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Through linkage and candidate gene screening, many breast cancer (BC) predisposition genes have been identified in the past 20 years. However, the majority of genetic risks that contribute to familial BC remains undetermined. In this study, we revisited whole exome sequencing datasets from non-BRCA1/2 familial BC patients, to search for novel BC predisposition genes. Based on the infinite mutation model, we supposed that rare non-silent variants that cooccurred between familial and TCGA-germline datasets, might play a predisposition contributing role. In our analysis, we not only identified novel potential pathogenic variants from known cancer predisposition genes, such as  MRE11 ,  CTR9  but also identified novel candidate predisposition genes, such as  NCK1 . According to the TCGA mRNA expression dataset of BC,  NCK1  was significantly upregulated in basal-like subtypes and downregulated in luminal subtypes.  In vitro , NCK1 mutants (D73H and R42Q) transfected MCF7 cell lines, which attributed to the luminal subtype, were much more viable and invasive than the wild type. On the other side, our results also showed that overall survival and disease-free survival of patients with  NCK1  variations might be dependent on the genomic context. In conclusion, genetic heterogeneity exists among non-BRCA1/2 BC pedigrees and  NCK1  could be a novel BC predisposition gene.

Revisiting Non-BRCA1/2 Familial Whole Exome Sequencing Datasets Implicates NCK1 as a Cancer Gene