 00014, Helsinki, Finland
- HUSLAB Laboratory of Genetics, HUS Diagnostic Center, HUS, Helsinki University Hospital, 00029, Helsinki, Finland
| | - Jukka-Pekka Mecklin
- Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
- Department of Surgery, Nova Hospital, Jyväskylä, Finland
| | - Lauri A Aaltonen
- Department of Medical and Clinical Genetics, University of Helsinki, Biomedicum Helsinki Haartmaninkatu 8), PO Box 63, 00014, Helsinki, Finland
- Applied Tumor Genomics, Research Programs Unit, University of Helsinki, Biomedicum Helsinki Haartmaninkatu 8), PO Box 63, 00014, Helsinki, Finland
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00290, Helsinki, Finland
| | - Toni T Seppälä
- Applied Tumor Genomics, Research Programs Unit, University of Helsinki, Biomedicum Helsinki Haartmaninkatu 8), PO Box 63, 00014, Helsinki, Finland.
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, 00290, Helsinki, Finland.
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
- Tays Cancer Centre, Tampere University Hospital, Tampere, Finland.
- Department of Gastrointestinal Surgery, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland.
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Strong Hereditary Predispositions to Colorectal Cancer. Genes (Basel) 2022; 13:genes13122326. [PMID: 36553592 PMCID: PMC9777620 DOI: 10.3390/genes13122326] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 12/01/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022] Open
Abstract
Cancer is one of the most common causes of death worldwide. A strong predisposition to cancer is generally only observed in colorectal cancer (5% of cases) and breast cancer (2% of cases). Colorectal cancer is the most common cancer with a strong genetic predisposition, but it includes dozens of various syndromes. This group includes familial adenomatous polyposis, attenuated familial adenomatous polyposis, MUTYH-associated polyposis, NTHL1-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, Lynch syndrome, and Muir-Torre syndrome. The common symptom of all these diseases is a very high risk of colorectal cancer, but depending on the condition, their course is different in terms of age and range of cancer occurrence. The rate of cancer development is determined by its conditioning genes, too. Hereditary predispositions to cancer of the intestine are a group of symptoms of heterogeneous diseases, and their proper diagnosis is crucial for the appropriate management of patients and their successful treatment. Mutations of specific genes cause strong colorectal cancer predispositions. Identifying mutations of predisposing genes will support proper diagnosis and application of appropriate screening programs to avoid malignant neoplasm.
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Pasanen A, Loukovaara M, Kaikkonen E, Olkinuora A, Pylvänäinen K, Alhopuro P, Peltomäki P, Mecklin JP, Bützow R. Testing for Lynch Syndrome in Endometrial Carcinoma: From Universal to Age-Selective MLH1 Methylation Analysis. Cancers (Basel) 2022; 14:cancers14051348. [PMID: 35267656 PMCID: PMC8909331 DOI: 10.3390/cancers14051348] [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: 12/28/2021] [Revised: 02/21/2022] [Accepted: 03/04/2022] [Indexed: 12/13/2022] Open
Abstract
International guidelines recommend universal screening of endometrial carcinoma (EC) patients for Lynch syndrome (LS). This screening is generally based on mismatch repair (MMR) protein immunohistochemistry followed by MLH1 methylation analysis of MLH1-negative cases to exclude the likely sporadic cases from germline testing. As LS-associated EC is uncommon in the elderly, age-selective methylation testing could improve cost-efficiency. We performed MMR immunohistochemistry on 821 unselected ECs (clinic-based cohort) followed by a MLH1 promoter methylation test of all MLH1/PMS2-negative tumors. Non-methylated MLH1-deficient cases underwent NGS and MLPA-based germline analyses to identify MLH1 mutation carriers. A reduction in the test burden and corresponding false negative rates for LS screening were investigated for various age cut-offs. In addition, the age distribution of 132 MLH1 mutation carriers diagnosed with EC (registry-based cohort) was examined. A germline MLH1 mutation was found in 2/14 patients with non-methylated MLH1-deficient EC. When compared to a universal methylation analysis, selective testing with a cut-off age of 65 years, would have reduced the testing effort by 70.7% with a false negative rate for LS detection of 0% and 3% in the clinic and registry-based cohorts, respectively. The use of age-selective methylation analysis is a feasible way of reducing the costs and laboratory burden in LS screening for EC patients.
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Affiliation(s)
- Annukka Pasanen
- Department of Pathology, Helsinki University Hospital, University of Helsinki, 00290 Helsinki, Finland;
- Correspondence:
| | - Mikko Loukovaara
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, 00290 Helsinki, Finland;
| | - Elina Kaikkonen
- Laboratory of Genetics, HUS Diagnostic Center, Helsinki University Hospital, University of Helsinki, 00209 Helsinki, Finland; (E.K.); (P.A.)
| | - Alisa Olkinuora
- Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland; (A.O.); (P.P.)
| | - Kirsi Pylvänäinen
- Department of Education and Science, Central Finland Health Care District, 40620 Jyväskylä, Finland;
| | - Pia Alhopuro
- Laboratory of Genetics, HUS Diagnostic Center, Helsinki University Hospital, University of Helsinki, 00209 Helsinki, Finland; (E.K.); (P.A.)
| | - Päivi Peltomäki
- Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland; (A.O.); (P.P.)
| | - Jukka-Pekka Mecklin
- Department of Surgery, Central Finland Health Care District; 40620 Jyväskylä, Finland;
- Department of Sport and Health Sciences, Jyväskylä University, 40014 Jyväskylä, Finland
| | - Ralf Bützow
- Department of Pathology, Helsinki University Hospital, University of Helsinki, 00290 Helsinki, Finland;
- Applied Tumor Genomics Research Program, University of Helsinki, 00290 Helsinki, Finland
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Sievänen T, Törmäkangas T, Laakkonen EK, Mecklin JP, Pylvänäinen K, Seppälä TT, Peltomäki P, Sipilä S, Sillanpää E. Body Weight, Physical Activity, and Risk of Cancer in Lynch Syndrome. Cancers (Basel) 2021; 13:1849. [PMID: 33924417 PMCID: PMC8069994 DOI: 10.3390/cancers13081849] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/02/2021] [Accepted: 04/07/2021] [Indexed: 12/24/2022] Open
Abstract
Lynch syndrome (LS) increases cancer risk. There is considerable individual variation in LS cancer occurrence, which may be moderated by lifestyle factors, such as body weight and physical activity (PA). The potential associations of lifestyle and cancer risk in LS are understudied. We conducted a retrospective study with cancer register data to investigate associations between body weight, PA, and cancer risk among Finnish LS carriers. The participants (n = 465, 54% women) self-reported their adulthood body weight and PA at 10-year intervals. Overall cancer risk and colorectal cancer (CRC) risk was analyzed separately for men and women with respect to longitudinal and near-term changes in body weight and PA using extended Cox regression models. The longitudinal weight change was associated with an increased risk of all cancers (HR 1.02, 95% CI 1.00-1.04) and CRC (HR 1.03, 1.01-1.05) in men. The near-term weight change was associated with a lower CRC risk in women (HR 0.96, 0.92-0.99). Furthermore, 77.6% of the participants retained their PA category over time. Men in the high-activity group had a reduced longitudinal cancer risk of 63% (HR 0.37, 0.15-0.98) compared to men in the low-activity group. PA in adulthood was not associated with cancer risk among women. These results emphasize the role of weight maintenance and high-intensity PA throughout the lifespan in cancer prevention, particularly in men with LS.
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Affiliation(s)
- Tero Sievänen
- Gerontology Research Centre and Faculty of Sport and Health Sciences, University of Jyväskylä, P.O. Box 35 (VIV), 40014 Jyväskylä, Finland; (T.T.); (E.K.L.); (S.S.); (E.S.)
| | - Timo Törmäkangas
- Gerontology Research Centre and Faculty of Sport and Health Sciences, University of Jyväskylä, P.O. Box 35 (VIV), 40014 Jyväskylä, Finland; (T.T.); (E.K.L.); (S.S.); (E.S.)
| | - Eija K. Laakkonen
- Gerontology Research Centre and Faculty of Sport and Health Sciences, University of Jyväskylä, P.O. Box 35 (VIV), 40014 Jyväskylä, Finland; (T.T.); (E.K.L.); (S.S.); (E.S.)
| | - Jukka-Pekka Mecklin
- Department of Surgery, Central Finland Health Care District, 40620 Jyväskylä, Finland;
- Faculty of Sport and Health Sciences, University of Jyväskylä, 40014 Jyväskylä, Finland
| | - Kirsi Pylvänäinen
- Department of Education, Central Finland Health Care District, 40620 Jyväskylä, Finland;
| | - Toni T. Seppälä
- Department of Surgical Oncology, Johns Hopkins University, Baltimore, MD 21218, USA;
- Department of Surgery, Helsinki University Hospital, University of Helsinki, 00100 Helsinki, Finland
| | - Päivi Peltomäki
- Department of Medical and Clinical Genetics, University of Helsinki, 00100 Helsinki, Finland;
| | - Sarianna Sipilä
- Gerontology Research Centre and Faculty of Sport and Health Sciences, University of Jyväskylä, P.O. Box 35 (VIV), 40014 Jyväskylä, Finland; (T.T.); (E.K.L.); (S.S.); (E.S.)
| | - Elina Sillanpää
- Gerontology Research Centre and Faculty of Sport and Health Sciences, University of Jyväskylä, P.O. Box 35 (VIV), 40014 Jyväskylä, Finland; (T.T.); (E.K.L.); (S.S.); (E.S.)
- Institute for Molecular Medicine Finland, University of Helsinki, 00100 Helsinki, Finland
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Li A, Wang WC, McAlister V, Zhou Q, Zheng X. Circular RNA in colorectal cancer. J Cell Mol Med 2021; 25:3667-3679. [PMID: 33687140 PMCID: PMC8051750 DOI: 10.1111/jcmm.16380] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 02/01/2021] [Accepted: 02/04/2021] [Indexed: 12/24/2022] Open
Abstract
Circular RNA (circRNA) is a highly abundant type of single-stranded non-coding RNA. Novel research has discovered many roles of circRNA in colorectal cancer (CRC) including proliferation, metastasis and apoptosis. Furthermore, circRNAs also play a role in the development of drug resistance and have unique associations with tumour size, staging and overall survival in CRC that lend circRNAs the potential to serve as diagnostic and prognostic biomarkers. Among cancers worldwide, CRC ranks second in mortality and third in incidence. In order to have a better understanding of the influence of circRNA on CRC development and progression, this review summarizes the role of specific circRNAs in CRC and evaluates their potential value as therapeutic targets and biomarkers for CRC. We aim to provide insight in the development of therapy and clinical decision-making.
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Affiliation(s)
- Anthony Li
- Department of Pathology and Laboratory MedicineWestern UniversityLondonCanada
- School of MedicineQueen’s UniversityKingstonCanada
| | - Wei Cen Wang
- Department of Microbiology & ImmunologyWestern UniversityLondonCanada
| | - Vivian McAlister
- Department of SurgeryWestern UniversityLondonCanada
- London Health Sciences CentreLondonCanada
| | - Qinfeng Zhou
- Department of Pathology and Laboratory MedicineWestern UniversityLondonCanada
- Department of Laboratory MedicineZhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese MedicineSuzhouChina
| | - Xiufen Zheng
- Department of Pathology and Laboratory MedicineWestern UniversityLondonCanada
- Department of SurgeryWestern UniversityLondonCanada
- Department of OncologyWestern UniversityLondonCanada
- Lawson Health Research InstituteLondonCanada
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Ahadova A, Seppälä TT, Engel C, Gallon R, Burn J, Holinski-Feder E, Steinke-Lange V, Möslein G, Nielsen M, Ten Broeke SW, Laghi L, Dominguez-Valentin M, Capella G, Macrae F, Scott R, Hüneburg R, Nattermann J, Hoffmeister M, Brenner H, Bläker H, von Knebel Doeberitz M, Sampson JR, Vasen H, Mecklin JP, Møller P, Kloor M. The "unnatural" history of colorectal cancer in Lynch syndrome: Lessons from colonoscopy surveillance. Int J Cancer 2021; 148:800-811. [PMID: 32683684 DOI: 10.1002/ijc.33224] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 06/12/2020] [Accepted: 06/24/2020] [Indexed: 12/14/2022]
Abstract
Individuals with Lynch syndrome (LS), one of the most common inherited cancer syndromes, are at increased risk of developing malignancies, in particular colorectal cancer (CRC). Regular colonoscopy with polypectomy is recommended to reduce CRC risk in LS individuals. However, recent independent studies demonstrated that a substantial proportion of LS individuals develop CRC despite regular colonoscopy. The reasons for this surprising observation confirmed by large prospective studies are a matter of debate. In this review, we collect existing evidence from clinical, epidemiological and molecular studies and interpret them with regard to the origins and progression of LS-associated CRC. Alongside with hypotheses addressing colonoscopy quality and pace of progression from adenoma to cancer, we discuss the role of alternative precursors and immune system in LS-associated CRC. We also identify gaps in current knowledge and make suggestions for future studies aiming at improved CRC prevention for LS individuals.
