In a search for new breast cancer (BC) predisposing genes, we performed a whole exome sequencing analysis using six patient samples of familial BC and identified a germline inactivating mutationc.183delG[p. Arg61fs] in an orphan G protein-coupled receptorGPRC5A. An extended case–control study revealed a tenfold enrichment for this mutation in BC patients carrying the 5382insC allele ofBRCA1, the major founder mutation in the Russian population, compared to wild-typeBRCA1BC cases [6/117 (5.1%)vs. 8/1578 (0.5%),p= 0.0002]. In mammary tumors (n= 60), the mRNA expression ofGPRC5Asignificantly correlated with that ofBRCA1(p= 0.00018). In addition, the amount ofGPRC5Atranscript was significantly lower in BC obtained fromBRCA1mutation carriers (n= 17) compared to noncarriers (n= 93) (p= 0.026). Accordingly, a siRNA-mediated knockdown of eitherBRCA1orGPRC5Ain the MDA-MB-231 human BC cell line reduced expression ofGPRC5AorBRCA1, respectively. Knockdown ofGPRC5Aalso attenuated radiation-induced BRCA1- and RAD51-containing nuclear DNA repair foci. Taken together, these data suggest thatGPRC5Ais a modifier of BC risk inBRCA1mutation carriers and reveals a functional interaction of these genes.What's new?
Founder populations provide an invaluable resource for genetic studies because the spectrum of disease-causing mutations is often limited to a few easily detectable alleles. Using whole exome sequencing of DNA samples from six familial breast cancer patients in Russia, this study identified a germline inactivating mutation in a cancer-related G protein-coupled receptor,GPRC5A. The mutation was overrepresented in breast cancer patients carrying the 5382insC allele ofBRCA1, the major founder mutation in the Russian population, compared with wild-typeBRCA1. The data suggest thatGPRC5Ais a modifier of breast cancer risk inBRCA1-mutation carriers and reveal functional interaction between the genes.