Real-world outcome of universal screening for Lynch syndrome in Japanese patients with colorectal cancer highlights the importance of targeting patients with young-onset disease

Atsushi Yamada; Yui Matsuoka; Sachiko Minamiguchi; Yoshihiro Yamamoto; Tomohiro Kondo; Tomohiko Sunami; Takahiro Horimatsu; Kenji Kawada; Hiroshi Seno; Masako Torishima; Hiromi Murakami; Takahiro Yamada; Shinji Kosugi; Kokichi Sugano; Manabu Muto

doi:10.3892/mco.2021.2409

Real-world outcome of universal screening for Lynch syndrome in Japanese patients with colorectal cancer highlights the importance of targeting patients with young-onset disease

Mol Clin Oncol. 2021 Dec;15(6):247. doi: 10.3892/mco.2021.2409. Epub 2021 Oct 1.

Authors

Affiliations

¹ Department of Clinical Oncology, Kyoto University Hospital, Kyoto City, Kyoto 606-8507, Japan.
² Department of Clinical Data Science Oncology, Graduate School of Medicine, Kyoto University, Kyoto City, Kyoto 606-8507, Japan.
³ Department of Diagnostic Pathology, Graduate School of Medicine, Kyoto University, Kyoto City, Kyoto 606-8507, Japan.
⁴ Department of Surgery, Kyoto University Hospital, Kyoto City, Kyoto 606-8507, Japan.
⁵ Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto City, Kyoto 606-8507, Japan.
⁶ Clinical Genetics Unit, Kyoto University Hospital, Kyoto City, Kyoto 606-8507, Japan.
⁷ Oncogene Research Unit and Cancer Prevention Unit, Tochigi Cancer Center Research Institute, Utsunomiya, Tochigi 320-0834, Japan.

Abstract

Despite the recommendations of the latest guidelines, the practical efficacy of universal screening for identifying Lynch syndrome (LS) among patients with colorectal cancer (CRC) may be limited in the real world due to infrequent referrals and the difficulties of genetic testing. Thus, the present study aimed to retrospectively analyze the results of universal screening of patients with CRC at a referral hospital in Japan. Immunohistochemistry was performed for mismatch repair proteins [including DNA mismatch repair protein MSH6 (MSH6), mismatch repair endonuclease PMS2 (PMS2), DNA mismatch repair protein Msh2 (MSH2) and DNA mismatch repair protein Mlh1 (MLH1)] and BRAF V600E mutation. Tumors that showed the following were considered to indicate LS and patients with such tumors were designated as genetic testing candidates (GTCs): i) Loss of MSH6/MSH2; ii) loss of MSH6 alone; iii) loss of PMS2 alone; and iv) loss of PMS2/MLH1 with negative BRAF V600E. MLH1 methylation and BRAF V600E mutation were analyzed in deficient mismatch repair (dMMR) tumors retrospectively. The frequency of dMMR and GTCs in an independent cohort of patients with young-onset CRC were also investigated. Universal screening revealed dMMR tumors, GTCs and LS probands in 7.3, 3.9 and 0.4%, respectively, of 463 patients with CRC. Although dMMR tumors were observed in both younger (<50 years) and older (≥60 years) patients, the GTCs were enriched in younger individuals. Evaluation of mismatch repair status in an independent cohort confirmed the high rate of GTCs in patients with young-onset CRC. The low detection rate of LS demonstrated in this study questions the implementation of routine universal screening in regions with low prevalence of LS. Considering the enrichment of GTCs in young-onset CRCs, age-restricted strategies may be simple and efficient practical alternatives to universal screening in the real world.

Keywords: Lynch syndrome; colorectal cancer; real-world; universal screening; young-onset.