Mismatch repair deficiency commonly precedes adenoma formation in Lynch Syndrome-Associated colorectal tumorigenesis

• Published in: Modern pathology 2017-08, Vol.30 (8), p.1144-1151
• Main Authors: Sekine, Shigeki, Mori, Taisuke, Ogawa, Reiko, Tanaka, Masahiro, Yoshida, Hiroshi, Taniguchi, Hirokazu, Nakajima, Takeshi, Sugano, Kokichi, Yoshida, Teruhiko, Kato, Mamoru, Furukawa, Eisaku, Ochiai, Atsushi, Hiraoka, Nobuyoshi
• Format: Article
• Language: English
• Subjects: 631/67/1504/1885; 692/308/2056; Adenocarcinoma - genetics; Adenoma; Adenoma - genetics; Adenomatous polyposis coli; Adult; Aged; Aged, 80 and over; Carcinogenesis - genetics; Colon; Colorectal cancer; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; DNA Mismatch Repair - genetics; Female; Genetic disorders; Humans; Immunohistochemistry; Laboratory Medicine; Male; Medicine; Medicine & Public Health; Microsatellite instability; Middle Aged; Mismatch repair; Mutation; original-article; Pathology; Tumorigenesis; Tumors; Wnt protein; Wnt Signaling Pathway - genetics; Young Adult
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/modpathol.2017.39

Lynch syndrome is a cancer predisposition syndrome caused by germline mutations in mismatch repair (MMR) genes. MMR deficiency is a ubiquitous feature of Lynch syndrome-associated colorectal adenocarcinomas; however, it remains unclear when the MMR-deficient phenotype is acquired during tumorigenesis. To probe this issue, the present study examined genetic alterations and MMR statuses in Lynch syndrome-associated colorectal adenomas and adenocarcinomas, in comparison with sporadic adenomas. Among the Lynch syndrome-associated colorectal tumors, 68 of 86 adenomas (79%) and all adenocarcinomas were MMR-deficient, whereas all the sporadic adenomas were MMR-proficient, as determined by microsatellite instability testing and immunohistochemistry for MMR proteins. Sequencing analyses identified APC or CTNNB1 mutations in the majority of sporadic adenomas (58/84, 69%) and MMR-proficient Lynch syndrome-associated adenomas (13/18, 72%). However, MMR-deficient Lynch syndrome-associated adenomas had less APC or CTNNB1 mutations (25/68, 37%) and frequent frameshift RNF43 mutations involving mononucleotide repeats (45/68, 66%). Furthermore, frameshift mutations affecting repeat sequences constituted 14 of 26 APC mutations (54%) in MMR-deficient adenomas whereas these frameshift mutations were rare in MMR-proficient adenomas in patients with Lynch syndrome (1/12, 8%) and in sporadic adenomas (3/52, 6%). Lynch syndrome-associated adenocarcinomas exhibited mutation profiles similar to those of MMR-deficient adenomas. Considering that WNT pathway activation sufficiently drives colorectal adenoma formation, the distinct mutation profiles of WNT pathway genes in Lynch syndrome-associated adenomas suggest that MMR deficiency commonly precedes adenoma formation.