Yamada Atsushi, Matsuoka Yui, Minamiguchi Sachiko, Yamamoto Yoshihiro, Kondo Tomohiro, Sunami Tomohiko, Horimatsu Takahiro, Kawada Kenji, Seno Hiroshi, Torishima Masako, Murakami Hiromi, Yamada Takahiro, Kosugi Shinji, Sugano Kokichi, Muto Manabu
Department of Clinical Oncology, Kyoto University Hospital, Kyoto City, Kyoto 606-8507, Japan.
Department of Clinical Data Science Oncology, Graduate School of Medicine, Kyoto University, Kyoto City, Kyoto 606-8507, Japan.
Mol Clin Oncol. 2021 Dec;15(6):247. doi: 10.3892/mco.2021.2409. Epub 2021 Oct 1.
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. methylation and 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.
尽管有最新指南的建议，但由于转诊不频繁和基因检测困难，在现实世界中，对结直肠癌（CRC）患者进行林奇综合征（LS）的普遍筛查的实际效果可能有限。因此，本研究旨在回顾性分析日本一家转诊医院对CRC患者进行普遍筛查的结果。对错配修复蛋白[包括DNA错配修复蛋白MSH6（MSH6）、错配修复内切酶PMS2（PMS2）、DNA错配修复蛋白Msh2（MSH2）和DNA错配修复蛋白Mlh1（MLH1）]和BRAF V600E突变进行免疫组织化学检测。出现以下情况的肿瘤被认为提示LS，患有此类肿瘤的患者被指定为基因检测候选者（GTC）：i）MSH6/MSH2缺失；ii）单独MSH6缺失；iii）单独PMS2缺失；iv）PMS2/MLH1缺失且BRAF V600E为阴性。对缺陷错配修复（dMMR）肿瘤进行回顾性分析，检测甲基化和V600E突变情况。还调查了年轻发病CRC患者独立队列中的dMMR和GTC频率。在463例CRC患者中，普遍筛查分别发现dMMR肿瘤、GTC和LS先证者的比例为7.3%、3.9%和0.4%。尽管在年轻（<50岁）和老年（≥60岁）患者中均观察到dMMR肿瘤，但GTC在年轻个体中更为富集。在一个独立队列中对错配修复状态的评估证实了年轻发病CRC患者中GTC的高比例。本研究中显示的LS低检出率对LS患病率低的地区实施常规普遍筛查提出了质疑。考虑到GTC在年轻发病CRC中的富集，年龄限制策略可能是现实世界中普遍筛查简单而有效的实用替代方案。
