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

Tetsuya Ito; Tatsuro Yamaguchi; Kensuke Kumamoto; Okihide Suzuki; Noriyasu Chika; Satoru Kawakami; Tomonori Nagai; Tsukasa Igawa; Kenji Fujiyoshi; Yoshito Akagi; Tomio Arai; Kiwamu Akagi; Hidetaka Eguchi; Yasushi Okazaki; Hideyuki Ishida

doi:10.1007/s10147-024-02518-y

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

Int J Clin Oncol. 2024 Apr 14. doi: 10.1007/s10147-024-02518-y. Online ahead of print.

Authors

Tetsuya Ito¹, Tatsuro Yamaguchi², Kensuke Kumamoto³, Okihide Suzuki^{4

5}, Noriyasu Chika⁴, Satoru Kawakami⁶, Tomonori Nagai⁷, Tsukasa Igawa⁸, Kenji Fujiyoshi⁹, Yoshito Akagi⁹, Tomio Arai¹⁰, Kiwamu Akagi¹¹, Hidetaka Eguchi¹², Yasushi Okazaki¹², Hideyuki Ishida^{4

5}

Affiliations

¹ Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan. tez1028@saitama-med.ac.jp.
² Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
³ Department of Gastroenterological Surgery, Kagawa University, Kagawa, Japan.
⁴ Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan.
⁵ Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
⁶ Department of Urology, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
⁷ Department of Obstetrics and Gynecology, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
⁸ Department of Urology, Kurume University School of Medicine, Kurume, Japan.
⁹ Department of Surgery, Kurume University, Kurume, Japan.
¹⁰ Department of Pathology, Tokyo Metropolitan Geriatric Institute for Geriatrics and Gerontology, Tokyo, Japan.
¹¹ Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan.
¹² Diagnostics and Therapeutics of Intractable Diseases and Intractable Disease Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.

PMID: 38615286
DOI: 10.1007/s10147-024-02518-y

Abstract

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.

Keywords: Deficient DNA mismatch repair (dMMR); Lynch-like syndrome; dMMR tumors.