Incidence and molecular characteristics of deficient mismatch repair conditions across nine different tumors and identification of germline variants involved in Lynch-like syndrome

• Published in: International journal of clinical oncology 2024-07, Vol.29 (7), p.953-963
• Main Authors: Ito, Tetsuya, Yamaguchi, Tatsuro, Kumamoto, Kensuke, Suzuki, Okihide, Chika, Noriyasu, Kawakami, Satoru, Nagai, Tomonori, Igawa, Tsukasa, Fujiyoshi, Kenji, Akagi, Yoshito, Arai, Tomio, Akagi, Kiwamu, Eguchi, Hidetaka, Okazaki, Yasushi, Ishida, Hideyuki
• Format: Article
• Language: English
• Subjects: Adult; Aged; BRCA1 protein; Cancer; Cancer Research; Colorectal carcinoma; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; Colorectal Neoplasms, Hereditary Nonpolyposis - pathology; DNA Methylation; DNA Mismatch Repair - genetics; DNA repair; Exome Sequencing; Female; Gastric cancer; Genetic analysis; Genetic counseling; Genetic screening; Germ-Line Mutation; Humans; Immunohistochemistry; Incidence; Male; Medicine; Medicine & Public Health; Middle Aged; Mismatch repair; MLH1 protein; MSH2 protein; MSH6 protein; MutL Protein Homolog 1 - genetics; Oncology; Original; Original Article; Ovarian cancer; Prostate cancer; Solid tumors; Surgical Oncology; Tumors; Urinary bladder; Urinary tract; Uterine cancer; Whole genome sequencing
• ISSN: 1341-9625; 1437-7772; 1437-7772
• DOI: 10.1007/s10147-024-02518-y

Background Based on molecular characteristics, deficient DNA mismatch repair (dMMR) solid tumors are largely divided into three categories: somatically MLH1 -hypermethylated tumors, Lynch syndrome (LS)-associated tumors, and Lynch-like syndrome (LLS)-associated tumors. The incidence of each of these conditions and the corresponding pathogenic genes related to LLS remain elusive. Methods We identified dMMR tumors in 3609 tumors from 9 different solid organs, including colorectal cancer, gastric cancer, small-bowel cancer, endometrial cancer, ovarian cancer, upper urinary tract cancer, urinary bladder cancer, prostate cancer, and sebaceous tumor, and comprehensively summarized the characterization of dMMR tumors. Characterization of dMMR tumors were performed as loss of at least one of MMR proteins (MLH1, MSH2, MSH6, and PMS2), by immunohistochemistry, followed by MLH1 promotor methylation analysis and genetic testing for MMR genes where appropriate. Somatic variant analysis of MMR genes and whole exome sequencing (WES) were performed in patients with LLS. Results In total, the incidence of dMMR tumors was 5.9% (24/3609). The incidence of dMMR tumors and the proportion of the three categorized dMMR tumors varied considerably with different tumor types. One to three likely pathogenic/pathogenic somatic MMR gene variants were detected in 15 out of the 16 available LLS tumors. One patient each from 12 patients who gave consent to WES demonstrated non- MMR germline variants affect function ( POLQ or BRCA1 ). Conclusions Our data regarding the LS to LLS ratio would be useful for genetic counseling in patients who are suspected to have LS, though the genetic backgrounds for the pathogenesis of LLS need further investigation.