Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Aug 7;43(9):879-882.
doi: 10.1038/ng.893.

Germline mutations in RAD51D confer susceptibility to ovarian cancer

Chey Loveday #  1 , Clare Turnbull #  1 , Emma Ramsay  1 , Deborah Hughes  1 , Elise Ruark  1 , Jessica R Frankum  2 , Georgina Bowden  1 , Bolot Kalmyrzaev  1 , Margaret Warren-Perry  1 , Katie Snape  1 , Julian W Adlard  3 , Julian Barwell  4 , Jonathan Berg  5 , Angela F Brady  6 , Carole Brewer  7 , Glen Brice  8 , Cyril Chapman  9 , Jackie Cook  10 , Rosemarie Davidson  11 , Alan Donaldson  12 , Fiona Douglas  13 , Lynn Greenhalgh  14 , Alex Henderson  15 , Louise Izatt  16 , Ajith Kumar  17 , Fiona Lalloo  18 , Zosia Miedzybrodzka  19 , Patrick J Morrison  20 , Joan Paterson  21 , Mary Porteous  22 , Mark T Rogers  23 , Susan Shanley  24 , Lisa Walker  25 ; Breast Cancer Susceptibility Collaboration (UK); Diana Eccles  26 , D Gareth Evans  18 , Anthony Renwick  1 , Sheila Seal  1 , Christopher J Lord  2 , Alan Ashworth  2 , Jorge S Reis-Filho  2 , Antonis C Antoniou  27 , Nazneen Rahman  1
Collaborators, Affiliations

Germline mutations in RAD51D confer susceptibility to ovarian cancer

Chey Loveday et al. Nat Genet. .

Abstract

Recently, RAD51C mutations were identified in families with breast and ovarian cancer. This observation prompted us to investigate the role of RAD51D in cancer susceptibility. We identified eight inactivating RAD51D mutations in unrelated individuals from 911 breast-ovarian cancer families compared with one inactivating mutation identified in 1,060 controls (P = 0.01). The association found here was principally with ovarian cancer, with three mutations identified in the 59 pedigrees with three or more individuals with ovarian cancer (P = 0.0005). The relative risk of ovarian cancer for RAD51D mutation carriers was estimated to be 6.30 (95% CI 2.86-13.85, P = 4.8 × 10(-6)). By contrast, we estimated the relative risk of breast cancer to be 1.32 (95% CI 0.59-2.96, P = 0.50). These data indicate that RAD51D mutation testing may have clinical utility in individuals with ovarian cancer and their families. Moreover, we show that cells deficient in RAD51D are sensitive to treatment with a PARP inhibitor, suggesting a possible therapeutic approach for cancers arising in RAD51D mutation carriers.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Abridged pedigrees of eight families with RAD51D mutations. Individuals with ovarian cancer are shown as red circles, individuals with breast cancer are shown as black circles, other cancers are shown as unfilled circles or squares. Where known, the age of cancer diagnosis is under the individual, with two ages given for metachronas bilateral breast cancers. The relevant RAD51D mutation is given under the affected individuals analysed but not the unaffected individuals, to preserve confidentiality. BC, breast cancer; BC bilat., bilateral breast cancer; OC, ovarian cancer; CRC, colorectal cancer; LC, lung cancer; NHL, non-Hodgkin lymphoma; PaC, pancreatic cancer; Pr, prostate cancer.
Figure 2
Figure 2
Average age-related cumulative risk of ovarian cancer in RAD51D mutation carriers, BRCA1 and BRCA2 mutation carriers and the population .
Figure 3
Figure 3
Effect of RAD51D silencing on Olaparib sensitivity. CAL51 (a) or MCF7 (b) cells were transfected with siCONTROL, siRNA directed against RAD51D or siRNA directed against BRCA2 and then treated with olaparib for 7 days before assaying for cell viability. Wild-type CHO cells or CHO cells mutated in RAD51D were treated with olaparib for 7 days before assaying for cell viability (c).
See this image and copyright information in PMC