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Affiliation(s)
- Aysel Ahadova
- Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
- Cooperation Unit Applied Tumour Biology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Toni T Seppälä
- Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
- Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Surgical Oncology, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Christoph Engel
- Department of Statistics and Epidemiology, Institute for Medical Informatics, University of Leipzig, Leipzig, Germany
| | - Richard Gallon
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, UK
| | - John Burn
- International Centre for Life, Central Parkway, Newcastle upon, Tyne, UK
| | - Elke Holinski-Feder
- Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany
- Centre of Medical Genetics, Munich, Germany
| | - Verena Steinke-Lange
- Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany
- Centre of Medical Genetics, Munich, Germany
| | - Gabriela Möslein
- Centre for Hereditary Tumors, HELIOS Klinikum Wuppertal, University Witten-Herdecke, Wuppertal, Germany
| | - Maartje Nielsen
- Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands
| | - Sanne W Ten Broeke
- Department of Clinical Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
| | - Luigi Laghi
- Molecular Gastroenterology and Department of Gastroenterology, Humanitas Clinical and Research Center, Milan, Italy
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Mev Dominguez-Valentin
- Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Gabriel Capella
- Hereditary Cancer Program, Institut Catala d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Finlay Macrae
- Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Australia
| | - Rodney Scott
- University of Newcastle and the Hunter Medical Research Institute, Callaghan, Australia
| | - Robert Hüneburg
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
- National Centre for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
- National Centre for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hermann Brenner
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hendrik Bläker
- Institute of Pathology, University Hospital Leipzig, Leipzig, Germany
| | - Magnus von Knebel Doeberitz
- Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Julian R Sampson
- Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK
| | - Hans Vasen
- Department of Gastroenterology & Hepatology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Jukka-Pekka Mecklin
- Department of Surgery, Central Finland Central Hospital, Jyväskylä, Finland
- Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - Pål Møller
- Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Matthias Kloor
- Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
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Gallon R, Gawthorpe P, Phelps RL, Hayes C, Borthwick GM, Santibanez-Koref M, Jackson MS, Burn J. How Should We Test for Lynch Syndrome? A Review of Current Guidelines and Future Strategies. Cancers (Basel) 2021; 13:406. [PMID: 33499123 PMCID: PMC7865939 DOI: 10.3390/cancers13030406] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/18/2021] [Accepted: 01/20/2021] [Indexed: 12/13/2022] Open
Abstract
International guidelines for the diagnosis of Lynch syndrome (LS) recommend molecular screening of colorectal cancers (CRCs) to identify patients for germline mismatch repair (MMR) gene testing. As our understanding of the LS phenotype and diagnostic technologies have advanced, there is a need to review these guidelines and new screening opportunities. We discuss the barriers to implementation of current guidelines, as well as guideline limitations, and highlight new technologies and knowledge that may address these. We also discuss alternative screening strategies to increase the rate of LS diagnoses. In particular, the focus of current guidance on CRCs means that approximately half of Lynch-spectrum tumours occurring in unknown male LS carriers, and only one-third in female LS carriers, will trigger testing for LS. There is increasing pressure to expand guidelines to include molecular screening of endometrial cancers, the most frequent cancer in female LS carriers. Furthermore, we collate the evidence to support MMR deficiency testing of other Lynch-spectrum tumours to screen for LS. However, a reliance on tumour tissue limits preoperative testing and, therefore, diagnosis prior to malignancy. The recent successes of functional assays to detect microsatellite instability or MMR deficiency in non-neoplastic tissues suggest that future diagnostic pipelines could become independent of tumour tissue.
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Affiliation(s)
| | | | | | | | | | | | | | - John Burn
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK; (P.G.); (R.L.P.); (C.H.); (G.M.B.); (M.S.-K.); (M.S.J.)
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9
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Porkka NK, Olkinuora A, Kuopio T, Ahtiainen M, Eldfors S, Almusa H, Mecklin JP, Peltomäki P. Does breast carcinoma belong to the Lynch syndrome tumor spectrum? - Somatic mutational profiles vs. ovarian and colorectal carcinomas. Oncotarget 2020; 11:1244-1256. [PMID: 32292574 PMCID: PMC7147090 DOI: 10.18632/oncotarget.27538] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 03/14/2020] [Indexed: 12/30/2022] Open
Abstract
Inherited DNA mismatch repair (MMR) defects cause predisposition to colorectal, endometrial, ovarian, and other cancers occurring in Lynch syndrome (LS). It is unsettled whether breast carcinoma belongs to the LS tumor spectrum. We approached this question through somatic mutational analysis of breast carcinomas from LS families, using established LS-spectrum tumors for comparison. Somatic mutational profiles of 578 cancer-relevant genes were determined for LS-breast cancer (LS-BC, n = 20), non-carrier breast cancer (NC-BC, n = 10), LS-ovarian cancer (LS-OC, n = 16), and LS-colorectal cancer (LS-CRC, n = 18) from the National LS Registry of Finland. Microsatellite and MMR protein analysis stratified LS-BCs into MMR-deficient (dMMR, n = 11) and MMR-proficient (pMMR, n = 9) subgroups. All NC-BCs were pMMR and all LS-OCs and LS-CRCs dMMR. All but one dMMR LS-BCs were hypermutated (> 10 non-synonymous mutations/Mb; average 174/Mb per tumor) and the frequency of MMR-deficiency-associated signatures 6, 20, and 26 was comparable to that in LS-OC and LS-CRC. LS-BCs that were pMMR resembled NC-BCs with respect to somatic mutational loads (4/9, 44%, hypermutated with average mutation count 33/Mb vs. 3/10, 30%, hypermutated with average 88 mutations/Mb), whereas mutational signatures shared features of dMMR LS-BC, LS-OC, and LS-CRC. Epigenetic regulatory genes were significantly enriched as mutational targets in LS-BC, LS-OC, and LS-CRC. Many top mutant genes of our LS-BCs have previously been identified as drivers of unselected breast carcinomas. In conclusion, somatic mutational signatures suggest that conventional MMR status of tumor tissues is likely to underestimate the significance of the predisposing MMR defects as contributors to breast tumorigenesis in LS.
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Affiliation(s)
- Noora K. Porkka
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
| | - Alisa Olkinuora
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
| | - Teijo Kuopio
- Department of Pathology, Jyväskylä Central Hospital, Jyväskylä, Finland
- Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland
| | - Maarit Ahtiainen
- Department of Education and Research, Jyväskylä Central Hospital and University of Eastern Finland, Jyväskylä, Finland
| | - Samuli Eldfors
- Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
| | - Henrikki Almusa
- Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
| | - Jukka-Pekka Mecklin
- Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
- Department of Surgery, Jyväskylä Central Hospital, Jyväskylä, Finland
- Department of Education & Science, Jyväskylä Central Hospital, Jyväskylä, Finland
| | - Päivi Peltomäki
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
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10
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Factors associated with decision-making on prophylactic hysterectomy and attitudes towards gynecological surveillance among women with Lynch syndrome (LS): a descriptive study. Fam Cancer 2020; 19:177-182. [PMID: 31997047 PMCID: PMC7101284 DOI: 10.1007/s10689-020-00158-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 01/13/2020] [Indexed: 12/26/2022]
Abstract
To prevent endometrial carcinoma in Lynch syndrome (LS), regular gynecological surveillance visits and prophylactic surgery are recommended. Previous data have shown that prophylactic hysterectomy is an effective means of cancer prevention, while the advantages and disadvantages of surveillance are somewhat unclear. We aimed to evaluate female LS carriers’ attitudes towards regular gynecological surveillance and factors influencing their decision-making on prophylactic surgery that have not been well documented. Pain experienced during endometrial biopsies was also evaluated. Postal questionnaires were sent to LS carriers undergoing regular gynecological surveillance. Questionnaires were sent to 112 women with LS, of whom 76 responded (68%). Forty-two (55%) had undergone prophylactic hysterectomy by the time of the study. The majority of responders (64/76; 84.2%) considered surveillance appointments beneficial. Pain level during endometrial biopsy was not associated with the decision to undergo prophylactic surgery. The level of satisfaction the women had with the information and advice provided during surveillance was significantly associated with the history of prophylactic hysterectomy (satisfaction rate of 73.2% versus 31.8% of nonoperated women, p = 0.003). The women who had undergone prophylactic surgery were older than the nonoperated women both at mutation testing (median of 42.3 years versus 31.6 years, p < 0.001) and at the time of the study (median of 56.9 years versus 46.0 years, respectively, p < 0.001). Women with LS pathogenic variants have positive experiences with gynecological surveillance visits, and their perception of the quality of the information and advice obtained plays an important role in their decision-making concerning prophylactic surgery.
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11
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Yanus GA, Akhapkina TA, Iyevleva AG, Kornilov AV, Suspitsin EN, Kuligina ES, Ivantsov AO, Aleksakhina SN, Sokolova TN, Sokolenko AP, Togo AV, Imyanitov EN. The spectrum of Lynch syndrome-associated germ-line mutations in Russia. Eur J Med Genet 2019; 63:103753. [PMID: 31491536 DOI: 10.1016/j.ejmg.2019.103753] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 08/15/2019] [Accepted: 08/31/2019] [Indexed: 01/21/2023]
Abstract
Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome (LS), is a common cancer-predisposing syndrome. This study aimed to investigate the spectrum of germ-line mutations in Russian LS patients. LS-related mismatch repair (MMR) genes were analyzed in 16 patients, who were forwarded to genetic testing due to strong clinical features of LS and had high-level microsatellite instability (MSI-H) in the tumor (n = 14) or unknown MSI status (n = 2). In addition, 672 consecutive colorectal cancer (CRC) cases were screened for family history; 15 patients were younger than 50 years and reported 2 or more instances of LS-related cancers in 1st- or 2nd-degree relatives. Seven of these cases demonstrated MSI-H and therefore were subjected to DNA germ-line testing. Overall, 17/23 (74%) subjects carried LS-associated gene variants (MLH1: 10; MSH2: 4; MSH6: 2; PMS2: 1), with 2 alleles (MLH1 c.677G > T and MSH2 с.1906G > C) detected twice. Testing for recurrent mutations of 30 consecutive MSI-H CRCs led to the identification of 2 additional subjects with LS. The analysis of all relevant publications identified 28 unrelated LS patients presented in Russian medical literature and 3 unrelated Russian LS subjects described in international journals. Overall, 15/49 (31%) genetic defects revealed in Russian LS patients were represented by six recurrent alleles (MLH1: c.350C > T, c.677G > T, c.1852_1854del; MSH2: c.942+3A > T, c.1861C > T, с.1906G > C). We conclude that the founder effect for LS in Russia is seemingly less pronounced than the one for hereditary breast-ovarian cancer syndrome, however testing for recurrent LS mutations may be considered feasible in some circumstances.
