Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.
J Med Genet. 2018 Oct;55(10):669-674. doi: 10.1136/jmedgenet-2017-104962. Epub 2018 Jan 12.
In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes , or .
We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a germline mutation for germline variants affecting , and using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes.
Predicted deleterious germline variants were not encountered in , but recurrently observed in (n=2) and (n=3) in our cohort of patients with GC. In contrast to deleterious variants in , deleterious variants in also occur frequently in the general population.
Based on our results should no longer be considered a GC predisposition gene, whereas deleterious variants are confirmed as an infrequent cause of GC susceptibility. Biallelic germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.
在大约 10%的所有胃癌（GC）病例中，怀疑存在遗传性病因。这些病例中有一部分存在致病的种系突变；然而，在大多数情况下，病因仍然未知。我们的目的是评估这些剩余病例在多大程度上可以用新型候选 GC 易感性基因 或 的种系突变来解释。
我们使用基于单分子分子反转探针的靶向下一代测序方法，对 286 名无种系突变的不明原因的年轻和/或家族性 GC 患者（n=286）进行了种系变异影响 和 的测序。
在我们的 GC 患者队列中，未发现 中的预测性有害种系变异，但在 （n=2）和 （n=3）中反复观察到。与 中的有害变异不同， 中的有害变异在普通人群中也经常发生。
基于我们的结果， 不应再被视为 GC 易感性基因，而 中的有害变异被确认为 GC 易感性的罕见原因。双等位基因 种系突变最多是 GC 易感性的非常罕见原因，因为没有发现其他病例。
