Germline mutations in RAD51D confer susceptibility to ovarian cancer

被引：389

作者：

Loveday, Chey ^{[1
]}

Turnbull, Clare ^{[1
]}

Ramsay, Emma ^{[1
]}

Hughes, Deborah ^{[1
]}

Ruark, Elise ^{[1
]}

Frankum, Jessica R. ^{[2
]}

Bowden, Georgina ^{[1
]}

Kalmyrzaev, Bolot ^{[1
]}

Warren-Perry, Margaret ^{[1
]}

Snape, Katie ^{[1
]}

Adlard, Julian W. ^{[3
]}

Barwell, Julian ^{[4
]}

Berg, Jonathan ^{[5
]}

Brady, Angela F. ^{[6
]}

Brewer, Carole ^{[7
]}

Brice, Glen ^{[8
]}

Chapman, Cyril ^{[9
]}

Cook, Jackie ^{[10
]}

Davidson, Rosemarie ^{[11
]}

Donaldson, Alan ^{[12
]}

Douglas, Fiona ^{[13
]}

Greenhalgh, Lynn ^{[14
]}

Henderson, Alex ^{[15
]}

Izatt, Louise ^{[16
]}

Kumar, Ajith ^{[17
]}

Lalloo, Fiona ^{[18
,19
]}

Miedzybrodzka, Zosia ^{[20
,21
]}

Morrison, Patrick J. ^{[22
,23
]}

Paterson, Joan ^{[24
]}

Porteous, Mary ^{[25
]}

Rogers, Mark T. ^{[26
]}

Shanley, Susan ^{[27
]}

Walker, Lisa ^{[28
]}

Eccles, Diana ^{[29
]}

Evans, D. Gareth ^{[18
,19
]}

Renwick, Anthony ^{[1
]}

Seal, Sheila ^{[1
]}

Lord, Christopher J. ^{[2
]}

Ashworth, Alan ^{[2
]}

Reis-Filho, Jorge S. ^{[2
]}

Antoniou, Antonis C. ^{[30
]}

Rahman, Nazneen ^{[1
]}

机构：

[1] Inst Canc Res, Sect Canc Genet, Sutton, Surrey, England

[2] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England

[3] Cookridge Hosp, Yorkshire Reg Ctr Canc Treatment, Leeds LS16 6QB, W Yorkshire, England

[4] Univ Hosp Leicester Natl Hlth Serv NHS Trust, Leicestershire Genet Ctr, Leicester, Leics, England

[5] Univ Dundee, Div Med Sci, Dundee, Scotland

[6] Kennedy Galton Ctr, NW Thames Reg Genet Serv, London, England

[7] Royal Devon & Exeter Hosp, Peninsula Reg Genet Serv, Exeter EX2 5DW, Devon, England

[8] St George Hosp, SW Thames Reg Genet Serv, London, England

[9] Birmingham Womens Hosp, W Midlands Reg Genet Serv, Birmingham, W Midlands, England

[10] Sheffield Childrens NHS Fdn Trust, Sheffield Reg Genet Serv, Sheffield, S Yorkshire, England

[11] FergusonSmith Ctr Clin Genet, W Scotland Reg Genet Serv, Glasgow, Lanark, Scotland

[12] Univ Hosp Bristol NHS Fdn Trust, S Western Reg Genet Serv, Bristol, Avon, England

[13] Newcastle Upon Tyne Hosp NHS Fdn Trust, No Genet Serv, Newcastle Upon Tyne, Tyne & Wear, England

[14] Alder Hey Childrens NHS Fdn Trust, Cheshire & Merseyside Clin Genet Serv, Liverpool, Merseyside, England

[15] Newcastle Upon Tyne Hosp NHS Trust, No Genet Serv Cumbria, Newcastle Upon Tyne, Tyne & Wear, England

[16] Guys & St Thomas NHS Fdn Trust, SE Thames Reg Genet Serv, London, England

[17] Great Ormond St Hosp Sick Children, NE Thames Reg Genet Serv, London, England

[18] St Marys Hosp, Univ Dept Med Genet, Manchester M13 0JH, Lancs, England

[19] St Marys Hosp, Reg Genet Serv, Manchester M13 0JH, Lancs, England

[20] Univ Aberdeen, Aberdeen, Scotland

[21] Aberdeen Royal Infirm, N Scotland Clin Genet Serv, Aberdeen, Scotland

[22] Queens Univ Belfast, Dept Med Genet, Belfast, Antrim, North Ireland

[23] Belfast Hlth & Social Care HSC Trust, No Ireland Reg Genet Serv, Belfast, Antrim, North Ireland

[24] Cambridge Univ Hosp NHS Fdn Trust, E Anglian Reg Genet Serv, Cambridge, England

[25] Western Gen Hosp, SE Scotland Clin Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland

[26] Univ Wales Hosp, All Wales Med Genet Serv, Cardiff CF4 4XW, S Glam, Wales

[27] Royal Marsden NHS Fdn Trust, London, England

[28] Oxford Radcliffe Hosp NHS Trust, Oxford Reg Genet Serv, Oxford, England

[29] Univ Southampton, Fac Med, Southampton Univ Hosp NHS Trust, Southampton SO9 5NH, Hants, England

[30] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England

来源：

NATURE GENETICS | 2011年 / 43卷 / 09期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

BREAST-CANCER; FANCONI-ANEMIA; BRCA2; MUTATIONS; HOMOLOGOUS RECOMBINATION; FAMILIAL OVARIAN; SPLICING SIGNALS; GENE; DNA; PREDICTION; SEQUENCE;

D O I：

10.1038/ng.893

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Recently, RAD51C mutations were identified in families with breast and ovarian cancer(1). 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 x 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.

引用

页码：879 / U90

页数：6

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