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Affiliation(s)
- Grigoriy A Yanus
- St.-Petersburg Pediatric Medical University, 194100, Russia; N.N. Petrov Institute of Oncology, 197758, Russia.
| | | | - Aglaya G Iyevleva
- St.-Petersburg Pediatric Medical University, 194100, Russia; N.N. Petrov Institute of Oncology, 197758, Russia
| | | | - Evgeny N Suspitsin
- St.-Petersburg Pediatric Medical University, 194100, Russia; N.N. Petrov Institute of Oncology, 197758, Russia
| | | | - Alexandr O Ivantsov
- St.-Petersburg Pediatric Medical University, 194100, Russia; N.N. Petrov Institute of Oncology, 197758, Russia
| | | | | | - Anna P Sokolenko
- St.-Petersburg Pediatric Medical University, 194100, Russia; N.N. Petrov Institute of Oncology, 197758, Russia
| | - Alexandr V Togo
- St.-Petersburg Pediatric Medical University, 194100, Russia; N.N. Petrov Institute of Oncology, 197758, Russia
| | - Evgeny N Imyanitov
- St.-Petersburg Pediatric Medical University, 194100, Russia; N.N. Petrov Institute of Oncology, 197758, Russia; I.I. Mechnikov North-Western Medical University, 191015, Russia; St.-Petersburg State University, 199034, St.-Petersburg, Russia
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12
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Friedenson B. A Genome Model to Explain Major Features of Neurodevelopmental Disorders in Newborns. BIOMEDICAL INFORMATICS INSIGHTS 2019; 11:1178222619863369. [PMID: 31391780 PMCID: PMC6669855 DOI: 10.1177/1178222619863369] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 06/21/2019] [Indexed: 12/15/2022]
Abstract
The purpose of this study was to test the hypothesis that infections are linked to chromosomal anomalies that cause neurodevelopmental disorders. In children with disorders in the development of their nervous systems, chromosome anomalies known to cause these disorders were compared with foreign DNAs, including known teratogens. Genes essential for neurons, lymphatic drainage, immunity, circulation, angiogenesis, cell barriers, structure, epigenetic and chromatin modifications were all found close together in polyfunctional clusters that were deleted or rearranged in neurodevelopmental disorders. In some patients, epigenetic driver mutations also changed access to large chromosome segments. These changes account for immune, circulatory, and structural deficits that accompany neurologic deficits. Specific and repetitive human DNA encompassing large deletions matched infections and passed rigorous artifact tests. Deletions of up to millions of bases accompanied infection-matching sequences and caused massive changes in human homologies to foreign DNAs. In data from 3 independent studies of private, familial, and recurrent chromosomal rearrangements, massive changes in homologous microbiomes were found and may drive rearrangements and encourage pathogens. At least 1 chromosomal anomaly was found to consist of human DNA fragments with a gap that corresponded to a piece of integrated foreign DNA. Microbial DNAs that match repetitive or specific human DNA segments are thus proposed to interfere with the epigenome and highly active recombination during meiosis, driven by massive changes in human DNA-foreign DNA homologies. Abnormal recombination in gametes produces zygotes containing rare chromosome anomalies that cause neurologic disorders and nonneurologic signs. Neurodevelopmental disorders may be examples of assault on the human genome by foreign DNAs at a critical stage. Some infections may be more likely tolerated because they resemble human DNA segments. Even rare developmental disorders can be screened for homology to infections within altered epigenomes and chromatin structures. Considering effects of foreign DNAs can assist prenatal and genetic counseling, diagnosis, prevention, and early intervention.
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Affiliation(s)
- Bernard Friedenson
- Department of Biochemistry and Molecular Genetics, College of Medicine, The University of Illinois at Chicago, Chicago, IL, USA
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13
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Abstract
Lynch syndrome (LS) predisposes to a spectrum of cancers and increases the lifetime risk of developing colorectal- or endometrial cancer to over 50%. Lynch syndrome is dominantly inherited and is caused by defects in DNA mismatch-repair genes MLH1, MSH2, MSH6 or PMS2, with the vast majority detected in MLH1 and MSH2. Recurrent LS-associated variants observed in apparently unrelated individuals, have either arisen de novo in different families due to mutation hotspots, or are inherited from a founder (a common ancestor) that lived several generations back. There are variants that recur in some populations while also acting as founders in other ethnic groups. Testing for founder mutations can facilitate molecular diagnosis of Lynch Syndrome more efficiently and more cost effective than screening for all possible mutations. Here we report a study of the missense mutation MLH1 c.2059C > T (p.Arg687Trp), a potential founder mutation identified in eight Swedish families and one Finnish family with Swedish ancestors. Haplotype analysis confirmed that the Finnish and Swedish families shared a haplotype of between 0.9 and 2.8 Mb. While MLH1 c.2059C > T exists worldwide, the Swedish haplotype was not found among mutation carriers from Germany or France, which indicates a common founder in the Swedish population. The geographic distribution of MLH1 c.2059C > T in Sweden suggests a single, ancient mutational event in the northern part of Sweden.
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14
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Porkka N, Lahtinen L, Ahtiainen M, Böhm JP, Kuopio T, Eldfors S, Mecklin JP, Seppälä TT, Peltomäki P. Epidemiological, clinical and molecular characterization of Lynch-like syndrome: A population-based study. Int J Cancer 2019; 145:87-98. [PMID: 30575961 DOI: 10.1002/ijc.32085] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 10/30/2018] [Accepted: 12/13/2018] [Indexed: 01/05/2023]
Abstract
Colorectal carcinomas that are mismatch repair (MMR)-deficient in the absence of MLH1 promoter methylation or germline mutations represent Lynch-like syndrome (LLS). Double somatic events inactivating MMR genes are involved in the etiology of LLS tumors. Our purpose was to define the clinical and broader molecular hallmarks of LLS tumors and the population incidence of LLS, which remain poorly characterized. We investigated 762 consecutive colorectal carcinomas operated in Central Finland in 2000-2010. LLS cases were identified by a stepwise protocol based on MMR protein expression, MLH1 methylation and MMR gene mutation status. LLS tumors were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations in 578 cancer-relevant genes. Among 107 MMR-deficient tumors, 81 (76%) were attributable to MLH1 promoter methylation and 9 (8%) to germline mutations (Lynch syndrome, LS), leaving 14 LLS cases (13%) (3 remained unclassified). LLS carcinomas were diagnosed at a mean age of 65 years (vs. 44 years in LS, p < 0.001), had a proximal to distal ratio of 1:1, and all were BRAF V600E-negative. Two somatic events in MMR genes were identifiable in 11 tumors (79%). As novel findings, the tumors contained an average of 31 nonsynonymous somatic mutations/Mb and 13/14 were CIMP-positive. In conclusion, we establish the epidemiological, clinical and molecular characteristics of LLS in a population-based study design. Significantly more frequent CIMP-positivity and lower rates of somatic mutations make a distinction to LS. The absence of BRAF V600E mutation separates LLS colorectal carcinomas from MLH1-methylated colorectal carcinomas with CIMP-positive phenotype.
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Affiliation(s)
- Noora Porkka
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
| | - Laura Lahtinen
- Department of Pathology, Jyväskylä Central Hospital, Jyväskylä, Finland
| | - Maarit Ahtiainen
- Department of Education and Research, Jyväskylä Central Hospital and University of Eastern Finland, Jyväskylä, Finland
| | - Jan P Böhm
- Department of Pathology, Jyväskylä Central Hospital, Jyväskylä, Finland
| | - Teijo Kuopio
- Department of Pathology, Jyväskylä Central Hospital, Jyväskylä, Finland.,Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland
| | - Samuli Eldfors
- Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
| | - Jukka-Pekka Mecklin
- Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland.,Department of Surgery, Jyväskylä Central Hospital, Jyväskylä, Finland.,Department of Education & Science, Jyväskylä Central Hospital, Jyväskylä, Finland
| | - Toni T Seppälä
- Department of Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Päivi Peltomäki
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
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15
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Cama A, Genuardi M, Guanti G, Radice P, Varesco L. Molecular Genetics of Hereditary Non-Polyposis Colorectal Cancer (HNPCC). TUMORI JOURNAL 2018; 82:122-35. [PMID: 8644374 DOI: 10.1177/030089169608200206] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The story of the molecular genetics of HNPCC is one of astonishingly rapid achievements. In just 16 months, from May 1993 to September 1994, four different genes, namely hMSH2, hMLH1, hPMS1 and hPMS2 have been identified and demonstrated to be associated with the disease. Their cloning was facilitated by the finding that tumor cells in HNPCC patients display a hypermutability of DNA short tandem repeats (microsatellite instability). In fact, HNPCC associated genes are the human counterparts of genetic elements known to control the fidelity of DNA replication in lower organisms. So far, more than 50 germline mutations of hMSH2 and hMLH1 genes have been reported in HNPCC kindreds. In addition, somatic mutations have been documented in hereditary as well as sporadic cancers. Unfortunately, the molecular diagnosis of HNPCC is hampered by the lack of mutational “hot spots” and of clearly defined genotype-phenotype correlations and different screening methods are to be employed for the analysis of affected and at-risk individuals.
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Affiliation(s)
- A Cama
- Cattedra di Patologia Generale, Università Gabriele D'Annuzio, Chieti,Italy
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16
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Tanskanen T, van den Berg L, Välimäki N, Aavikko M, Ness-Jensen E, Hveem K, Wettergren Y, Bexe Lindskog E, Tõnisson N, Metspalu A, Silander K, Orlando G, Law PJ, Tuupanen S, Gylfe AE, Hänninen UA, Cajuso T, Kondelin J, Sarin AP, Pukkala E, Jousilahti P, Salomaa V, Ripatti S, Palotie A, Järvinen H, Renkonen-Sinisalo L, Lepistö A, Böhm J, Mecklin JP, Al-Tassan NA, Palles C, Martin L, Barclay E, Tenesa A, Farrington S, Timofeeva MN, Meyer BF, Wakil SM, Campbell H, Smith CG, Idziaszczyk S, Maughan TS, Kaplan R, Kerr R, Kerr D, Buchanan DD, Win AK, Hopper J, Jenkins M, Newcomb PA, Gallinger S, Conti D, Schumacher FR, Casey G, Cheadle JP, Dunlop MG, Tomlinson IP, Houlston RS, Palin K, Aaltonen LA. Genome-wide association study and meta-analysis in Northern European populations replicate multiple colorectal cancer risk loci. Int J Cancer 2018; 142:540-546. [PMID: 28960316 PMCID: PMC6383773 DOI: 10.1002/ijc.31076] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 08/04/2017] [Accepted: 09/01/2017] [Indexed: 12/14/2022]
Abstract
Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10-4 ; OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p = 1.50 × 10-9 ; OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.
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Affiliation(s)
- Tomas Tanskanen
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
- Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Linda van den Berg
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
- Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Niko Välimäki
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
- Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Mervi Aavikko
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
- Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Eivind Ness-Jensen
- HUNT Research Centre, Department of Public Health, NTNU, Norwegian University of Science and Technology, Levanger, Norway
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway
| | - Kristian Hveem
- HUNT Research Centre, Department of Public Health, NTNU, Norwegian University of Science and Technology, Levanger, Norway
- K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Yvonne Wettergren
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Elinor Bexe Lindskog
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Neeme Tõnisson
- Estonian Genome Center, University of Tartu, Tartu, Estonia
| | | | - Kaisa Silander
- National Institute for Health and Welfare, Helsinki, Finland
| | - Giulia Orlando
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Philip J. Law
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Sari Tuupanen
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
- Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Alexandra E. Gylfe
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
- Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Ulrika A. Hänninen
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
- Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Tatiana Cajuso
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
- Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Johanna Kondelin
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
- Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Antti-Pekka Sarin
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Eero Pukkala
- Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland
- Faculty of Social Sciences, University of Tampere, Tampere, Finland
| | | | - Veikko Salomaa
- National Institute for Health and Welfare, Helsinki, Finland
| | - Samuli Ripatti
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Aarno Palotie
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
| | - Heikki Järvinen
- Department of Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
| | | | - Anna Lepistö
- Department of Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
| | - Jan Böhm
- Department of Pathology, Central Finland Central Hospital, Jyväskylä, Finland
| | - Jukka-Pekka Mecklin
- Department of Surgery, Jyväskylä Central Hospital, University of Eastern Finland, Jyväskylä, Finland
| | - Nada A. Al-Tassan
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Claire Palles
- Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, UK
| | - Lynn Martin
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Ella Barclay
- Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, UK
| | - Albert Tenesa
- Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK
- The Roslin Institute, University of Edinburgh, Easter Bush, Roslin, UK
| | - Susan Farrington
- Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK
| | - Maria N. Timofeeva
- Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK
| | - Brian F. Meyer
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Salma M. Wakil
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Harry Campbell
- Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK
| | - Christopher G. Smith
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK
| | - Shelley Idziaszczyk
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK
| | - Tim S. Maughan
- CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK
| | | | - Rachel Kerr
- Oxford Cancer Centre, Department of Oncology, University of Oxford, Churchill Hospital, Oxford, UK
| | - David Kerr
- Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Daniel D. Buchanan
- Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, VIC, Australia
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, VIC, Australia
| | - Aung K. Win
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, VIC, Australia
| | - John Hopper
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, VIC, Australia
| | - Mark Jenkins
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, VIC, Australia
| | - Polly A. Newcomb
- Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Steve Gallinger
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - David Conti
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
| | - Fredrick R. Schumacher
- Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Jeremy P. Cheadle
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, UK
| | - Malcolm G. Dunlop
- Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK
| | - Ian P. Tomlinson
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Richard S. Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Kimmo Palin
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
- Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Lauri A. Aaltonen
- Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
- Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
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17
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De Lellis L, Mammarella S, Curia MC, Veschi S, Mokini Z, Bassi C, Sala P, Battista P, Mariani-Costantini R, Radice P, Cama A. Analysis of Gene Copy Number Variations using a Method Based on Lab-on-a-Chip Technology. TUMORI JOURNAL 2018; 98:126-36. [DOI: 10.1177/030089161209800118] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Aims and Background Copy number variations (CNVs) contribute to genome variability and their pathogenic role is becoming evident in an increasing number of human disorders. Commercial assays for routine diagnosis of CNVs are available only for a fraction of known genomic rearrangements. Thus, it is important to develop flexible and cost-effective methods that can be adapted to the detection of CNVs of interest, both in research and clinical settings. Methods We describe a new multiplex PCR-based method for CNV analysis that exploits automated microfluidic capillary electrophoresis through lab-on-a-chip technology (LOC-CNV). We tested the reproducibility of the method and compared the results obtained by LOC-CNV with those obtained using previously validated semiquantitative assays such as multiplex ligation-dependent probe amplification (MLPA) and nonfluorescent multiplex PCR coupled to HPLC (NFMP-HPLC). Results The results obtained by LOC-CNV in control individuals and carriers of pathogenic MLH1 or BRCA1 genomic rearrangements (losses or gains) were concordant with those obtained by previously validated methods, indicating that LOC-CNV is a reliable method for the detection of genomic rearrangements. Conclusion Because of its advantages with respect to time, costs, easy adaptation of previously developed multiplex assays and flexibility in novel assay design, LOC-CNV may represent a practical option to evaluate relative copy number changes in genomic targets of interest, including those identified in genome-wide analyses.
