Nat Genet. 2011 Aug 7;43(9):879-882. doi: 10.1038/ng.893.
Germline mutations in RAD51D confer susceptibility to ovarian cancer.
Loveday C#1,
Turnbull C#1,
Ramsay E1,
Hughes D1,
Ruark E1,
Frankum JR2,
Bowden G1,
Kalmyrzaev B1,
Warren-Perry M1,
Snape K1,
Adlard JW3,
Barwell J4,
Berg J5,
Brady AF6,
Brewer C7,
Brice G8,
Chapman C9,
Cook J10,
Davidson R11,
Donaldson A12,
Douglas F13,
Greenhalgh L14,
Henderson A15,
Izatt L16,
Kumar A17,
Lalloo F18,
Miedzybrodzka Z19,
Morrison PJ20,
Paterson J21,
Porteous M22,
Rogers MT23,
Shanley S24,
Walker L25;
Breast Cancer Susceptibility Collaboration (UK),
Eccles D26,
Evans DG18,
Renwick A1,
Seal S1,
Lord CJ2,
Ashworth A2,
Reis-Filho JS2,
Antoniou AC27,
Rahman N1.
Ardern-Jones A, Adlard J, Attard G, Bailey K, Bancroft E, Bardsley C, Barton D, Barwell J, Baxter L, Belk R, Berg J, Bishop T, Boyes L, Bradshaw N, Brady A, Brant S, Brewer C, Brice G, Bromilow G, Brooks C, Bruce A, Bulman B, Burgess L, Campbell J, Castle B, Cetnarskyj R, Chapman C, Claber O, Coates N, Cole T, Collins A, Cook J, Coulson S, Crawford G, Cruger D, Cummings C, D'Mello L, Davidson R, Day L, de Silva L, Dell B, Dolling C, Donaldson A, Donaldson A, Dorkins H, Douglas F, Downing S, Drummond S, Dunlop J, Durrell S, Eccles D, Eddy C, Edwards M, Edwards E, Edwardson J, Eeles R, Ellis I, Elmslie F, Evans G, Gibbens B, Gardiner C, Giblin C, Gibson S, Goff S, Goodman S, Goudie D, Greenhalgh L, Greer J, Gregory H, Halliday D, Hardy R, Hartigan C, Heaton T, Henderson A, Higgins C, Hodgson S, Holt T, Homfray T, Horrigan D, Houghton C, Houlston RS, Hughes L, Hunt V, Irvine L, Izatt L, Jackson L, Jacobs C, James S, James M, Jeffers L, Jobson I, Jones W, Kennedy MJ, Kenwrick S, Kightley C, Kirk C, Kirk L, Kivuva E, Kumar A, Lalloo F, Lambord N, Langman C, Leonard P, Levene S, Locker S, Logan P, Longmuir M, Lucassen A, Lyus V, Magee A, Male A, Mansour S, McBride D, McCann E, McConnell V, McEntagart M, McDermot K, McKeown C, McLeish L, McLeod D, Mercer L, Mercer C, Miedzybrodzka Z, Miller J, Mitra A, Morrison P, Murday V, Murray A, Myring J, Paterson J, Pearson P, Pichert G, Platt K, Porteous M, Pottinger C, Price S, Protheroe L, Pugh S, Quarrell O, Riddick C, Robertson L, Robinson A, Roffey-Johnson V, Rogers M, Rose S, Rowe S, Schofield A, Rahman N, Scott G, Scott J, Searle A, Shanley S, Sharif S, Shaw J, Shea-Simonds J, Side L, Sillibourne J, Simon K, Simpson S, Slater S, Smith K, Snadden L, Soloway J, Stait Y, Stayner B, Steel M, Steel C, Stewart H, Stirling D, Thomas M, Thomas S, Tomkins S, Turner H, Tyler E, Wakeling E, Waldrup F, Walker L, Watt C, Watts S, Webber A, Whyte C, Wiggins J, Williams E, Winchester L.
- 1
- Section of Cancer Genetics, The Institute of Cancer Research, Sutton.
- 2
- The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, Fulham Road, London.
- 3
- Yorkshire Regional Centre for Cancer Treatment, Cookridge Hospital, Leeds.
- 4
- Leicestershire Genetics Centre, University Hospitals of Leicester NHS Trust.
- 5
- Human genetics, Division of Medical Sciences, University of Dundee.
- 6
- NW Thames Regional Genetics Service, Kennedy Galton Centre, London.
- 7
- Peninsula Regional Genetics Service, Royal Devon & Exeter Hospital, Exeter.
- 8
- SW Thames Regional Genetics Service, St George's Hospital, London.
- 9
- West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham.
- 10
- Sheffield Regional Genetics Service, Sheffield Children's NHS Foundation Trust.
- 11
- West of Scotland Regional Genetics Service, FergusonSmith Centre for Clinical Genetics, Glasgow.
- 12
- South Western Regional Genetics Service, University Hospitals of Bristol NHS Foundation Trust.
- 13
- Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust.
- 14
- Cheshire and Merseyside Clinical Genetics Service, Alder Hey Children's NHS Foundation Trust, Liverpool.
- 15
- Northern Genetics Service (Cumbria), Newcastle upon Tyne Hospitals NHS Trust.
- 16
- SE Thames Regional Genetics Service, Guy's and St Thomas NHS Foundation Trust.
- 17
- NE Thames Regional Genetics Service, Great Ormond St Hospital, London.
- 18
- University Dept of Medical Genetics & Regional Genetics Service, St Mary's Hospital, Manchester.
- 19
- University of Aberdeen and North of Scotland Clinical Genetics Service, Aberdeen Royal Infirmary.
- 20
- Northern Ireland Regional Genetics Service, Belfast HSC Trust, & Department of Medical Genetics, Queen's University Belfast.
- 21
- East Anglian Regional Genetics Service, Cambridge University Hospitals NHS Foundation Trust.
- 22
- South East of Scotland Clinical Genetics Service, Western General Hospital, Edinburgh.
- 23
- All Wales Medical Genetics Service, University Hospital of Wales, Cardiff.
- 24
- Royal Marsden NHS Foundation Trust, Royal Marsden NHS Foundation Trust.
- 25
- Oxford Regional Genetics Service, Oxford Radcliffe Hospitals NHS Trust.
- 26
- Faculty of Medicine, University of Southampton, Southampton University Hospitals NHS Trust.
- 27
- Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge.
- #
- Contributed equally
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.
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.
Nat Genet. ;43(9):879-882.
Figure 2
Average age-related cumulative risk of ovarian cancer in RAD51D mutation carriers, BRCA1 and BRCA2 mutation carriers and the population .
Nat Genet. ;43(9):879-882.
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).
Nat Genet. ;43(9):879-882.
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