Open AccessGermline MLH 1, MSH 2 and MSH 6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome
Author(s) -
Schneider Nayê Balzan,
Pastor Tatiane,
Paula André Escremim de,
Achatz Maria Isabel,
Santos Ândrea Ribeiro dos,
Vianna Fernanda Sales Luiz,
Rosset Clévia,
Pinheiro Manuela,
AshtonProlla Patricia,
Moreira Miguel Ângelo Martins,
Palmero Edenir Inêz
Publication year - 2018
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.1316
Subject(s) - lynch syndrome , germline , genetics , biology , dna mismatch repair , sanger sequencing , frameshift mutation , germline mutation , missense mutation , proband , mutyh , population , multiplex ligation dependent probe amplification , gene , colorectal cancer , mutation , cancer , medicine , exon , environmental health
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 ): MLH 1 , MSH 2 , MSH 6 and more rarely, PMS 2 . Recently, germline deletions in EPCAM have been also associated to the syndrome. Most of the pathogenic MMR mutations found in LS families occur in MLH 1 or MSH 2 . 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 ( MLH 1, MSH 2, EPCAM and MSH 6 ) was done by Sanger sequencing and MLPA . Pathogenic or likely pathogenic variants were identified in MLH 1 or MSH 2 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 MLH 1 . Our results suggest that MSH 6 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.