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Affiliation(s)
- Laura De Lellis
- Department of Drug Sciences, “G. d'Annunzio” University, Chieti
- Aging Research Center, “G. d'Annunzio” University Foundation, Chieti
| | - Sandra Mammarella
- Department of Drug Sciences, “G. d'Annunzio” University, Chieti
- Aging Research Center, “G. d'Annunzio” University Foundation, Chieti
| | - Maria Cristina Curia
- Aging Research Center, “G. d'Annunzio” University Foundation, Chieti
- Department of Oral Sciences, Nano and Biotechnology, “G. d'Annunzio” University, Chieti
| | - Serena Veschi
- Unit of Molecular Pathology and Genomics, Aging Research Center, “G. d'Annunzio” University Foundation, Chieti
| | - Zhirajr Mokini
- Department of Drug Sciences, “G. d'Annunzio” University, Chieti
- Aging Research Center, “G. d'Annunzio” University Foundation, Chieti
| | - Chiara Bassi
- Unit of Genetic Susceptibility to Cancer, Department of Experimental Oncology and Molecular Medicine, IRCCS Foundation, National Cancer Institute, Milan
- FIRC Institute of Molecular Oncology Foundation (IFOM), Milan
| | - Paola Sala
- Department of Surgery, IRCCS Foundation, National Cancer Institute, Milan
| | - Pasquale Battista
- Department of Biomedical Sciences, “G. d'Annunzio” University, Chieti, Italy
| | - Renato Mariani-Costantini
- Aging Research Center, “G. d'Annunzio” University Foundation, Chieti
- Department of Oral Sciences, Nano and Biotechnology, “G. d'Annunzio” University, Chieti
| | - Paolo Radice
- Unit of Genetic Susceptibility to Cancer, Department of Experimental Oncology and Molecular Medicine, IRCCS Foundation, National Cancer Institute, Milan
- FIRC Institute of Molecular Oncology Foundation (IFOM), Milan
| | - Alessandro Cama
- Department of Drug Sciences, “G. d'Annunzio” University, Chieti
- Aging Research Center, “G. d'Annunzio” University Foundation, Chieti
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18
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Bhangu JS, Taghizadeh H, Braunschmid T, Bachleitner-Hofmann T, Mannhalter C. Circulating cell-free DNA in plasma of colorectal cancer patients - A potential biomarker for tumor burden. Surg Oncol 2017; 26:395-401. [DOI: 10.1016/j.suronc.2017.08.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 07/05/2017] [Accepted: 08/04/2017] [Indexed: 12/19/2022]
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19
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Rossi BM, Palmero EI, López-Kostner F, Sarroca C, Vaccaro CA, Spirandelli F, Ashton-Prolla P, Rodriguez Y, de Campos Reis Galvão H, Reis RM, Escremim de Paula A, Capochin Romagnolo LG, Alvarez K, Della Valle A, Neffa F, Kalfayan PG, Spirandelli E, Chialina S, Gutiérrez Angulo M, Castro-Mujica MDC, Sanchez de Monte J, Quispe R, da Silva SD, Rossi NT, Barletta-Carrillo C, Revollo S, Taborga X, Morillas LL, Tubeuf H, Monteiro-Santos EM, Piñero TA, Dominguez-Barrera C, Wernhoff P, Martins A, Hovig E, Møller P, Dominguez-Valentin M. A survey of the clinicopathological and molecular characteristics of patients with suspected Lynch syndrome in Latin America. BMC Cancer 2017; 17:623. [PMID: 28874130 PMCID: PMC5586063 DOI: 10.1186/s12885-017-3599-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 08/23/2017] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America. METHODS Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome. RESULTS We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet. CONCLUSION The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.
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Affiliation(s)
| | - Edenir Inêz Palmero
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP Brazil
| | | | - Carlos Sarroca
- Hospital Fuerzas Armadas, Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Montevideo, Uruguay
| | | | - Florencia Spirandelli
- Servicio de Coloproctologia y Asesoria Genetica en Cancer, Hospital Español de Rosario, Rosario, Argentina
| | - Patricia Ashton-Prolla
- Departamento de Genética da Universidade Federal do Rio Grande do Sul (UFRGS) e Serviço de Genética Médica do Hospital de Clinicas de Porto Alegre (HCPA) & Rede Brasileira de Câncer Hereditário, Porto Alegre, Rio Grande Do Sul Brazil
| | | | | | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital & Life and Health Sciences Research Institute (ICVS), Health Sciences School, University of Minho, Braga, Portugal
- ICVS/3B’s-PT Government Associate Laboratory, Braga, Guimarães Portugal
| | | | | | - Karin Alvarez
- Laboratorio de Oncología y Genética Molecular, Clínica Los Condes, Santiago, Chile
| | - Adriana Della Valle
- Hospital Fuerzas Armadas, Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Montevideo, Uruguay
| | - Florencia Neffa
- Hospital Fuerzas Armadas, Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Montevideo, Uruguay
| | | | - Enrique Spirandelli
- Servicio de Coloproctologia y Asesoria Genetica en Cancer, Hospital Español de Rosario, Rosario, Argentina
| | - Sergio Chialina
- Servicio de Coloproctologia y Asesoria Genetica en Cancer, Hospital Español de Rosario, Rosario, Argentina
| | | | | | | | - Richard Quispe
- Laboratorio de Genética Molecular del Instituto de Servicios de Laboratorio de Diagnóstico e Investigación en Salud (SELADIS), La Paz, Bolivia
| | - Sabrina Daniela da Silva
- Lady Davis Institute for Medical Research and Segal Cancer Center, Jewish General Hospital, Montreal, Quebec, Canada
- Department of Otolaryngology-Head and Neck Surgery, McGill University, Montreal, Quebec, Canada
| | | | - Claudia Barletta-Carrillo
- Equipo Funcional de Genética y Biologia Molecular, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru
| | - Susana Revollo
- Laboratorio de Genética Molecular del Instituto de Servicios de Laboratorio de Diagnóstico e Investigación en Salud (SELADIS), La Paz, Bolivia
| | - Ximena Taborga
- Laboratorio de Genética Molecular del Instituto de Servicios de Laboratorio de Diagnóstico e Investigación en Salud (SELADIS), La Paz, Bolivia
| | | | - Hélène Tubeuf
- Inserm-U1079-IRIB, UNIROUEN, Normandie Univ, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
- Interactive Biosoftware, Rouen, France
| | | | - Tamara Alejandra Piñero
- Instituto de Ciencias Basicas y Medicina Experimental (ICBME), Hospital Italiano, Buenos Aires, Argentina
| | - Constantino Dominguez-Barrera
- Department of Preventive Medicine, Faculty of Medicine, Universidad Nacional Mayor de San Marcos (UNMSM), Lima, Peru
| | - Patrik Wernhoff
- Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, Lørenskog, Norway
| | - Alexandra Martins
- Inserm-U1079-IRIB, UNIROUEN, Normandie Univ, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
| | - Eivind Hovig
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Institute of Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway
| | - Pål Møller
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
- Department of Human Medicine, Universität Witten/Herdecke, Witten, Germany
| | - Mev Dominguez-Valentin
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
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20
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Dymerska D, Gołębiewska K, Kuświk M, Rudnicka H, Scott RJ, Billings R, Pławski A, Boruń P, Siołek M, Kozak-Klonowska B, Szwiec M, Kilar E, Huzarski T, Byrski T, Lubiński J, Kurzawski G. New EPCAM founder deletion in Polish population. Clin Genet 2017; 92:649-653. [PMID: 28369810 DOI: 10.1111/cge.13026] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Revised: 03/23/2017] [Accepted: 03/28/2017] [Indexed: 01/30/2023]
Abstract
It is well known that founder mutations associated with cancer risk have useful implications for molecular diagnostics. We report the presence of a founder mutation in EPCAM involved in the etiology of Lynch syndrome (LS). The mutation extends nearly 8.7 kb (c.858 + 2478_*4507del) and is shared by 8 Polish families. Family members suffered almost exclusively from colorectal cancer; however, pancreatic and gastric cancers were also apparent. Next to mutations c. 2041G>A in MLH1 gene and c.942+3A>T in MSH2, the deletion mutation encompassing EPCAM is one of the most common causative changes responsible for LS in Poland.
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Affiliation(s)
- D Dymerska
- Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - K Gołębiewska
- Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - M Kuświk
- Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - H Rudnicka
- Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - R J Scott
- Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.,Discipline of Medical Genetics, University of Newcastle, Newcastle, Australia.,Division of Genetics, John Hunter Hospital, Newcastle, Australia
| | - R Billings
- Division of Genetics, John Hunter Hospital, Newcastle, Australia
| | - A Pławski
- Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland.,Department of General, Endocrinological Surgery and Gastroenterological Oncology, Poznan University of Medical Sciences, Poznań, Poland
| | - P Boruń
- Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland
| | - M Siołek
- Department of General, Endocrinological Surgery and Gastroenterological Oncology, Poznan University of Medical Sciences, Poznań, Poland.,Holy Cross Cancer Center, Counselling Unit, Kielce, Poland
| | - B Kozak-Klonowska
- Department of General, Endocrinological Surgery and Gastroenterological Oncology, Poznan University of Medical Sciences, Poznań, Poland.,Holy Cross Cancer Center, Counselling Unit, Kielce, Poland
| | - M Szwiec
- Holy Cross Cancer Center, Counselling Unit, Kielce, Poland.,Regional Oncology Center, Counselling Unit, Opole, Poland
| | - E Kilar
- Regional Oncology Center, Counselling Unit, Opole, Poland.,Regional Oncology Center, Counselling Unit, Świdnica, Poland
| | - T Huzarski
- Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - T Byrski
- Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - J Lubiński
- Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
| | - G Kurzawski
- Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
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21
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Genetics in an isolated population like Finland: a different basis for genomic medicine? J Community Genet 2017; 8:319-326. [PMID: 28730583 PMCID: PMC5614886 DOI: 10.1007/s12687-017-0318-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 06/29/2017] [Indexed: 11/24/2022] Open
Abstract
A unique genetic background in an isolated population like that of Finland offers special opportunities for genetic research as well as for applying the genetic developments to the health care. On the other hand, the different genetic background may require local attempts to develop diagnostics and treatment as the selection of diseases and mutations differs from that in the other populations. In this review, we describe the experiences of research and health care in this genetic isolate starting from the identification of specific monogenic diseases enriched in the Finnish population all the way to implementing the knowledge of the unique genetic background to genomic medicine at population level.
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22
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Lagerstedt-Robinson K, Rohlin A, Aravidis C, Melin B, Nordling M, Stenmark-Askmalm M, Lindblom A, Nilbert M. Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population. Oncol Rep 2016; 36:2823-2835. [PMID: 27601186 DOI: 10.3892/or.2016.5060] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 05/31/2016] [Indexed: 12/21/2022] Open
Abstract
Lynch syndrome caused by constitutional mismatch‑repair defects is one of the most common hereditary cancer syndromes with a high risk for colorectal, endometrial, ovarian and urothelial cancer. Lynch syndrome is caused by mutations in the mismatch repair (MMR) genes i.e., MLH1, MSH2, MSH6 and PMS2. After 20 years of genetic counseling and genetic testing for Lynch syndrome, we have compiled the mutation spectrum in Sweden with the aim to provide a population-based perspective on the contribution from the different MMR genes, the various types of mutations and the influence from founder mutations. Mutation data were collected on a national basis from all laboratories involved in genetic testing. Mutation analyses were performed using mainly Sanger sequencing and multiplex ligation-dependent probe amplification. A total of 201 unique disease-predisposing MMR gene mutations were identified in 369 Lynch syndrome families. These mutations affected MLH1 in 40%, MSH2 in 36%, MSH6 in 18% and PMS2 in 6% of the families. A large variety of mutations were identified with splice site mutations being the most common mutation type in MLH1 and frameshift mutations predominating in MSH2 and MSH6. Large deletions of one or several exons accounted for 21% of the mutations in MLH1 and MSH2 and 22% in PMS2, but were rare (4%) in MSH6. In 66% of the Lynch syndrome families the variants identified were private and the effect from founder mutations was limited and predominantly related to a Finnish founder mutation that accounted for 15% of the families with mutations in MLH1. In conclusion, the Swedish Lynch syndrome mutation spectrum is diverse with private MMR gene mutations in two-thirds of the families, has a significant contribution from internationally recognized mutations and a limited effect from founder mutations.