Similar articles

  • Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D.
    Yang X, Song H, Leslie G, Engel C, Hahnen E, Auber B, Horváth J, Kast K, Niederacher D, Turnbull C, Houlston R, Hanson H, Loveday C, Dolinsky JS, LaDuca H, Ramus SJ, Menon U, Rosenthal AN, Jacobs I, Gayther SA, Dicks E, Nevanlinna H, Aittomäki K, Pelttari LM, Ehrencrona H, Borg Å, Kvist A, Rivera B, Hansen TVO, Djursby M, Lee A, Dennis J, Bowtell DD, Traficante N, Diez O, Balmaña J, Gruber SB, Chenevix-Trench G, Investigators K, Jensen A, Kjær SK, Høgdall E, Castéra L, Garber J, Janavicius R, Osorio A, Golmard L, Vega A, Couch FJ, Robson M, Gronwald J, Domchek SM, Culver JO, de la Hoya M, Easton DF, Foulkes WD, Tischkowitz M, Meindl A, Schmutzler RK, Pharoah PDP, Antoniou AC. Yang X, et al. J Natl Cancer Inst. 2020 Dec 14;112(12):1242-1250. doi: 10.1093/jnci/djaa030. J Natl Cancer Inst. 2020. PMID: 32107557 Free PMC article.
  • Germline mutations in RAD51C and RAD51D and hereditary predisposition to ovarian cancer.
    Soukupová J, Lhotová K, Janatová M, Kleiblová P, Vočka M, Foretová L, Zikán M, Kleibl Z. Soukupová J, et al. Klin Onkol. 2021 Winter;34(1):26-32. doi: 10.48095/ccko202126. Klin Onkol. 2021. PMID: 33657816 Review. English.
  • Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population.
    Song H, Dicks E, Ramus SJ, Tyrer JP, Intermaggio MP, Hayward J, Edlund CK, Conti D, Harrington P, Fraser L, Philpott S, Anderson C, Rosenthal A, Gentry-Maharaj A, Bowtell DD, Alsop K, Cicek MS, Cunningham JM, Fridley BL, Alsop J, Jimenez-Linan M, Høgdall E, Høgdall CK, Jensen A, Kjaer SK, Lubiński J, Huzarski T, Jakubowska A, Gronwald J, Poblete S, Lele S, Sucheston-Campbell L, Moysich KB, Odunsi K, Goode EL, Menon U, Jacobs IJ, Gayther SA, Pharoah PD. Song H, et al. J Clin Oncol. 2015 Sep 10;33(26):2901-7. doi: 10.1200/JCO.2015.61.2408. Epub 2015 Aug 10. J Clin Oncol. 2015. PMID: 26261251 Free PMC article.
  • About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants.
    Gutiérrez-Enríquez S, Bonache S, de Garibay GR, Osorio A, Santamariña M, Ramón y Cajal T, Esteban-Cardeñosa E, Tenés A, Yanowsky K, Barroso A, Montalban G, Blanco A, Cornet M, Gadea N, Infante M, Caldés T, Díaz-Rubio E, Balmaña J, Lasa A, Vega A, Benítez J, de la Hoya M, Diez O. Gutiérrez-Enríquez S, et al. Int J Cancer. 2014 May 1;134(9):2088-97. doi: 10.1002/ijc.28540. Int J Cancer. 2014. PMID: 24130102
  • A decade of RAD51C and RAD51D germline variants in cancer.
    Boni J, Idani A, Roca C, Feliubadaló L, Tomiak E, Weber E, Foulkes WD, Orthwein A, El Haffaf Z, Lazaro C, Rivera B. Boni J, et al. Hum Mutat. 2022 Mar;43(3):285-298. doi: 10.1002/humu.24319. Epub 2021 Dec 30. Hum Mutat. 2022. PMID: 34923718 Review.
See all similar articles

Cited by

See all "Cited by" articles

References

    1. Meindl A, et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet. 2010;42:410–4. - PubMed
    1. Heyer W-D, Ehmsen KT, Liu J. Regulation of homologous recombination in eukaryotes. Annu Rev Genet. 2010;44:113–39. - PMC - PubMed
    1. Futreal PA, et al. A census of human cancer genes. Nat Rev Cancer. 2004;4:177–83. - PMC - PubMed
    1. Turnbull C, Rahman N. Genetic predisposition to breast cancer: past, present, and future. Annu Rev Genomics Hum Genet. 2008;9:321–45. - PubMed
    1. Easton DF, Bishop DT, Ford D, Crockford GP. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1993;52:678–701. - PMC - PubMed

Publication types

Substances