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Cancer Med. 2018 May;7(5):2078-2088. doi: 10.1002/cam4.1316. Epub 2018 Mar 25.

Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome.

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Laboratório 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, Brazil.
Genetics Program, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.
AC Camargo Cancer Center, São Paulo, Brazil.
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Núcleo de Pesquisas Oncológicas and Laboratório de Genética Humana e Médica, Universidade Federal do Pará Universidade Federal do Pará (UFPA), Belém, Brazil.
Laboratório de Pesquisa em Bioética e Ética na Ciência- LAPEBEC - Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
Serviço de Genética, Instituto Português de Oncologia do Porto (IPO Porto), Porto, Portugal.
Barretos School of Health Sciences, Dr. Paulo Prata - FACISB, Barretos, Brazil.


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.


Colorectal cancer; Lynch syndrome; MMR genes

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