High prevalence of GPRC5A germline mutations in BRCA1-mutant breast cancer patients.
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.
Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia; Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg, Russia.
Anna P
AP
Sokolenko
Daria R
DR
Bulanova
Aglaya G
AG
Iyevleva
Svetlana N
SN
Aleksakhina
Elena V
EV
Preobrazhenskaya
Alexandr O
AO
Ivantsov
Ekatherina Sh
ESh
Kuligina
Natalia V
NV
Mitiushkina
Evgeny N
EN
Suspitsin
Grigoriy A
GA
Yanus
Olga A
OA
Zaitseva
Olga S
OS
Yatsuk
Alexandr V
AV
Togo
Poojitha
P
Kota
J Michael
JM
Dixon
Alexey A
AA
Larionov
Sergey G
SG
Kuznetsov
Evgeny N
EN
Imyanitov
D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA / Q000379:methods
D019313:BRCA1 Protein; C116760:GPRC5A protein, human; D043562:Receptors, G-Protein-Coupled
BRCA1; GPRC5A; breast cancer; genetic predisposition