Distinct clinical phenotype and genetic testing strategy for Lynch syndrome in China based on a large colorectal cancer cohort

Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) predisposition syndrome. We performed a large‐scale study to assess a screening strategy for identifying LS in Chinese CRC patients in routine clinical testing. A total of 4,195 eligible CRCs were universally screened. Then, 8.7% of CRCs were detected with dMMR. The incidence of LS was 2.7% (115 of 4,195) in this cohort; among patients over 70 years of age, only 0.3% (2 of 678) were diagnosed as LS. Then, 17.4% of LS cases showed large genomic deletions/duplications. LS probands developed CRCs predominantly at proximal colon location. The frequency of BRAF V600E mutation among Chinese CRCs was significantly lower than that among Western populations, and MLH1 promoter methylation significantly improved the efficiency of genetic screening for LS among MLH1‐deficient patients. A comprehensive molecular testing strategy that includes detection of large genomic rearrangements is imperative for the diagnosis of LS. Among CRC patients aged 70 years or younger, a selective strategy for LS screening might be considered for routine clinical testing. What's new? Early diagnosis of Lynch syndrome (LS) can reduce colorectal cancer (CRC) morbidity and mortality. However, in China, where CRC is a significant cause of morbidity, the importance of LS screening remains largely unexplored. This study, based on universal screening of tissues from nearly 4,200 CRC patients in China, reveals an overall LS prevalence of at least 2.7 percent, comparable to prevalence in Western populations. The detection of MLH1 promoter methylation and large genomic rearrangements in DNA mismatch repair genes improved the effectiveness of LS testing, suggesting that modification of LS screening strategies could improve early LS diagnosis in China.