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- Title
High prevalence of GPRC5A germline mutations in BRCA1-mutant breast cancer patients.
- Authors
Sokolenko, Anna P.; Bulanova, Daria R.; Iyevleva, Aglaya G.; Aleksakhina, Svetlana N.; Preobrazhenskaya, Elena V.; Ivantsov, Alexandr O.; Kuligina, Ekatherina Sh.; Mitiushkina, Natalia V.; Suspitsin, Evgeny N.; Yanus, Grigoriy A.; Zaitseva, Olga A.; Yatsuk, Olga S.; Togo, Alexandr V.; Kota, Poojitha; Dixon, J. Michael; Larionov, Alexey A.; Kuznetsov, Sergey G.; Imyanitov, Evgeny N.
- Abstract
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 mutation c.183delG [p. Arg61fs] in an orphan G protein-coupled receptor GPRC5A. An extended case-control study revealed a tenfold enrichment for this mutation in BC patients carrying the 5382insC allele of BRCA1, the major founder mutation in the Russian population, compared to wild-type BRCA1 BC cases [6/117 (5.1%) vs. 8/1578 (0.5%), p = 0.0002]. In mammary tumors ( n = 60), the mRNA expression of GPRC5A significantly correlated with that of BRCA1 ( p = 0.00018). In addition, the amount of GPRC5A transcript was significantly lower in BC obtained from BRCA1 mutation carriers ( n = 17) compared to noncarriers ( n = 93) ( p = 0.026). Accordingly, a siRNA-mediated knockdown of either BRCA1 or GPRC5A in the MDA-MB-231 human BC cell line reduced expression of GPRC5A or BRCA1, respectively. Knockdown of GPRC5A also attenuated radiation-induced BRCA1- and RAD51-containing nuclear DNA repair foci. Taken together, these data suggest that GPRC5A is a modifier of BC risk in BRCA1 mutation carriers and reveals a functional interaction of these genes.
- Publication
International Journal of Cancer, 2014, Vol 134, Issue 10, p2352
- ISSN
0020-7136
- Publication type
Article
- DOI
10.1002/ijc.28569