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Germline MLH 1, MSH 2 and MSH 6 variants in Brazilian patients with colorectal cancer and clinical features suggestive of Lynch Syndrome

2018; Wiley; Volume: 7; Issue: 5 Linguagem: Inglês

10.1002/cam4.1316

2045-7634

Nayê Balzan Schneider, Tatiane Pastor, André Escremim de Paula, Maria Isabel Achatz, Ândrea Ribeiro‐dos‐Santos, Fernanda Sales Luiz Vianna, Clévia Rosset, Manuela Pinheiro, Patrícia Ashton‐Prolla, María Manuela Martins, Edenir Inêz Palmero,

Cancer Genomics and Diagnostics

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 ): 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.