Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study.
Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study.
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DOI：
10.1016/s1470-2045(21)00189-3
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发表时间：
2021-07
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影响因子：
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通讯作者：
International Mismatch Repair Consortium
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作者：
International Mismatch Repair Consortium
目前关于DNA错配修复基因致病变种携带者(林奇综合征)的临床实践指南是基于同一基因中致病变种携带者患结直肠癌的平均年龄特定累积风险(外显率)。我们的目的是根据携带者的性别和居住的大陆来估计同一基因中致病变异的携带者之间的外显差异。我们研究了来自至少三个亲属的5,255个家庭的79,809个亲属，其中至少有一个是错配修复基因的致病或可能致病变异的确诊携带者(1,829个MLH1，2,179个MSH2,798个MSH6,449个PMS2)，由国际错配修复联盟的合作中心从北美、欧洲和澳大拉西亚的15个国家招募。我们使用基于确定条件的改进分离分析来估计平均外显率，并模拟未测量的多基因因素来估计结直肠癌外显率的变异。对于多基因标准差为零的零假设，使用Wald p值检验了影响Lynch综合征携带者患结直肠癌风险的家族危险因素的存在。有强有力的证据表明，存在影响林奇综合征携带者患结直肠癌风险的家族危险因素(P<；三大洲均为0.0001)。这些结果导致来自各大洲的男性和女性在所有致病变种的携带者之间以及MSH2 C.942+3A和GT；T变种的携带者之间患结直肠癌的风险存在广泛的基因内差异。这种变异在MLH1和MSH2变异携带者中更为明显；取决于基因、性别和大陆，7-56%的携带者在80岁之前患结直肠癌的风险低于20%，9-44%的携带者风险超过80%，而只有10%-19%的携带者有40%-60%的风险。我们的研究结果强调了风险修饰物的重要作用，这可能导致个性化的风险评估，以精确预防和早期发现Lynch综合征的结直肠癌。
Current clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the average age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate how much penetrance varies between carriers of pathogenic variants in the same gene by sex and continent of residence of the carrier. We studied 79,809 relatives from 5,255 families, of at least three relatives, in which at least one was a confirmed carrier of a pathogenic or likely pathogenic variant in a mismatch repair gene (1,829 MLH1, 2,179 MSH2, 798 MSH6, 449 PMS2), recruited in 15 countries from North America, Europe and Australasia by the collaborative centres of the International Mismatch Repair Consortium. We used modified segregation analysis conditioned on ascertainment to estimate the average penetrance and modelled unmeasured polygenic factors to estimate the variation in penetrance of colorectal cancer. The existence of familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested using a Wald p-value for the null hypothesis that the polygenic standard deviation is zero. There was strong evidence of the existence of familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p<0.0001 for all three continents). These resulted in a wide within-gene variation in the risk of colorectal cancer for males and females from each continent among carriers of all pathogenic variants combined of each gene, and among carriers of the MSH2 c.942+3A>T variant. The variation was more prominent for MLH1 and MSH2 variant carriers; depending on gene, sex, and continent, with 7–56% of carriers having a risk of colorectal cancer to age 80 of less than 20%, and 9–44% having a risk of more than 80%, while only 10–19% had a risk of 40–60%. Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessment for precision prevention and early detection of colorectal cancer for Lynch syndrome.