Comparisons of screening strategies for identifying Lynch syndrome among patients with MLH1-deficient colorectal cancer


BRAF and MLH1 promoter methylation testings have been proven effective prescreens for Lynch Syndrome. We aimed to compare different screening strategies for Lynch Syndrome in patients with MLH1(−) CRC. Patients with MLH1(−) CRC who had been tested for BRAF mutation and germline variants of DNA mismatch repair genes were included. We compared the sensitivities and specificities for identifying Lynch Syndrome and the cost-effectiveness of four screening approaches that used the following tests as prescreens: BRAF testing, MLH1 methylation testing, MLH1 methylation & BRAF testing, and MLH1 methylation testing & Revised Bethesda Criteria. Of 109 patients included, 23 (21.1%) were Lynch Syndrome patients. BRAF mutation and MLH1 methylation occurred in 6 (5.5%) and 40 (36.7%) patients, respectively. The sensitivity for identifying Lynch syndrome of BRAF testing was 100%, but the specificity was only 7%. MLH1 methylation testing had a lower sensitivity than BRAF testing (97.5% vs 100%), but had a markedly higher specificity (45.3% vs 7%). The combination of the two testings had a slightly higher specificity than MLH1 methylation testing alone (47.7% vs 45.3%). The MLH1 methylation testing approach had a 10% lower cost of identifying MLH1(−) Lynch syndrome carriers per case than universal genetic testing, but it missed 4.5% of patients. BRAF and MLH1 promoter methylation testings as prescreens for Lynch syndrome are less effective in Chinese patients with MLH1(−) CRC than in their Western counterparts. Universal genetic testing could be considered an up-front option for this population.

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This study was funded by the National Natural Science Foundation of China (No. 81871971 to PD), the Science and Technology Planning Project of Guangzhou City of China (No. 201803010117 to PD), and Science and Technology Program Project of Guangzhou (No. 201802020030 to LM). We also thank the Research Data Deposit public platform ( for validating the authenticity of the data of this article (the approval number RDDA2020001429).

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Conceptualization: P-RD and WJ; Methodology: JL, BX and LM; Formal analysis and investigation: JL, EX; Resources: EX, LK, QS, DL, WL, ZH and JT; Writing—original draft preparation: BX and JL; Writing—review and editing: BX and PD; Supervision: WJ and PD; Project administration: ZP and PD; Funding acquisition: ZP and PD.

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Correspondence to Zhizhong Pan or Wu Jiang or Pei-Rong Ding.

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Xiao, B., Luo, J., Xie, E. et al. Comparisons of screening strategies for identifying Lynch syndrome among patients with MLH1-deficient colorectal cancer. Eur J Hum Genet 28, 1555–1562 (2020).

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