Germline mutations in RAD51D confer susceptibility to ovarian cancer

Chey Loveday; Clare Turnbull; Emma Ramsay; Deborah Hughes; Elise Ruark; Jessica R Frankum; Georgina Bowden; Bolot Kalmyrzaev; Margaret Warren-Perry; Katie Snape; Julian W Adlard; Julian Barwell; Jonathan Berg; Angela F Brady; Carole Brewer; Glen Brice; Cyril Chapman; Jackie Cook; Rosemarie Davidson; Alan Donaldson; Fiona Douglas; Lynn Greenhalgh; Alex Henderson; Louise Izatt; Ajith Kumar; Fiona Lalloo; Zosia Miedzybrodzka; Patrick J Morrison; Joan Paterson; Mary Porteous; Mark T Rogers; Susan Shanley; Lisa Walker; Diana Eccles; D Gareth Evans; Anthony Renwick; Sheila Seal; Christopher J Lord; Alan Ashworth; Jorge S Reis-Filho; Antonis C Antoniou; Nazneen Rahman; Breast Cancer Susceptibility Collaboration (UK)

doi:10.1038/ng.893

Germline mutations in RAD51D confer susceptibility to ovarian cancer

Chey Loveday, Clare Turnbull, Emma Ramsay, Deborah Hughes, Elise Ruark, Jessica R Frankum, Georgina Bowden, Bolot Kalmyrzaev, Margaret Warren-Perry, Katie Snape, Julian W Adlard, Julian Barwell, Jonathan Berg, Angela F Brady, Carole Brewer, Glen Brice, Cyril Chapman, Jackie Cook, Rosemarie Davidson, Alan DonaldsonFiona Douglas, Lynn Greenhalgh, Alex Henderson, Louise Izatt, Ajith Kumar, Fiona Lalloo, Zosia Miedzybrodzka, Patrick J Morrison, Joan Paterson, Mary Porteous, Mark T Rogers, Susan Shanley, Lisa Walker, Diana Eccles, D Gareth Evans, Anthony Renwick, Sheila Seal, Christopher J Lord, Alan Ashworth, Jorge S Reis-Filho, Antonis C Antoniou, Nazneen Rahman, Breast Cancer Susceptibility Collaboration (UK)

Applied Medicine

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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.

Original language	English
Pages (from-to)	879-882
Number of pages	4
Journal	Nature Genetics
Volume	43
Issue number	9
Early online date	7 Aug 2011
DOIs	https://doi.org/10.1038/ng.893
Publication status	Published - Sept 2011

Keywords

age factors
animals
CHO cells
cricetinae
cricetulus
DNA-binding proteins
drug resistance, neoplasm
female
genetic predisposition to disease
germ-line mutation
heterozygote
humans
ovarian neoplasms
pedigree
poly(ADP-ribose) polymerases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.893

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Loveday, C., Turnbull, C., Ramsay, E., Hughes, D., Ruark, E., Frankum, J. R., Bowden, G., Kalmyrzaev, B., Warren-Perry, M., Snape, K., Adlard, J. W., Barwell, J., Berg, J., Brady, A. F., Brewer, C., Brice, G., Chapman, C., Cook, J., Davidson, R., ... Breast Cancer Susceptibility Collaboration (UK) (2011). Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nature Genetics, 43(9), 879-882. https://doi.org/10.1038/ng.893

Loveday, C, Turnbull, C, Ramsay, E, Hughes, D, Ruark, E, Frankum, JR, Bowden, G, Kalmyrzaev, B, Warren-Perry, M, Snape, K, Adlard, JW, Barwell, J, Berg, J, Brady, AF, Brewer, C, Brice, G, Chapman, C, Cook, J, Davidson, R, Donaldson, A, Douglas, F, Greenhalgh, L, Henderson, A, Izatt, L, Kumar, A, Lalloo, F, Miedzybrodzka, Z, Morrison, PJ, Paterson, J, Porteous, M, Rogers, MT, Shanley, S, Walker, L, Eccles, D, Evans, DG, Renwick, A, Seal, S, Lord, CJ, Ashworth, A, Reis-Filho, JS, Antoniou, AC, Rahman, N & Breast Cancer Susceptibility Collaboration (UK) 2011, 'Germline mutations in RAD51D confer susceptibility to ovarian cancer', Nature Genetics, vol. 43, no. 9, pp. 879-882. https://doi.org/10.1038/ng.893

