High prevalence of GPRC5A germline mutations in BRCA1-mutant breast cancer patients

Anna Sokolenko, Daria Bulanova, Aglaya Iyevleva, Svetlana Aleksakhina, Elena Preobrazhenskaya, Alexandr Ivantsov, Ekatherina Kuligina, Natalia Mitiushkina, Evgeny Suspitsin, Grigoriy Yanus, Olga Zaitseva, Olga Yatsuk, Alexandr Togo, Poojitha Ojamies, Michael Dixon, Alexey Larionov, Sergey Kuznetsov, Evgeny Imyanitov

Research output: Contribution to journalArticleScientificpeer-review

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.
Original languageEnglish
JournalInternational Journal of Cancer
Volume134
Issue number10
Pages (from-to)2352-2358
Number of pages7
ISSN0020-7136
DOIs
Publication statusPublished - 2014
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 3122 Cancers

Cite this

Sokolenko, A., Bulanova, D., Iyevleva, A., Aleksakhina, S., Preobrazhenskaya, E., Ivantsov, A., ... Imyanitov, E. (2014). High prevalence of GPRC5A germline mutations in BRCA1-mutant breast cancer patients. International Journal of Cancer, 134(10), 2352-2358. https://doi.org/10.1002/ijc.28569
Sokolenko, Anna ; Bulanova, Daria ; Iyevleva, Aglaya ; Aleksakhina, Svetlana ; Preobrazhenskaya, Elena ; Ivantsov, Alexandr ; Kuligina, Ekatherina ; Mitiushkina, Natalia ; Suspitsin, Evgeny ; Yanus, Grigoriy ; Zaitseva, Olga ; Yatsuk, Olga ; Togo, Alexandr ; Ojamies, Poojitha ; Dixon, Michael ; Larionov, Alexey ; Kuznetsov, Sergey ; Imyanitov, Evgeny. / High prevalence of GPRC5A germline mutations in BRCA1-mutant breast cancer patients. In: International Journal of Cancer. 2014 ; Vol. 134, No. 10. pp. 2352-2358.
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title = "High prevalence of GPRC5A germline mutations in BRCA1-mutant breast cancer patients",
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.",
keywords = "3122 Cancers",
author = "Anna Sokolenko and Daria Bulanova and Aglaya Iyevleva and Svetlana Aleksakhina and Elena Preobrazhenskaya and Alexandr Ivantsov and Ekatherina Kuligina and Natalia Mitiushkina and Evgeny Suspitsin and Grigoriy Yanus and Olga Zaitseva and Olga Yatsuk and Alexandr Togo and Poojitha Ojamies and Michael Dixon and Alexey Larionov and Sergey Kuznetsov and Evgeny Imyanitov",
year = "2014",
doi = "10.1002/ijc.28569",
language = "English",
volume = "134",
pages = "2352--2358",
journal = "International Journal of Cancer",
issn = "0020-7136",
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Sokolenko, A, Bulanova, D, Iyevleva, A, Aleksakhina, S, Preobrazhenskaya, E, Ivantsov, A, Kuligina, E, Mitiushkina, N, Suspitsin, E, Yanus, G, Zaitseva, O, Yatsuk, O, Togo, A, Ojamies, P, Dixon, M, Larionov, A, Kuznetsov, S & Imyanitov, E 2014, 'High prevalence of GPRC5A germline mutations in BRCA1-mutant breast cancer patients', International Journal of Cancer, vol. 134, no. 10, pp. 2352-2358. https://doi.org/10.1002/ijc.28569

High prevalence of GPRC5A germline mutations in BRCA1-mutant breast cancer patients. / Sokolenko, Anna; Bulanova, Daria; Iyevleva, Aglaya; Aleksakhina, Svetlana; Preobrazhenskaya, Elena; Ivantsov, Alexandr; Kuligina, Ekatherina; Mitiushkina, Natalia; Suspitsin, Evgeny ; Yanus, Grigoriy; Zaitseva, Olga; Yatsuk, Olga; Togo, Alexandr; Ojamies, Poojitha; Dixon, Michael; Larionov, Alexey; Kuznetsov, Sergey; Imyanitov, Evgeny.

In: International Journal of Cancer, Vol. 134, No. 10, 2014, p. 2352-2358.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - High prevalence of GPRC5A germline mutations in BRCA1-mutant breast cancer patients

AU - Sokolenko, Anna

AU - Bulanova, Daria

AU - Iyevleva, Aglaya

AU - Aleksakhina, Svetlana

AU - Preobrazhenskaya, Elena

AU - Ivantsov, Alexandr

AU - Kuligina, Ekatherina

AU - Mitiushkina, Natalia

AU - Suspitsin, Evgeny

AU - Yanus, Grigoriy

AU - Zaitseva, Olga

AU - Yatsuk, Olga

AU - Togo, Alexandr

AU - Ojamies, Poojitha

AU - Dixon, Michael

AU - Larionov, Alexey

AU - Kuznetsov, Sergey

AU - Imyanitov, Evgeny

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - 3122 Cancers

U2 - 10.1002/ijc.28569

DO - 10.1002/ijc.28569

M3 - Article

VL - 134

SP - 2352

EP - 2358

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 10

ER -

Sokolenko A, Bulanova D, Iyevleva A, Aleksakhina S, Preobrazhenskaya E, Ivantsov A et al. High prevalence of GPRC5A germline mutations in BRCA1-mutant breast cancer patients. International Journal of Cancer. 2014;134(10):2352-2358. https://doi.org/10.1002/ijc.28569