Article
Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome
Registro en:
SCHNEIDER, Nayê Balzan; et al. Germline MLH1, MSH2 and MSH6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome. Cancer Medicine, v.7, n.5, p.2078-2088, 2018.
2045-7634
10.1002/cam4.1316
Autor
Schneider, Nayê Balzan
Pastor, Tatiane
Paula, André Escremim de
Achatz, Maria Isabel
Santos, Ândrea Ribeiro dos
Vianna, Fernanda Sales Luiz
Rosset, Clévia
Pinheiro, Manuela
Ashton-Prolla, Patricia
Moreira, Miguel Ângelo Martins
Palmero, Edenir Inêz
Vargas, Fernando Regla
Múltipla autoria - ver em Notas
Resumen
Brazilian Lynch Study Group
Patrícia Santos Silva, Patrícia Koehler-Santos,
Silvia Liliana
Cossio, Cristina Netto, Gustavo Stumpf da Silva
(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); Fernando Regla Vargas,
Maria Angélica de Lima (Genetics Program Instituto
Nacional de Câncer, Rio de Janeiro, Brazil); Cristovam
Scapulatempo-Neto,
Rui Manuel Reis, André Lopes
Carvalho (Molecular Oncology Research Center, Barretos
Cancer Hospital, Barretos, Brazil); Carla Pinto, Manuel
Rui Teixeira (Serviço de Genética, Instituto Português de
Oncologia do Porto (IPO Porto), Porto, Portugal); Danilo
Vilela Viana, Benedito Mauro Rossi Junea Caris Oliveira,
Henrique Campos Galvão (Oncogenetics Department,
Barretos Cancer Hospital, Barretos, Brazil). Paulo
Assumpção, Geraldo Ishak, Sérgio Lima Júnior (Núcleo
de Pesquisas Oncológicas, Universidade Federal do Pará
e Serviço de Cirurgia Geral e do Aparelho Digestivo,
Hospital Universitário João Barros Barreto, Universidade
Federal do Pará). 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.