title: Lynch-like syndrome: characterization and comparison with EPCAM deletion carriers.
abstract: 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.
authors.affiliation: Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Genetic Engineering, Sungkyunkwan University, Suwon, Korea.
authors.forename: So Young
authors.initials: SY
authors.lastname: Kang
authors.forename: Cheol Keun
authors.initials: CK
authors.lastname: Park
authors.forename: Dong Kyung
authors.initials: DK
authors.lastname: Chang
authors.forename: Jong Won
authors.initials: JW
authors.lastname: Kim
authors.forename: Hee Jung
authors.initials: HJ
authors.lastname: Son
authors.forename: Yong Beom
authors.initials: YB
authors.lastname: Cho
authors.forename: Seong Hyeon
authors.initials: SH
authors.lastname: Yun
authors.forename: Hee Cheol
authors.initials: HC
authors.lastname: Kim
authors.forename: Moosik
authors.initials: M
authors.lastname: Kwon
authors.forename: Kyoung-Mee
authors.initials: KM
authors.lastname: Kim
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics*; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D004258:DNA Polymerase III / Q000235:genetics; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D055815:Young Adult
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D004258:DNA Polymerase III
keywords: Lynch-like syndrome; familial colon cancer; mismatch repair deficiency; polymerase