Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database
Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database
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DOI：
10.1038/s41436-019-0596-9
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发表时间：
2020-01-01
影响因子：
8.8
通讯作者：
Moller, Pal
中科院分区：
文献类型：
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作者：
Dominguez-Valentin, Mev;Sampson, Julian R.;Moller, Pal
目的影响MLH1、MSH2、MSH6和PMS2的致病性变异引起Lynch综合征，并导致不同但不精确的癌症风险。这项研究旨在根据基因和性别提供年龄和器官特异性癌症风险，并确定癌症后的生存率。方法：我们进行了一项国际性、多中心、前瞻性、观察性研究，使用独立的4类或5类变异携带者的测试和验证队列。验证后，将队列合并，提供6350名参与者和51，646年随访。结果前瞻性观察肿瘤1808例。致病性MLH1和MSH2变异体引起的高转移率显性癌症综合征具有相似的结直肠癌、子宫内膜癌和卵巢癌风险，但年龄较大的MSH2携带者患上尿路癌、上胃肠道癌、脑癌，特别是前列腺癌的风险更高。致病性MSH6变异导致了具有高子宫内膜癌风险的性别限制性特征，但在两种性别中仅适度增加了结直肠癌风险。我们没有证明致病性PMS2变异携带者的癌症风险显著增加。结肠癌、子宫内膜癌或卵巢癌患者的10年粗生存率超过80%。结论Lynch综合征的治疗指南可能需要根据这些不同的基因和性别特异性风险以及最常见的相关癌症的良好预后进行修订。
Purpose Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. Methods We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. Results There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. Conclusion Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.