Gene-gene interactions in breast cancer susceptibility

Clare Turnbull; Sheila Seal; Anthony Renwick; Margaret Warren-Perry; Deborah Hughes; Anna Elliott; David Pernet; Susan Peock; 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; Munaza Ahmed; Diana Eccles; D Gareth Evans; Peter Donnelly; Douglas F Easton; Michael R Stratton; Nazneen Rahman; Breast Cancer Susceptibility Collaboration (UK), EMBRACE

doi:10.1093/hmg/ddr525

Gene-gene interactions in breast cancer susceptibility

Clare Turnbull, Sheila Seal, Anthony Renwick, Margaret Warren-Perry, Deborah Hughes, Anna Elliott, David Pernet, Susan Peock, 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 GreenhalghAlex Henderson, Louise Izatt, Ajith Kumar, Fiona Lalloo, Zosia Miedzybrodzka, Patrick J Morrison, Joan Paterson, Mary Porteous, Mark T Rogers, Susan Shanley, Lisa Walker, Munaza Ahmed, Diana Eccles, D Gareth Evans, Peter Donnelly, Douglas F Easton, Michael R Stratton, Nazneen Rahman, Breast Cancer Susceptibility Collaboration (UK), EMBRACE

Research output: Contribution to journal › Article › peer-review

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Abstract

There have been few definitive examples of gene-gene interactions in humans. Through mutational analyses in 7325 individuals, we report four interactions (defined as departures from a multiplicative model) between mutations in the breast cancer susceptibility genes ATM and CHEK2 with BRCA1 and BRCA2 (case-only interaction between ATM and BRCA1/BRCA2 combined, P = 5.9 × 10(-4); ATM and BRCA1, P= 0.01; ATM and BRCA2, P= 0.02; CHEK2 and BRCA1/BRCA2 combined, P = 2.1 × 10(-4); CHEK2 and BRCA1, P= 0.01; CHEK2 and BRCA2, P= 0.01). The interactions are such that the resultant risk of breast cancer is lower than the multiplicative product of the constituent risks, and plausibly reflect the functional relationships of the encoded proteins in DNA repair. These findings have important implications for models of disease predisposition and clinical translation.

Original language	English
Pages (from-to)	958-962
Number of pages	5
Journal	Human Molecular Genetics
Volume	21
Issue number	4
Early online date	9 Nov 2011
DOIs	https://doi.org/10.1093/hmg/ddr525
Publication status	Published - 15 Feb 2012

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Turnbull, C., Seal, S., Renwick, A., Warren-Perry, M., Hughes, D., Elliott, A., Pernet, D., Peock, S., Adlard, J. W., Barwell, J., Berg, J., Brady, A. F., Brewer, C., Brice, G., Chapman, C., Cook, J., Davidson, R., Donaldson, A., Douglas, F., ... Breast Cancer Susceptibility Collaboration (UK), EMBRACE (2012). Gene-gene interactions in breast cancer susceptibility. Human Molecular Genetics, 21(4), 958-962. https://doi.org/10.1093/hmg/ddr525

Turnbull, C, Seal, S, Renwick, A, Warren-Perry, M, Hughes, D, Elliott, A, Pernet, D, Peock, S, 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, Ahmed, M, Eccles, D, Evans, DG, Donnelly, P, Easton, DF, Stratton, MR, Rahman, N & Breast Cancer Susceptibility Collaboration (UK), EMBRACE 2012, 'Gene-gene interactions in breast cancer susceptibility', Human Molecular Genetics, vol. 21, no. 4, pp. 958-962. https://doi.org/10.1093/hmg/ddr525

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abstract = "There have been few definitive examples of gene-gene interactions in humans. Through mutational analyses in 7325 individuals, we report four interactions (defined as departures from a multiplicative model) between mutations in the breast cancer susceptibility genes ATM and CHEK2 with BRCA1 and BRCA2 (case-only interaction between ATM and BRCA1/BRCA2 combined, P = 5.9 × 10(-4); ATM and BRCA1, P= 0.01; ATM and BRCA2, P= 0.02; CHEK2 and BRCA1/BRCA2 combined, P = 2.1 × 10(-4); CHEK2 and BRCA1, P= 0.01; CHEK2 and BRCA2, P= 0.01). The interactions are such that the resultant risk of breast cancer is lower than the multiplicative product of the constituent risks, and plausibly reflect the functional relationships of the encoded proteins in DNA repair. These findings have important implications for models of disease predisposition and clinical translation.",

author = "Clare Turnbull and Sheila Seal and Anthony Renwick and Margaret Warren-Perry and Deborah Hughes and Anna Elliott and David Pernet and Susan Peock 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 Munaza Ahmed and Diana Eccles and Evans, {D Gareth} and Peter Donnelly and Easton, {Douglas F} and Stratton, {Michael R} and Nazneen Rahman and {Breast Cancer Susceptibility Collaboration (UK), EMBRACE}",

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AU - Elliott, Anna

AU - Pernet, David

AU - Peock, Susan

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 - Ahmed, Munaza

AU - Eccles, Diana

AU - Evans, D Gareth

AU - Donnelly, Peter

AU - Easton, Douglas F

AU - Stratton, Michael R

AU - Rahman, Nazneen

AU - Breast Cancer Susceptibility Collaboration (UK), EMBRACE

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AB - There have been few definitive examples of gene-gene interactions in humans. Through mutational analyses in 7325 individuals, we report four interactions (defined as departures from a multiplicative model) between mutations in the breast cancer susceptibility genes ATM and CHEK2 with BRCA1 and BRCA2 (case-only interaction between ATM and BRCA1/BRCA2 combined, P = 5.9 × 10(-4); ATM and BRCA1, P= 0.01; ATM and BRCA2, P= 0.02; CHEK2 and BRCA1/BRCA2 combined, P = 2.1 × 10(-4); CHEK2 and BRCA1, P= 0.01; CHEK2 and BRCA2, P= 0.01). The interactions are such that the resultant risk of breast cancer is lower than the multiplicative product of the constituent risks, and plausibly reflect the functional relationships of the encoded proteins in DNA repair. These findings have important implications for models of disease predisposition and clinical translation.

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JO - Human Molecular Genetics

JF - Human Molecular Genetics

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Gene-gene interactions in breast cancer susceptibility

Abstract

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