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Affiliation(s)
- Kristina Lagerstedt-Robinson
- Department of Molecular Medicine and Surgery, Karolinska Institute and Department of Clinical Genetics, Karolinska University Hospital, Solna, SE-17176 Stockholm, Sweden
| | - Anna Rohlin
- Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, SE-41345 Gothenburg, Sweden
| | - Christos Aravidis
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-75185 Uppsala, Sweden
| | - Beatrice Melin
- Department of Radiation Sciences, Division of Oncology, Umeå University, SE-90187 Umeå, Sweden
| | - Margareta Nordling
- Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, SE-41345 Gothenburg, Sweden
| | | | - Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institute and Department of Clinical Genetics, Karolinska University Hospital, Solna, SE-17176 Stockholm, Sweden
| | - Mef Nilbert
- Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, SE-22381 Lund, Sweden
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23
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Liu Q, Hesson LB, Nunez AC, Packham D, Williams R, Ward RL, Sloane MA. A cryptic paracentric inversion of MSH2 exons 2-6 causes Lynch syndrome. Carcinogenesis 2015; 37:10-17. [PMID: 26498247 DOI: 10.1093/carcin/bgv154] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 10/19/2015] [Indexed: 12/28/2022] Open
Abstract
Lynch syndrome is an autosomal dominant disorder that predisposes carriers of DNA mismatch repair (MMR) gene mutations to early-onset cancer. Germline testing screens exons and splice sites for mutations, but does not examine introns or RNA transcripts for alterations. Pathogenic mutations have not been detected in ~30% of suspected Lynch syndrome cases with standard screening practices. We present a 38-year-old male with a clinicopathological and family history consistent with Lynch syndrome, including loss of MSH2 expression in his tumor. Germline testing revealed normal MSH2 coding sequence, splice sites and exon copy number, however, cDNA sequencing identified an aberrant MSH2 transcript lacking exons 2-6. An inversion PCR on germline DNA identified an ~18kb unbalanced, paracentric inversion within MSH2, with breakpoints in a long terminal repeat in intron 1 and an Alu repeat in intron 6. The 3' end of the inversion had a 1.2 kb deletion and an 8 bp insertion at the junction with intron 6. Screening of 55 additional Australian patients presenting with MSH2-deficient tumors who were negative in germline genetic tests for MSH2 mutations identified another inversion-positive patient. We propose an Alu-mediated recombination model to explain the origin of the inversion. Our study illustrates the potential value of cDNA screening to identify patients with cryptic MMR gene rearrangements, clarifies why standard testing may not detect some pathogenic alterations, and provides a genetic test for screening individuals with suspected Lynch syndrome that present with unexplained MSH2-deficient tumors.
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Affiliation(s)
- Qing Liu
- Adult Cancer Program , Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia , Sydney New South Wales 2052 , Australia
| | - Luke B Hesson
- Adult Cancer Program , Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia , Sydney New South Wales 2052 , Australia
| | - Andrea C Nunez
- Adult Cancer Program , Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia , Sydney New South Wales 2052 , Australia
| | - Deborah Packham
- Adult Cancer Program , Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia , Sydney New South Wales 2052 , Australia
| | - Rachel Williams
- Hereditary Cancer Clinic , Prince of Wales Hospital , Randwick, New South Wales 2031 , Australia and
| | - Robyn L Ward
- Adult Cancer Program, Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia, Sydney New South Wales 2052, Australia.,Level 3 Brian Wilson Chancellery, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Mathew A Sloane
- Adult Cancer Program , Lowy Cancer Research Centre and Prince of Wales Clinical School, UNSW Australia , Sydney New South Wales 2052 , Australia
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24
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Germline MLH1 Mutations Are Frequently Identified in Lynch Syndrome Patients With Colorectal and Endometrial Carcinoma Demonstrating Isolated Loss of PMS2 Immunohistochemical Expression. Am J Surg Pathol 2015; 39:1114-20. [DOI: 10.1097/pas.0000000000000425] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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25
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Morales ME, Servant G, Ade C, Roy-Enge AM. Altering Genomic Integrity: Heavy Metal Exposure Promotes Transposable Element-Mediated Damage. Biol Trace Elem Res 2015; 166:24-33. [PMID: 25774044 PMCID: PMC4696754 DOI: 10.1007/s12011-015-0298-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 03/03/2015] [Indexed: 12/13/2022]
Abstract
Maintenance of genomic integrity is critical for cellular homeostasis and survival. The active transposable elements (TEs) composed primarily of three mobile element lineages LINE-1, Alu, and SVA comprise approximately 30% of the mass of the human genome. For the past 2 decades, studies have shown that TEs significantly contribute to genetic instability and that TE-caused damages are associated with genetic diseases and cancer. Different environmental exposures, including several heavy metals, influence how TEs interact with its host genome increasing their negative impact. This mini-review provides some basic knowledge on TEs, their contribution to disease, and an overview of the current knowledge on how heavy metals influence TE-mediated damage.
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Affiliation(s)
- Maria E. Morales
- Department of Epidemiology and Tulane Cancer Center, SL-66, Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112
| | - Geraldine Servant
- Department of Epidemiology and Tulane Cancer Center, SL-66, Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112
| | - Catherine Ade
- Department of Cellular and Molecular Biology, Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112
| | - Astrid M. Roy-Enge
- Department of Epidemiology and Tulane Cancer Center, SL-66, Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112
- Corresponding author: Astrid M. Roy-Engel, Ph.D., Department of Epidemiology, Tulane Cancer Center, SL66, Tulane University Health Sciences Center, 1430 Tulane Ave., New Orleans, LA 70112. , Phone: (504) 988-6316, Fax: (504) 988-5516
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26
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SINE transcription by RNA polymerase III is suppressed by histone methylation but not by DNA methylation. Nat Commun 2015; 6:6569. [PMID: 25798578 PMCID: PMC4382998 DOI: 10.1038/ncomms7569] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Accepted: 02/03/2015] [Indexed: 12/31/2022] Open
Abstract
Short interspersed nuclear elements (SINEs), such as Alu, spread by retrotransposition, which requires their transcripts to be copied into DNA and then inserted into new chromosomal sites. This can lead to genetic damage through insertional mutagenesis and chromosomal rearrangements between non-allelic SINEs at distinct loci. SINE DNA is heavily methylated and this was thought to suppress its accessibility and transcription, thereby protecting against retrotransposition. Here we provide several lines of evidence that methylated SINE DNA is occupied by RNA polymerase III, including the use of high-throughput bisulphite sequencing of ChIP DNA. We find that loss of DNA methylation has little effect on accessibility of SINEs to transcription machinery or their expression in vivo. In contrast, a histone methyltransferase inhibitor selectively promotes SINE expression and occupancy by RNA polymerase III. The data suggest that methylation of histones rather than DNA plays a dominant role in suppressing SINE transcription.
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27
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Morales ME, White TB, Streva VA, DeFreece CB, Hedges DJ, Deininger PL. The contribution of alu elements to mutagenic DNA double-strand break repair. PLoS Genet 2015; 11:e1005016. [PMID: 25761216 PMCID: PMC4356517 DOI: 10.1371/journal.pgen.1005016] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 01/22/2015] [Indexed: 11/18/2022] Open
Abstract
Alu elements make up the largest family of human mobile elements, numbering 1.1 million copies and comprising 11% of the human genome. As a consequence of evolution and genetic drift, Alu elements of various sequence divergence exist throughout the human genome. Alu/Alu recombination has been shown to cause approximately 0.5% of new human genetic diseases and contribute to extensive genomic structural variation. To begin understanding the molecular mechanisms leading to these rearrangements in mammalian cells, we constructed Alu/Alu recombination reporter cell lines containing Alu elements ranging in sequence divergence from 0%-30% that allow detection of both Alu/Alu recombination and large non-homologous end joining (NHEJ) deletions that range from 1.0 to 1.9 kb in size. Introduction of as little as 0.7% sequence divergence between Alu elements resulted in a significant reduction in recombination, which indicates even small degrees of sequence divergence reduce the efficiency of homology-directed DNA double-strand break (DSB) repair. Further reduction in recombination was observed in a sequence divergence-dependent manner for diverged Alu/Alu recombination constructs with up to 10% sequence divergence. With greater levels of sequence divergence (15%-30%), we observed a significant increase in DSB repair due to a shift from Alu/Alu recombination to variable-length NHEJ which removes sequence between the two Alu elements. This increase in NHEJ deletions depends on the presence of Alu sequence homeology (similar but not identical sequences). Analysis of recombination products revealed that Alu/Alu recombination junctions occur more frequently in the first 100 bp of the Alu element within our reporter assay, just as they do in genomic Alu/Alu recombination events. This is the first extensive study characterizing the influence of Alu element sequence divergence on DNA repair, which will inform predictions regarding the effect of Alu element sequence divergence on both the rate and nature of DNA repair events. DNA double-strand breaks (DSBs) are a highly mutagenic form of DNA damage that can be repaired through one of several pathways with varied degrees of sequence preservation. Faithful repair of DSBs often occurs through gene conversion in which a sister chromatid is used as a repair template. Unfaithful repair of DSBs can occur through non-allelic homologous or homeologous recombination, which leads to chromosomal abnormalities such as deletions, duplications, and translocations and has been shown to cause several human genetic diseases. Substrates for these homologous and homeologous events include Alu elements, which are approximately 300 bp elements that comprise ~11% of the human genome. We use a new reporter assay to show that repair of DSBs results in Alu-mediated deletions that resolve through several distinct repair pathways. Either single-strand annealing (SSA) repair or microhomology-mediated end joining occurs ‘in register’ between two Alu elements when Alu sequence divergence is low. However, with more diverged Alu elements, like those typically found in the human genome, repair of DSBs appears to use the Alu/Alu homeology to direct non-homologous end joining in the general vicinity of the Alu elements. Mutagenic NHEJ repair involving divergent Alu elements may represent a common repair event in primate genomes.
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Affiliation(s)
- Maria E. Morales
- Tulane Cancer Center and Department of Epidemiology, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America
| | - Travis B. White
- Tulane Cancer Center and Department of Epidemiology, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America
| | - Vincent A. Streva
- Tulane Cancer Center and Department of Epidemiology, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America
| | - Cecily B. DeFreece
- Department of Biology, Xavier University of Louisiana, New Orleans, Louisiana, United States of America
| | - Dale J. Hedges
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Prescott L. Deininger
- Tulane Cancer Center and Department of Epidemiology, Tulane University Health Sciences Center, New Orleans, Louisiana, United States of America
- * E-mail:
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28
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Abstract
Lynch syndrome, which is now recognized as the most common hereditary colorectal cancer condition, is characterized by the predisposition to a spectrum of cancers, primarily colorectal cancer and endometrial cancer. We chronicle over a century of discoveries that revolutionized the diagnosis and clinical management of Lynch syndrome, beginning in 1895 with Warthin's observations of familial cancer clusters, through the clinical era led by Lynch and the genetic era heralded by the discovery of causative mutations in mismatch repair (MMR) genes, to ongoing challenges.
