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L ynch‐like syndrome: Characterization and comparison with EPCAM deletion carriers
Author(s) -
Kang So Young,
Park Cheol Keun,
Chang Dong Kyung,
Kim Jong Won,
Son Hee Jung,
Cho Yong Beom,
Yun Seong Hyeon,
Kim Hee Cheol,
Kwon Moosik,
Kim KyoungMee
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.29133
Subject(s) - lynch syndrome , mlh1 , msh2 , microsatellite instability , germline mutation , germline , dna mismatch repair , biology , pms2 , cancer research , mutation , genetics , cancer , colorectal cancer , gene , microsatellite , allele
Colorectal cancers (CRCs) with microsatellite instability‐high (MSI+) but without detectable germline mutation or hypermethylation in DNA mismatch repair (MMR) genes can be classified as Lynch‐like syndrome (LLS). The underlying mechanism and clinical significances of LLS are largely unknown. We measured MSI and MMR protein expression in 4,765 consecutive CRC cases. Among these, MSI+ cases were further classified based on clinical parameters, germline sequencing of MMR genes or polymerase ε ( POLE ) and δ ( POLD1 ) and promoter methylation analysis of MLH1 and MSH2 . We found that MSI+ and MMR protein‐deficient CRCs comprised 6.3% ( N = 302) of this cohort. On the basis of germline sequencing of 124 cases, we identified 54 LS with MMR germline mutation (LS‐MMR), 15 LS with EPCAM deletions (LS‐EPCAM) and 55 LLS patients. Of the 55 LLS patients, six (10.9%) had variants of unknown significance in the genes tested, and one patient had a novel somatic mutation (p.S459P) in POLE . In patients with biallelic deletions of EPCAM , all tumors and their matched normal mucosa showed promoter hypermethylation of MSH2 . Finally, we found that patients with LLS and LS‐EPCAM shared clinical features that differed from LS‐MMR patients, including lower frequency of fulfillment of the revised Bethesda guidelines (83.6 and 86.7% vs . 98.1% for LS‐MMR) and older mean age at CRC diagnosis (52.6 and 52.7 years vs . 43.9 years for LS‐MMR). We identified somatic mutation in POLE as a rare underlying cause for MMR deficiency in LLS. The similarity between LLS and LS‐EPCAM suggests LLS as a subset of familial MSI+ CRC.