@article{d52f28e4cb484666a8268d5328b6b5b8,

title = "Germline mutations in RAD51D confer susceptibility to ovarian cancer",

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.",

keywords = "age factors, animals, CHO cells, cricetinae, cricetulus, DNA-binding proteins, drug resistance, neoplasm, female, genetic predisposition to disease, germ-line mutation, heterozygote, humans, ovarian neoplasms, pedigree, poly(ADP-ribose) polymerases",

author = "Chey Loveday and Clare Turnbull and Emma Ramsay and Deborah Hughes and Elise Ruark and Frankum, {Jessica R} and Georgina Bowden and Bolot Kalmyrzaev and Margaret Warren-Perry and Katie Snape and Adlard, {Julian W} and Julian Barwell and Jonathan Berg and Brady, {Angela F} and Carole Brewer and Glen Brice and Cyril Chapman and Jackie Cook and Rosemarie Davidson and Alan Donaldson and Fiona Douglas and Lynn Greenhalgh and Alex Henderson and Louise Izatt and Ajith Kumar and Fiona Lalloo and Zosia Miedzybrodzka and Morrison, {Patrick J} and Joan Paterson and Mary Porteous and Rogers, {Mark T} and Susan Shanley and Lisa Walker and Diana Eccles and Evans, {D Gareth} and Anthony Renwick and Sheila Seal and Lord, {Christopher J} and Alan Ashworth and Reis-Filho, {Jorge S} and Antoniou, {Antonis C} and Nazneen Rahman and {Breast Cancer Susceptibility Collaboration (UK)}",

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month = sep,

doi = "10.1038/ng.893",

language = "English",

volume = "43",

pages = "879--882",

journal = "Nature Genetics",

issn = "1061-4036",

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T1 - Germline mutations in RAD51D confer susceptibility to ovarian cancer

AU - Loveday, Chey

AU - Turnbull, Clare

AU - Ramsay, Emma

AU - Hughes, Deborah

AU - Ruark, Elise

AU - Frankum, Jessica R

AU - Bowden, Georgina

AU - Kalmyrzaev, Bolot

AU - Warren-Perry, Margaret

AU - Snape, Katie

AU - Adlard, Julian W

AU - Barwell, Julian

AU - Berg, Jonathan

AU - Brady, Angela F

AU - Brewer, Carole

AU - Brice, Glen

AU - Chapman, Cyril

AU - Cook, Jackie

AU - Davidson, Rosemarie

AU - Donaldson, Alan

AU - Douglas, Fiona

AU - Greenhalgh, Lynn

AU - Henderson, Alex

AU - Izatt, Louise

AU - Kumar, Ajith

AU - Lalloo, Fiona

AU - Miedzybrodzka, Zosia

AU - Morrison, Patrick J

AU - Paterson, Joan

AU - Porteous, Mary

AU - Rogers, Mark T

AU - Shanley, Susan

AU - Walker, Lisa

AU - Eccles, Diana

AU - Evans, D Gareth

AU - Renwick, Anthony

AU - Seal, Sheila

AU - Lord, Christopher J

AU - Ashworth, Alan

AU - Reis-Filho, Jorge S

AU - Antoniou, Antonis C

AU - Rahman, Nazneen

AU - Breast Cancer Susceptibility Collaboration (UK)

PY - 2011/9

Y1 - 2011/9

N2 - 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.

AB - 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.

KW - age factors

KW - animals

KW - CHO cells

KW - cricetinae

KW - cricetulus

KW - DNA-binding proteins

KW - drug resistance, neoplasm

KW - female

KW - genetic predisposition to disease

KW - germ-line mutation

KW - heterozygote

KW - humans

KW - ovarian neoplasms

KW - pedigree

KW - poly(ADP-ribose) polymerases

U2 - 10.1038/ng.893

DO - 10.1038/ng.893

M3 - Article

C2 - 21822267

SN - 1061-4036

VL - 43

SP - 879

EP - 882

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

Germline mutations in RAD51D confer susceptibility to ovarian cancer

Abstract

Keywords

UN SDGs

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