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Affiliation(s)
- Henry T Lynch
- Department of Preventive Medicine and Public Health, Creighton University, 2500 California Plaza, Omaha, Nebraska 68178, USA
| | - Carrie L Snyder
- Department of Preventive Medicine and Public Health, Creighton University, 2500 California Plaza, Omaha, Nebraska 68178, USA
| | - Trudy G Shaw
- Department of Preventive Medicine and Public Health, Creighton University, 2500 California Plaza, Omaha, Nebraska 68178, USA
| | - Christopher D Heinen
- Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut 06030-3101, USA
| | - Megan P Hitchins
- Department of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Grant Building S169, 1291 Welch Road, Stanford, California 94305, USA
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29
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Lee WP, Wu J, Marth GT. Toolbox for mobile-element insertion detection on cancer genomes. Cancer Inform 2015; 14:37-44. [PMID: 25931804 PMCID: PMC4338948 DOI: 10.4137/cin.s24657] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 06/03/2014] [Accepted: 06/05/2014] [Indexed: 11/05/2022] Open
Abstract
Mobile elements constitute greater than 45% of the human genome as a result of repeated insertion events during human genome evolution. Although most of mobile elements are fixed within the human population, some elements (including ALU, long interspersed elements (LINE) 1 (L1), and SVA) are still actively duplicating and may result in life-threatening human diseases such as cancer, motivating the need for accurate mobile-element insertion (MEI) detection tools. We developed a software package, TANGRAM, for MEI detection in next-generation sequencing data, currently serving as the primary MEI detection tool in the 1000 Genomes Project. TANGRAM takes advantage of valuable mapping information provided by our own MOSAIK mapper, and until recently required MOSAIK mappings as its input. In this study, we report a new feature that enables TANGRAM to be used on alignments generated by any mainstream short-read mapper, making it accessible for many genomic users. To demonstrate its utility for cancer genome analysis, we have applied TANGRAM to the TCGA (The Cancer Genome Atlas) mutation calling benchmark 4 dataset. TANGRAM is fast, accurate, easy to use, and open source on https://github.com/jiantao/Tangram.
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Affiliation(s)
- Wan-Ping Lee
- Department of Biology, Boston College, Chestnut Hill, MA, USA. ; Currently at Seven Bridges Genomics, Cambridge, MA, USA
| | - Jiantao Wu
- Department of Biology, Boston College, Chestnut Hill, MA, USA. ; Currently at Yelp, Inc. San Francisco, CA, USA
| | - Gabor T Marth
- Department of Biology, Boston College, Chestnut Hill, MA, USA. ; Currently at the Department of Human Genetics and Utah Center for Genetic Discovery, University of Utah, Salt Lake City, UT, USA
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Park RW, Kim TM, Kasif S, Park PJ. Identification of rare germline copy number variations over-represented in five human cancer types. Mol Cancer 2015; 14:25. [PMID: 25644941 PMCID: PMC4381456 DOI: 10.1186/s12943-015-0292-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Accepted: 01/08/2015] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Copy number variations (CNVs) are increasingly recognized as significant disease susceptibility markers in many complex disorders including cancer. The availability of a large number of chromosomal copy number profiles in both malignant and normal tissues in cancer patients presents an opportunity to characterize not only somatic alterations but also germline CNVs, which may confer increased risk for cancer. RESULTS We explored the germline CNVs in five cancer cohorts from the Cancer Genome Atlas (TCGA) consisting of 351 brain, 336 breast, 342 colorectal, 370 renal, and 314 ovarian cancers, genotyped on Affymetrix SNP6.0 arrays. Comparing these to ~3000 normal controls from another study, our case-control association study revealed 39 genomic loci (9 brain, 3 breast, 4 colorectal, 11 renal, and 12 ovarian cancers) as potential candidates of tumor susceptibility loci. Many of these loci are new and in some cases are associated with a substantial increase in disease risk. The majority of the observed loci do not overlap with coding sequences; however, several observed genomic loci overlap with known cancer genes including RET in brain cancers, ERBB2 in renal cell carcinomas, and DCC in ovarian cancers, all of which have not been previously associated with germline changes in cancer. CONCLUSIONS This large-scale genome-wide association study for CNVs across multiple cancer types identified several novel rare germline CNVs as cancer predisposing genomic loci. These loci can potentially serve as clinically useful markers conferring increased cancer risk.
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Affiliation(s)
- Richard W Park
- Bioinformatics Program, Boston University, Boston, MA, USA. .,Center for Biomedical Informatics, Harvard Medical School, 10 Shattuck St, Boston, MA, 02115, USA.
| | - Tae-Min Kim
- Center for Biomedical Informatics, Harvard Medical School, 10 Shattuck St, Boston, MA, 02115, USA. .,Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, 137-701, South Korea.
| | - Simon Kasif
- Bioinformatics Program, Boston University, Boston, MA, USA. .,Department of Biomedical Engineering, Boston University, Boston, MA, USA. .,Children's Hospital Informatics Program, Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA.
| | - Peter J Park
- Center for Biomedical Informatics, Harvard Medical School, 10 Shattuck St, Boston, MA, 02115, USA. .,Children's Hospital Informatics Program, Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA.
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Ponti G, Castellsagué E, Ruini C, Percesepe A, Tomasi A. Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome. Clin Genet 2014; 87:507-16. [PMID: 25345868 DOI: 10.1111/cge.12529] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Revised: 10/03/2014] [Accepted: 10/17/2014] [Indexed: 12/18/2022]
Abstract
Founder mutations in specific populations are common in several Mendelian disorders. They are shared by apparently unrelated families that inherited them from a common ancestor that existed hundreds to thousands of years ago. They have been proven to impact in molecular diagnostics strategies in specific populations, where they can be assessed as the first screening step and, if positive, avoid further expensive gene scanning. In Lynch syndrome (LS), a dominantly inherited colorectal cancer disease, more than 50 founder pathogenic mutations have been described so far in the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2). We here provide a comprehensive summary of the founder mutations found in the MMR genes and an overview of their main characteristics. At a time when high-throughput strategies are being introduced in the molecular diagnostics of cancer, genetic testing for founder mutations can complement next generation sequencing (NGS) technologies to most efficiently identify MMR gene mutations in any given population. Additionally, special attention is paid to MMR founder mutations with interesting anthropological significance.
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Affiliation(s)
- G Ponti
- Department of Diagnostic and Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy
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Lee WP, Wu J, Marth GT. Toolbox for mobile-element insertion detection on cancer genomes. Cancer Inform 2014; 13:45-52. [PMID: 25452688 PMCID: PMC4218655 DOI: 10.4137/cin.s13979] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 06/03/2014] [Accepted: 06/05/2014] [Indexed: 11/05/2022] Open
Abstract
Mobile elements constitute greater than 45% of the human genome as a result of repeated insertion events during human genome evolution. Although most of mobile elements are fixed within the human population, some elements (including ALU, long interspersed elements (LINE) 1 (L1), and SVA) are still actively duplicating and may result in life-threatening human diseases such as cancer, motivating the need for accurate mobile-element insertion (MEI) detection tools. We developed a software package, TANGRAM, for MEI detection in next-generation sequencing data, currently serving as the primary MEI detection tool in the 1000 Genomes Project. TANGRAM takes advantage of valuable mapping information provided by our own MOSAIK mapper, and until recently required MOSAIK mappings as its input. In this study, we report a new feature that enables TANGRAM to be used on alignments generated by any mainstream short-read mapper, making it accessible for many genomic users. To demonstrate its utility for cancer genome analysis, we have applied TANGRAM to the TCGA (The Cancer Genome Atlas) mutation calling benchmark 4 dataset. TANGRAM is fast, accurate, easy to use, and open source on https://github.com/jiantao/Tangram.
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Affiliation(s)
- Wan-Ping Lee
- Department of Biology, Boston College, Chestnut Hill, MA, USA. ; Currently at Seven Bridges Genomics, Cambridge, MA, USA
| | - Jiantao Wu
- Department of Biology, Boston College, Chestnut Hill, MA, USA. ; Currently at Yelp, Inc. San Francisco, CA, USA
| | - Gabor T Marth
- Department of Biology, Boston College, Chestnut Hill, MA, USA. ; Currently at the Department of Human Genetics and Utah Center for Genetic Discovery, University of Utah, Salt Lake City, UT, USA
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Masson AL, Talseth-Palmer BA, Evans TJ, Grice DM, Hannan GN, Scott RJ. Expanding the genetic basis of copy number variation in familial breast cancer. Hered Cancer Clin Pract 2014; 12:15. [PMID: 24955146 PMCID: PMC4064283 DOI: 10.1186/1897-4287-12-15] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Accepted: 05/14/2014] [Indexed: 12/13/2022] Open
Abstract
Introduction Familial breast cancer (fBC) is generally associated with an early age of diagnosis and a higher frequency of disease among family members. Over the past two decades a number of genes have been identified that are unequivocally associated with breast cancer (BC) risk but there remain a significant proportion of families that cannot be accounted for by these genes. Copy number variants (CNVs) are a form of genetic variation yet to be fully explored for their contribution to fBC. CNVs exert their effects by either being associated with whole or partial gene deletions or duplications and by interrupting epigenetic patterning thereby contributing to disease development. CNV analysis can also be used to identify new genes and loci which may be associated with disease risk. Methods The Affymetrix Cytogenetic Whole Genome 2.7 M (Cyto2.7 M) arrays were used to detect regions of genomic re-arrangement in a cohort of 129 fBC BRCA1/BRCA2 mutation negative patients with a young age of diagnosis (<50 years) compared to 40 unaffected healthy controls (>55 years of age). Results CNV analysis revealed the presence of 275 unique rearrangements that were not present in the control population suggestive of their involvement in BC risk. Several CNVs were found that have been previously reported as BC susceptibility genes. This included CNVs in RPA3, NBN (NBS1), MRE11A and CYP19A1 in five unrelated fBC patients suggesting that these genes are involved in BC initiation and/or progression. Of special interest was the identification of WWOX and FHIT rearrangements in three unrelated fBC patients. Conclusions This study has identified a number of CNVs that potentially contribute to BC initiation and/or progression. The identification of CNVs that are associated with known tumour suppressor genes is of special interest that warrants further larger studies to understand their precise role in fBC.
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Affiliation(s)
- Amy L Masson
- Information Based Medicine Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW 2305, Australia ; School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Newcastle, NSW 2308, Australia
| | - Bente A Talseth-Palmer
- Information Based Medicine Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW 2305, Australia ; School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Newcastle, NSW 2308, Australia
| | - Tiffany-Jane Evans
- Information Based Medicine Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW 2305, Australia ; School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Newcastle, NSW 2308, Australia
| | - Desma M Grice
- Information Based Medicine Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW 2305, Australia ; CSIRO Preventative Health Flagship and Animal, CSIRO Food and Health Sciences Division, North Ryde, NSW 2113, Australia
| | - Garry N Hannan
- CSIRO Preventative Health Flagship and Animal, CSIRO Food and Health Sciences Division, North Ryde, NSW 2113, Australia
| | - Rodney J Scott
- Information Based Medicine Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW 2305, Australia ; Division of Molecular Medicine, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW 2305, Australia ; School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Newcastle, NSW 2308, Australia
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Abstract
Alus are transposable elements belonging to the short interspersed element family. They occupy over 10% of human genome and have been spreading through genomes over the past 65 million years. In the past, they were considered junk DNA with little function that took up genome volumes. Today, Alus and other transposable elements emerge to be key players in cellular function, including genomic activities, gene expression regulations, and evolution. Here we summarize the current understanding of Alu function in genome and gene expression regulation in human cell nuclei.
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Affiliation(s)
- Chen Wang
- Department of Cell and Molecular Biology; Northwestern University; Feinberg School of Medicine; Chicago, IL USA
| | - Sui Huang
- Department of Cell and Molecular Biology; Northwestern University; Feinberg School of Medicine; Chicago, IL USA
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White RR, Sung P, Vestal CG, Benedetto G, Cornelio N, Richardson C. Double-strand break repair by interchromosomal recombination: an in vivo repair mechanism utilized by multiple somatic tissues in mammals. PLoS One 2013; 8:e84379. [PMID: 24349572 PMCID: PMC3862804 DOI: 10.1371/journal.pone.0084379] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Accepted: 11/22/2013] [Indexed: 01/22/2023] Open
Abstract
Homologous recombination (HR) is essential for accurate genome duplication and maintenance of genome stability. In eukaryotes, chromosomal double strand breaks (DSBs) are central to HR during specialized developmental programs of meiosis and antigen receptor gene rearrangements, and form at unusual DNA structures and stalled replication forks. DSBs also result from exposure to ionizing radiation, reactive oxygen species, some anti-cancer agents, or inhibitors of topoisomerase II. Literature predicts that repair of such breaks normally will occur by non-homologous end-joining (in G1), intrachromosomal HR (all phases), or sister chromatid HR (in S/G2). However, no in vivo model is in place to directly determine the potential for DSB repair in somatic cells of mammals to occur by HR between repeated sequences on heterologs (i.e., interchromosomal HR). To test this, we developed a mouse model with three transgenes—two nonfunctional green fluorescent protein (GFP) transgenes each containing a recognition site for the I-SceI endonuclease, and a tetracycline-inducible I-SceI endonuclease transgene. If interchromosomal HR can be utilized for DSB repair in somatic cells, then I-SceI expression and induction of DSBs within the GFP reporters may result in a functional GFP+ gene. Strikingly, GFP+ recombinant cells were observed in multiple organs with highest numbers in thymus, kidney, and lung. Additionally, bone marrow cultures demonstrated interchromosomal HR within multiple hematopoietic subpopulations including multi-lineage colony forming unit–granulocyte-erythrocyte-monocyte-megakaryocte (CFU-GEMM) colonies. This is a direct demonstration that somatic cells in vivo search genome-wide for homologous sequences suitable for DSB repair, and this type of repair can occur within early developmental populations capable of multi-lineage differentiation.
