Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome
Abstract Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome, caused by germline mutations in one of the major genes involved in mismatch repair (MMR): MLH1, MSH2, MSH6 and more rarely, PMS2. Recently, germline deletions in EPCAM have been also associated to the syndrome. Mo...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2018-05-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.1316 |
| _version_ | 1811154926325202944 |
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| author | Nayê Balzan Schneider Tatiane Pastor André Escremim de Paula Maria Isabel Achatz Ândrea Ribeiro dos Santos Fernanda Sales Luiz Vianna Clévia Rosset Manuela Pinheiro Patricia Ashton‐Prolla Miguel Ângelo Martins Moreira Edenir Inêz Palmero Brazilian Lynch Syndrome Study Group |
| author_facet | Nayê Balzan Schneider Tatiane Pastor André Escremim de Paula Maria Isabel Achatz Ândrea Ribeiro dos Santos Fernanda Sales Luiz Vianna Clévia Rosset Manuela Pinheiro Patricia Ashton‐Prolla Miguel Ângelo Martins Moreira Edenir Inêz Palmero Brazilian Lynch Syndrome Study Group |
| author_sort | Nayê Balzan Schneider |
| collection | DOAJ |
| description | Abstract Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome, caused by germline mutations in one of the major genes involved in mismatch repair (MMR): MLH1, MSH2, MSH6 and more rarely, PMS2. Recently, germline deletions in EPCAM have been also associated to the syndrome. Most of the pathogenic MMR mutations found in LS families occur in MLH1 or MSH2. Gene variants include missense, nonsense, frameshift mutations, large genomic rearrangements and splice‐site variants and most of the studies reporting the molecular characterization of LS families have been conducted outside South America. In this study, we analyzed 60 unrelated probands diagnosed with colorectal cancer and LS criteria. Testing for germline mutations and/or rearrangements in the most commonly affected MMR genes (MLH1, MSH2, EPCAM and MSH6) was done by Sanger sequencing and MLPA. Pathogenic or likely pathogenic variants were identified in MLH1 or MSH2 in 21 probands (35.0%). Of these, approximately one‐third were gene rearrangements. In addition, nine variants of uncertain significance (VUS) were identified in 10 (16.6%) of the sixty probands analyzed. Other four novel variants were identified, only in MLH1. Our results suggest that MSH6 pathogenic variants are not common among Brazilian LS probands diagnosed with CRC and that MMR gene rearrangements account for a significant proportion of the germline variants in this population underscoring the need to include rearrangement analysis in the molecular testing of Brazilian individuals with suspected Lynch syndrome. |
| first_indexed | 2024-04-10T04:25:28Z |
| format | Article |
| id | doaj.art-cb5a310aee374f4c9feb6231d782cc58 |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-04-10T04:25:28Z |
| publishDate | 2018-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-cb5a310aee374f4c9feb6231d782cc582023-03-10T15:42:22ZengWileyCancer Medicine2045-76342018-05-01752078208810.1002/cam4.1316Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch SyndromeNayê Balzan Schneider0Tatiane Pastor1André Escremim de Paula2Maria Isabel Achatz3Ândrea Ribeiro dos Santos4Fernanda Sales Luiz Vianna5Clévia Rosset6Manuela Pinheiro7Patricia Ashton‐Prolla8Miguel Ângelo Martins Moreira9Edenir Inêz Palmero10Brazilian Lynch Syndrome Study GroupLaboratório de Medicina Genômica Centro de Pesquisa Experimental Hospital de Clínicas de Porto Alegre (HCPA) and Programa de Pós Graduação em Genética e Biologia Molecular Universidade Federal do Rio Grande do Sul (UFRGS) Porto Alegre BrazilGenetics Program Instituto Nacional de Câncer Rio de Janeiro BrazilMolecular Oncology Research Center Barretos Cancer Hospital Barretos BrazilAC Camargo Cancer Center São Paulo BrazilNúcleo de Pesquisas Oncológicas and Laboratório de Genética Humana e Médica Universidade Federal do Pará Universidade Federal do Pará (UFPA) Belém BrazilLaboratório de Pesquisa em Bioética e Ética na Ciência‐ LAPEBEC ‐ Centro de Pesquisa Experimental Hospital de Clínicas de Porto Alegre Porto Alegre BrazilLaboratório de Medicina Genômica Centro de Pesquisa Experimental Hospital de Clínicas de Porto Alegre (HCPA) and Programa de Pós Graduação em Genética e Biologia Molecular Universidade Federal do Rio Grande do Sul (UFRGS) Porto Alegre BrazilServiço de Genética Instituto Português de Oncologia do Porto (IPO Porto) Porto PortugalLaboratório de Medicina Genômica Centro de Pesquisa Experimental Hospital de Clínicas de Porto Alegre (HCPA) and Programa de Pós Graduação em Genética e Biologia Molecular Universidade Federal do Rio Grande do Sul (UFRGS) Porto Alegre BrazilGenetics Program Instituto Nacional de Câncer Rio de Janeiro BrazilMolecular Oncology Research Center Barretos Cancer Hospital Barretos BrazilAbstract Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome, caused by germline mutations in one of the major genes involved in mismatch repair (MMR): MLH1, MSH2, MSH6 and more rarely, PMS2. Recently, germline deletions in EPCAM have been also associated to the syndrome. Most of the pathogenic MMR mutations found in LS families occur in MLH1 or MSH2. Gene variants include missense, nonsense, frameshift mutations, large genomic rearrangements and splice‐site variants and most of the studies reporting the molecular characterization of LS families have been conducted outside South America. In this study, we analyzed 60 unrelated probands diagnosed with colorectal cancer and LS criteria. Testing for germline mutations and/or rearrangements in the most commonly affected MMR genes (MLH1, MSH2, EPCAM and MSH6) was done by Sanger sequencing and MLPA. Pathogenic or likely pathogenic variants were identified in MLH1 or MSH2 in 21 probands (35.0%). Of these, approximately one‐third were gene rearrangements. In addition, nine variants of uncertain significance (VUS) were identified in 10 (16.6%) of the sixty probands analyzed. Other four novel variants were identified, only in MLH1. Our results suggest that MSH6 pathogenic variants are not common among Brazilian LS probands diagnosed with CRC and that MMR gene rearrangements account for a significant proportion of the germline variants in this population underscoring the need to include rearrangement analysis in the molecular testing of Brazilian individuals with suspected Lynch syndrome.https://doi.org/10.1002/cam4.1316Colorectal cancerLynch syndromeMMR genes |
| spellingShingle | Nayê Balzan Schneider Tatiane Pastor André Escremim de Paula Maria Isabel Achatz Ândrea Ribeiro dos Santos Fernanda Sales Luiz Vianna Clévia Rosset Manuela Pinheiro Patricia Ashton‐Prolla Miguel Ângelo Martins Moreira Edenir Inêz Palmero Brazilian Lynch Syndrome Study Group Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome Cancer Medicine Colorectal cancer Lynch syndrome MMR genes |
| title | Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome |
| title_full | Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome |
| title_fullStr | Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome |
| title_full_unstemmed | Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome |
| title_short | Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome |
| title_sort | germline mlh1 msh2 and msh6 variants in brazilian patients with colorectal cancer and clinical features suggestive of lynch syndrome |
| topic | Colorectal cancer Lynch syndrome MMR genes |
| url | https://doi.org/10.1002/cam4.1316 |
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