Schubert Stephanie A, Ruano Dina, Tiersma Yvonne, Drost Mark, de Wind Niels, Nielsen Maartje, van Hest Liselotte P, Morreau Hans, de Miranda Noel F C C, van Wezel Tom
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Genes Chromosomes Cancer. 2020 Jul 2;59(12):697-701. doi: 10.1002/gcc.22883.
We describe a family severely affected by colorectal cancer (CRC) where whole-exome sequencing identified the coinheritance of the germline variants encoding MSH6 p.Thr1100Met and MUTYH p.Tyr179Cys in, at least, three CRC patients diagnosed before 60 years of age. Digenic inheritance of monoallelic MSH6 variants of uncertain significance and MUTYH variants has been suggested to predispose to Lynch syndrome-associated cancers; however, cosegregation with disease in the familial setting has not yet been established. The identification of individuals carrying multiple potential cancer risk variants is expected to rise with the increased application of whole-genome sequencing and large multigene panel testing in clinical genetic counseling of familial cancer patients. Here we demonstrate the coinheritance of monoallelic variants in MSH6 and MUTYH consistent with cosegregation with CRC, further supporting a role for digenic inheritance in cancer predisposition.
我们描述了一个受结直肠癌（CRC）严重影响的家族，通过全外显子测序发现，在至少三名60岁之前被诊断出患有CRC的患者中，存在编码MSH6 p.Thr1100Met和MUTYH p.Tyr179Cys的种系变异的共同遗传。意义不确定的单等位基因MSH6变异和MUTYH变异的双基因遗传被认为易患林奇综合征相关癌症；然而，在家族环境中与疾病的共分离尚未得到证实。随着全基因组测序和大型多基因检测在家族性癌症患者临床遗传咨询中的应用增加，预计携带多种潜在癌症风险变异的个体的识别将会增多。在这里，我们证明了MSH6和MUTYH中与CRC共分离一致的单等位基因变异的共同遗传，进一步支持了双基因遗传在癌症易感性中的作用。