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Affiliation(s)
- Ryan R. White
- Department of Biology, University of North Carolina-Charlotte, Charlotte, North Carolina, United States of America
| | - Patricia Sung
- Developmental Biology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - C. Greer Vestal
- Department of Biology, University of North Carolina-Charlotte, Charlotte, North Carolina, United States of America
| | - Gregory Benedetto
- Department of Biology, University of North Carolina-Charlotte, Charlotte, North Carolina, United States of America
| | - Noelle Cornelio
- Department of Biology, University of North Carolina-Charlotte, Charlotte, North Carolina, United States of America
| | - Christine Richardson
- Department of Biology, University of North Carolina-Charlotte, Charlotte, North Carolina, United States of America
- * E-mail:
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Borelli I, Barberis MA, Spina F, Casalis Cavalchini GC, Vivanet C, Balestrino L, Micheletti M, Allavena A, Sala P, Carcassi C, Pasini B. A unique MSH2 exon 8 deletion accounts for a major portion of all mismatch repair gene mutations in Lynch syndrome families of Sardinian origin. Eur J Hum Genet 2012; 21:154-61. [PMID: 22781090 DOI: 10.1038/ejhg.2012.150] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Lynch syndrome is an autosomal-dominant hereditary condition predisposing to the development of specific cancers, because of germline mutations in the DNA-mismatch repair (MMR) genes. Large genomic deletions represent a significant fraction of germline mutations, particularly among the MSH2 gene, in which they account for 20% of the mutational spectrum. In this study we analyzed 13 Italian families carrying MSH2 exon 8 deletions, 10 of which of ascertained Sardinian origin. The overrepresentation of Sardinians was unexpected, as families from Sardinia account for a small quota of MMR genes mutation tests performed in our laboratory. The hypothesis that such a result is owing to founder effects in Sardinia was tested by breakpoint junctions sequencing and haplotype analyses. Overall, five different exon eight deletions were identified, two of which recurrent in families, all apparently unrelated, of Sardinian origin (one in eight families, one in two families). The c.1277-1180_1386+2226del3516insCATTCTCTTTGAAAA deletion shares the same haplotype between all families and appears so far restricted to the population of South-West Sardinia, showing the typical features of a founder effect. The three non-Sardinian families showed three different breakpoint junctions and haplotypes, suggesting independent mutational events. This work has useful implications in genetic testing for Lynch syndrome. We developed a quick test for each of the identified deletions: this can be particularly useful in families of Sardinian origin, in which MSH2 exon 8 deletions may represent 50% of the overall mutational spectrum of the four MMR genes causing Lynch syndrome.
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Affiliation(s)
- Iolanda Borelli
- Department of Genetics, Biology and Biochemistry, University of Turin, Via Santena 19, Turin, Italy.
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Lotsari JE, Gylling A, Abdel-Rahman WM, Nieminen TT, Aittomäki K, Friman M, Pitkänen R, Aarnio M, Järvinen HJ, Mecklin JP, Kuopio T, Peltomäki P. Breast carcinoma and Lynch syndrome: molecular analysis of tumors arising in mutation carriers, non-carriers, and sporadic cases. Breast Cancer Res 2012; 14:R90. [PMID: 22691310 PMCID: PMC3446353 DOI: 10.1186/bcr3205] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Revised: 05/24/2012] [Accepted: 06/12/2012] [Indexed: 11/24/2022] Open
Abstract
INTRODUCTION Breast carcinoma is the most common cancer in women, but its incidence is not increased in Lynch syndrome (LS) and studies on DNA mismatch repair deficiency (MMR) in LS-associated breast cancers have arrived at conflicting results. This study aimed to settle the question as to whether breast carcinoma belongs to the LS tumor spectrum. METHODS MMR status and epigenetic profiles were determined for all available breast carcinomas identified among 200 LS families from a nation-wide registry (23 tumors from mutation carriers and 18 from non-carriers). Sporadic breast carcinomas (n = 49) and other cancers (n = 105) from MMR gene mutation carriers were studied for comparison. RESULTS The proportion of breast carcinomas that were MMR-deficient based on absent MMR protein, presence of microsatellite instability, or both was significantly (P = 0.00016) higher among breast carcinomas from mutation carriers (13/20, 65%) compared to non-carriers (0/14, 0%). While the average age at breast carcinoma diagnosis was similar in carriers (56 years) and non-carriers (54 years), it was lower for MMR-deficient versus proficient tumors in mutation carriers (53 years versus 61 years, P = 0.027). Among mutation carriers, absent MMR protein was less frequent in breast carcinoma (65%) than in any of seven other tumor types studied (75% to 100%). Tumor suppressor promoter methylation patterns were organ-specific and similar between breast carcinomas from mutation carriers and non-carriers. CONCLUSIONS Breast carcinoma from MMR gene mutation carriers resembles common breast carcinoma in many respects (for example, general clinicopathological and epigenetic profiles). MMR status makes a distinction: over half are MMR-deficient typical of LS spectrum tumors, while the remaining subset which is MMR-proficient may develop differently. The results are important for appropriate surveillance in mutation carriers and may be relevant for LS diagnosis in selected cases.
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Affiliation(s)
- Johanna E Lotsari
- Department of Medical Genetics, Biomedicum Helsinki, P.O.Box 63 (Haartmaninkatu 8), University of Helsinki, Helsinki, Finland, FIN-00014
| | - Annette Gylling
- Department of Medical Genetics, Biomedicum Helsinki, P.O.Box 63 (Haartmaninkatu 8), University of Helsinki, Helsinki, Finland, FIN-00014
| | - Wael M Abdel-Rahman
- Department of Medical Genetics, Biomedicum Helsinki, P.O.Box 63 (Haartmaninkatu 8), University of Helsinki, Helsinki, Finland, FIN-00014
- College of Health Sciences, University of Sharjah, P.O. 27272 Sharjah, United Arab Emirates
| | - Taina T Nieminen
- Department of Medical Genetics, Biomedicum Helsinki, P.O.Box 63 (Haartmaninkatu 8), University of Helsinki, Helsinki, Finland, FIN-00014
| | - Kristiina Aittomäki
- Department of Clinical Genetics, Helsinki University Central Hospital, P.O. Box 160 (Meilahdentie 2), Helsinki, Finland, FIN-00029
| | - Marjukka Friman
- Department of Pathology, Jyväskylä Central Hospital, (Keskussairaalantie 19), Jyväskylä, Finland, FIN-40620
| | - Reino Pitkänen
- Department of Pathology, Jyväskylä Central Hospital, (Keskussairaalantie 19), Jyväskylä, Finland, FIN-40620
| | - Markku Aarnio
- Department of Surgery, Jyväskylä Central Hospital, (Keskussairaalantie 19), Jyväskylä, Finland, FIN-40620
| | - Heikki J Järvinen
- Department of Surgery, Helsinki University Central Hospital, P.O Box 340 (Haartmaninkatu 4), Helsinki, Finland, FIN-00029
| | - Jukka-Pekka Mecklin
- Department of Surgery, Jyväskylä Central Hospital, (Keskussairaalantie 19), Jyväskylä, Finland, FIN-40620
| | - Teijo Kuopio
- Department of Pathology, Jyväskylä Central Hospital, (Keskussairaalantie 19), Jyväskylä, Finland, FIN-40620
| | - Päivi Peltomäki
- Department of Medical Genetics, Biomedicum Helsinki, P.O.Box 63 (Haartmaninkatu 8), University of Helsinki, Helsinki, Finland, FIN-00014
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Tomsic J, Senter L, Liyanarachchi S, Clendenning M, Vaughn CP, Jenkins MA, Hopper JL, Young J, Samowitz W, de la Chapelle A. Recurrent and founder mutations in the PMS2 gene. Clin Genet 2012; 83:238-43. [PMID: 22577899 DOI: 10.1111/j.1399-0004.2012.01898.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2012] [Revised: 05/04/2012] [Indexed: 12/22/2022]
Abstract
Germline mutations in PMS2 are associated with Lynch syndrome (LS), the most common known cause of hereditary colorectal cancer. Mutation detection in PMS2 has been difficult due to the presence of several pseudogenes, but a custom-designed long-range PCR strategy now allows adequate mutation detection. Many mutations are unique. However, some mutations are observed repeatedly across individuals not known to be related due to the mutation being either recurrent, arising multiple times de novo at hot spots for mutations, or of founder origin, having occurred once in an ancestor. Previously, we observed 36 distinct mutations in a sample of 61 independently ascertained Caucasian probands of mixed European background with PMS2 mutations. Eleven of these mutations were detected in more than one individual not known to be related and of these, six were detected more than twice. These six mutations accounted for 31 (51%) ostensibly unrelated probands. Here, we performed genotyping and haplotype analysis in four mutations observed in multiple probands and found two (c.137G>T and exon 10 deletion) to be founder mutations and one (c.903G>T) a probable founder. One (c.1A>G) could not be evaluated for founder mutation status. We discuss possible explanations for the frequent occurrence of founder mutations in PMS2.
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Affiliation(s)
- J Tomsic
- Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
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Considerations on the Performance of Immunohistochemistry for Mismatch Repair Gene Proteins in Cases of Sebaceous Neoplasms and Keratoacanthomas With Reference to Muir–Torre Syndrome. Am J Dermatopathol 2012; 34:416-22. [DOI: 10.1097/dad.0b013e3182226a28] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Solyom S, Kazazian HH. Mobile elements in the human genome: implications for disease. Genome Med 2012; 4:12. [PMID: 22364178 PMCID: PMC3392758 DOI: 10.1186/gm311] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Accepted: 02/22/2012] [Indexed: 02/07/2023] Open
Abstract
Perhaps as much as two-thirds of the mammalian genome is composed of mobile genetic elements ('jumping genes'), a fraction of which is still active or can be reactivated. By their sheer number and mobility, retrotransposons, DNA transposons and endogenous retroviruses have shaped our genotype and phenotype both on an evolutionary scale and on an individual level. Notably, at least the non-long terminal repeat retrotransposons are still able to cause disease by insertional mutagenesis, recombination, providing enzymatic activities for other mobile DNA, and perhaps by transcriptional overactivation and epigenetic effects. Currently, there are nearly 100 examples of known retroelement insertions that cause disease. In this review, we highlight those genome-scale technologies that have expanded our knowledge of the diseases that these mobile elements can elicit, and we discuss the potential impact of these findings for medicine. It is now likely that at least some types of cancer and neurological disorders arise as a result of retrotransposon mutagenesis.
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Affiliation(s)
- Szilvia Solyom
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Broadway Research Building, Room 412, 733 N, Broadway, Baltimore, MD 21205, USA.
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Abstract
Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline loss of a DNA mismatch repair gene. In a significant proportion of cases, loss of function of the MSH2 mismatch repair gene is caused by large heterogeneous deletions involving MSH2 and/or the adjacent EPCAM gene. These deletions usually result from homologous malrecombination events between Alu elements, a family of short interspersed nuclear elements (SINE). Recent recognition that the extent of these deletions influences phenotypic outcome provided new impetus for fine-mapping the breakpoints. In doing so, Pérez-Cabornero and colleagues uncovered new evidence for Alu-mediated ancestral founder deletions within MSH2 in the Spanish Lynch syndrome population (as reported beginning on pages 1546 and 1556 in this issue of the journal). This is the first such finding to date and prompted a revisitation of the role of Alu elements in the causation of Lynch syndrome. Whether Alu density is a danger sign for genomic regions prone to rearrangement and what additional factors may be required to actuate these events remain to be discovered.
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Affiliation(s)
- Megan P Hitchins
- Medical Epigenetics Laboratory, Lowy Cancer Research Centre, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.
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Alterations of copy number of methylation pattern in mismatch repair genes by methylation specific-multiplex ligation-dependent probe amplification in cases of colon cancer. Balkan J Med Genet 2011; 14:25-34. [PMID: 24052709 PMCID: PMC3776700 DOI: 10.2478/v10034-011-0044-x] [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] [Indexed: 11/21/2022] Open
Abstract
Genetic alterations and changes in genomic DNA cytosine methylation patterns are associated with all types of cancer and are caused by germline mutations in DNA mismatch repair (MMR) genes, predominantly MLH1 (MutL homolog 1, 19 exons) and MSH2 (MutS homolog 2, 16 exons). Genomic DNA was extracted from tissue samples embedded in paraffin from 49 patients with adenocarcinoma and from 21 patients with carcinoma for the study group; genomic DNA was extracted from lymphocytes from 10 healthy donors for the control group. We used methylation specific multiplex ligation-dependent probe amplification (MS-ML-PA), which allows the detection of copy number changes and unusual methylation levels of 10 to 50 different sequences in one reaction by use of the methylation-sensitive restriction enzyme HhaI and sequence-specific capillary electrophoresis for the study of 24 genes. We found the mean methylation rates for MLH1 (97.14%), MSH2 (24.28%), MSH6 (MutS homolog 6) (67.14%), MSH3 (MutS homolog 3) (78.57%), MLH3 (MutL homolog 3) (75.71%), PMS2 (postmeiotic segregation increased 2) (65.71%), MGMT(O-6-methylguanine-DNA methyltransferase ) (82.85%). We conclude that the mismatch repair (MMR) system is critical for the maintenance of genomic stability.
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A novel exonic rearrangement affecting MLH1 and the contiguous LRRFIP2 is a founder mutation in Portuguese Lynch syndrome families. Genet Med 2011; 13:895-902. [DOI: 10.1097/gim.0b013e31821dd525] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
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Tomsic J, Liyanarachchi S, Hampel H, Morak M, Thomas BC, Raymond VM, Chittenden A, Schackert HK, Gruber SB, Syngal S, Viel A, Holinski-Feder E, Thibodeau SN, de la Chapelle A. An American founder mutation in MLH1. Int J Cancer 2011; 130:2088-95. [PMID: 21671475 DOI: 10.1002/ijc.26233] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2011] [Accepted: 05/19/2011] [Indexed: 01/10/2023]
Abstract
Mutations in the mismatch repair genes cause Lynch syndrome (LS), conferring high risk of colorectal, endometrial and some other cancers. After the same splice site mutation in the MLH1 gene (c.589-2A>G) had been observed in four ostensibly unrelated American families with typical LS cancers, its occurrence in comprehensive series of LS cases (Mayo Clinic, Germany and Italy) was determined. It occurred in 10 out of 995 LS mutation carriers (1.0%) diagnosed in the Mayo Clinic diagnostic laboratory. It did not occur among 1,803 cases tested for MLH1 mutations by the German HNPCC consortium, while it occurred in three probands and an additional five family members diagnosed in Italy. In the U.S., the splice site mutation occurs on a large (∼4.8 Mb) shared haplotype that also harbors the variant c.2146G>A, which predicts a missense change in codon 716 referred to here as V716M. In Italy, it occurs on a different, shorter shared haplotype (∼2.2 Mb) that does not carry V716M. The V716M variant was found to be present by itself in the U.S., German and Italian populations with individuals sharing a common haplotype of 280 kb, allowing us to calculate that the variant arose around 5,600 years ago (225 generations; 95% confidence interval 183-272). The splice site mutation in America arose or was introduced some 450 years ago (18 generations; 95% confidence interval 14-23); it accounts for 1.0% all LS in the Unites States and can be readily screened for.
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Affiliation(s)
- Jerneja Tomsic
- Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
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Abstract
Colorectal cancer is common in the Western world; ~5% of individuals diagnosed with colorectal cancer have an identifiable inherited genetic predisposition to this malignancy. Genetic testing and rational clinical management recommendations currently exist for the management of individuals with a variety of colorectal cancer syndromes, including hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome), familial adenomatous polyposis (FAP), MYH-associated polyposis (MAP), and the hamartomatous polyposis syndromes (Peutz-Jeghers, juvenile polyposis, and Cowden disease). In addition to colorectal neoplasia, these syndromes frequently predispose carriers to a variety of extracolonic cancers. The elucidation of the genetic basis of several colorectal cancer predisposition syndromes over the past two decades has allowed for better management of individuals who are either affected with, or at-risk for inherited colorectal cancer syndromes. Appropriate multidisciplinary management of these individuals includes genetic counseling, genetic testing, clinical screening, and treatment recommendations.
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Affiliation(s)
- Robert Gryfe
- Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada
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Abstract
PURPOSE Lynch syndrome accounts for 2-4% of all colorectal cancer, and is mainly caused by germline mutations in the DNA mismatch repair genes. Our aim was to characterize the genetic mutation responsible for Lynch syndrome in an extensive Colombian family and to study its prevalence in Antioquia. METHODS A Lynch syndrome family fulfilling Amsterdam criteria II was studied by immunohistochemistry and by multiplex ligation-dependent probe amplification (MLPA). Results were confirmed by additional independent MLPA, Southern blotting, and sequencing. RESULTS Index case tumor immunohistochemistry results were MLH1-, MSH2+, MSH6+, and PMS2-. MLPA analysis detected a duplication of exons 12 and 13 of MLH1. This mutation was confirmed and characterized precisely to span 4219 base pairs. Duplication screening in this family led to the identification of six additional carriers and 13 noncarriers. We also screened 123 early-onset independent colorectal cancer cases from the same area and identified an additional unrelated carrier. CONCLUSION A novel duplication of exons 12 and 13 of the MLH1 gene was detected in two independent Lynch syndrome families from Colombia. A putative founder effect and prescreening Lynch syndrome Antioquia families for this specific mutation before thorough mismatch repair mutational screening could be suggested.
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Kaneko H, Dridi S, Tarallo V, Gelfand BD, Fowler BJ, Cho WG, Kleinman ME, Ponicsan SL, Hauswirth WW, Chiodo VA, Karikó K, Yoo JW, Lee DK, Hadziahmetovic M, Song Y, Misra S, Chaudhuri G, Buaas FW, Braun RE, Hinton DR, Zhang Q, Grossniklaus HE, Provis JM, Madigan MC, Milam AH, Justice NL, Albuquerque RJC, Blandford AD, Bogdanovich S, Hirano Y, Witta J, Fuchs E, Littman DR, Ambati BK, Rudin CM, Chong MMW, Provost P, Kugel JF, Goodrich JA, Dunaief JL, Baffi JZ, Ambati J. DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature 2011; 471:325-30. [PMID: 21297615 PMCID: PMC3077055 DOI: 10.1038/nature09830] [Citation(s) in RCA: 476] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2010] [Accepted: 01/18/2011] [Indexed: 12/15/2022]
Abstract
Geographic atrophy (GA), an untreatable advanced form of age-related macular degeneration, results from retinal pigmented epithelium (RPE) cell degeneration. Here we show that the microRNA (miRNA)-processing enzyme DICER1 is reduced in the RPE of humans with GA, and that conditional ablation of Dicer1, but not seven other miRNA-processing enzymes, induces RPE degeneration in mice. DICER1 knockdown induces accumulation of Alu RNA in human RPE cells and Alu-like B1 and B2 RNAs in mouse RPE. Alu RNA is increased in the RPE of humans with GA, and this pathogenic RNA induces human RPE cytotoxicity and RPE degeneration in mice. Antisense oligonucleotides targeting Alu/B1/B2 RNAs prevent DICER1 depletion-induced RPE degeneration despite global miRNA downregulation. DICER1 degrades Alu RNA, and this digested Alu RNA cannot induce RPE degeneration in mice. These findings reveal a miRNA-independent cell survival function for DICER1 involving retrotransposon transcript degradation, show that Alu RNA can directly cause human pathology, and identify new targets for a major cause of blindness.
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Affiliation(s)
- Hiroki Kaneko
- Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40506, USA
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Borràs E, Pineda M, Blanco I, Jewett EM, Wang F, Teulé A, Caldés T, Urioste M, Martínez-Bouzas C, Brunet J, Balmaña J, Torres A, Ramón y Cajal T, Sanz J, Pérez-Cabornero L, Castellví-Bel S, Alonso A, Lanas A, González S, Moreno V, Gruber SB, Rosenberg NA, Mukherjee B, Lázaro C, Capellá G. MLH1 founder mutations with moderate penetrance in Spanish Lynch syndrome families. Cancer Res 2010; 70:7379-91. [PMID: 20858721 DOI: 10.1158/0008-5472.can-10-0570] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The variants c.306+5G>A and c.1865T>A (p.Leu622His) of the DNA repair gene MLH1 occur frequently in Spanish Lynch syndrome families. To understand their ancestral history and clinical effect, we performed functional assays and a penetrance analysis and studied their genetic and geographic origins. Detailed family histories were taken from 29 carrier families. Functional analysis included in silico and in vitro assays at the RNA and protein levels. Penetrance was calculated using a modified segregation analysis adjusted for ascertainment. Founder effects were evaluated by haplotype analysis. The identified MLH1 c.306+5G>A and c.1865T>A (p.Leu622His) variants are absent in control populations and segregate with the disease. Tumors from carriers of both variants show microsatellite instability and loss of expression of the MLH1 protein. The c.306+5G>A variant is a pathogenic mutation affecting mRNA processing. The c.1865T>A (p.Leu622His) variant causes defects in MLH1 expression and stability. For both mutations, the estimated penetrance is moderate (age-cumulative colorectal cancer risk by age 70 of 20.1% and 14.1% for c.306+5G>A and of 6.8% and 7.3% for c.1865T>A in men and women carriers, respectively) in the lower range of variability estimated for other pathogenic Spanish MLH1 mutations. A common haplotype was associated with each of the identified mutations, confirming their founder origin. The ages of c.306+5G>A and c.1865T>A mutations were estimated to be 53 to 122 and 12 to 22 generations, respectively. Our results confirm the pathogenicity, moderate penetrance, and founder origin of the MLH1 c.306+5G>A and c.1865T>A mutations. These findings have important implications for genetic counseling and molecular diagnosis of Lynch syndrome.
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Affiliation(s)
- Ester Borràs
- Laboratori de Recerca Translacional, Institut Català d'Oncologia, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
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Abstract
Mutations in DNA mismatch repair genes underlie lynch syndrome (HNPCC). Lynch syndrome resulting from mutations in MSH6 is considered to be attenuated in comparison to that caused by mutations in MLH1 and MSH2, thus more likely to be under diagnosed. In this study we report of a common mutation in the MSH6 gene in Ashkenazi Jews. Genetic counseling and diagnostic work-up for HNPCC was conducted in families who attended the high risk clinic for inherited cancer. We identified the mutation c.3984_3987dup in the MSH6 gene in 19 members of four unrelated Ashkenazi families. This mutation results in truncation of the transcript and in loss of expression of the MSH6 protein in tumors. Tumor spectrum among carriers included colon, endometrial, gastric, ovarian, urinary, and breast cancer. All but one family qualified for the Bethesda guidelines and none fulfilled the Amsterdam Criteria. Members of one family also co-inherited the c.6174delT mutation in the BRCA2 gene. The c.3984_3987dup in the MSH6 gene is a mutation leading to HNPCC among Ashkenazi Jews. This is most probably a founder mutation. In contrast to the c.1906G>C founder mutation in the MSH2 gene, tumors tend to occur later in life, and none of the families qualified for the Amsterdam criteria. c.3984_3987dup is responsible for 1/6 of the mutations identified among Ashkenazi HNPCC families in our cohort. Both mutations: c.3984_3987dup and c.1906G>C account for 61% of HNPCC Ashkenazi families in this cohort. These findings are of great importance for counseling, diagnosis, management and surveillance for Ashkenazi families with Lynch syndrome.
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Abstract
Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is the most common hereditary colorectal cancer (CRC) syndrome, accounting for approximately 2-5% of all newly diagnosed cases of CRC. Patients with LS have an increased lifetime risk of colorectal (52.2% in women and 68.7% in men) and endometrial cancer (15-70%), as well as certain extra-colonic cancers. Germline mutations in one of several DNA mismatch repair genes underlie LS. Molecular testing has emerged as an indispensable strategy for the diagnosis of LS. The diagnostic work-up of at-risk individuals includes a careful family history evaluation, microsatellite instability, immunohistochemistry and germline DNA analysis. A positive test result can guide clinicians in formulating the appropriate screening, surveillance and management strategies. However, because of the absence of an overt phenotype, such as a diffuse polyposis, it is not always straightforward to recognize LS clinically.
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Affiliation(s)
- Maria S Pino
- Gastrointestinal Unit, Massachusetts General Hospital, 50 Blossom Street, Boston, MA 02114, USA
| | - Daniel C Chung
- Gastrointestinal Unit, Massachusetts General Hospital, 50 Blossom Street, Boston, MA 02114, USA
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