Modification of BRCA1-associated breast and ovarian cancer risk by BRCA1-interacting genes

Timothy R. Rebbeck; Nandita Mitra; Susan M. Domchek; Fei Wan; Tara M. Friebel; Teo V. Tran; Christian F. Singer; Muy Kheng Maria Tea; Joanne L. Blum; Nadine Tung; Olufunmilayo I. Olopade; Jeffrey N. Weitzel; Henry T. Lynch; Carrie L. Snyder; Judy E. Garber; Antonis C. Antoniou; Susan Peock; D. Gareth Evans; Joan Paterson; M. John Kennedy; Alan Donaldson; Huw Dorkins; Douglas F. Easton; Wendy S. Rubinstein; Mary B. Daly; Claudine Isaacs; Heli Nevanlinna; Fergus J. Couch; Irene L. Andrulis; Eitan Freidman; Yael Laitman; Patricia A. Ganz; Gail E. Tomlinson; Susan L. Neuhausen; Steven A. Narod; Catherine M. Phelan; Roger Greenberg; Katherine L. Nathanson

doi:10.1158/0008-5472.CAN-11-0773

Modification of BRCA1-associated breast and ovarian cancer risk by BRCA1-interacting genes

Timothy R. Rebbeck, Nandita Mitra, Susan M. Domchek, Fei Wan, Tara M. Friebel, Teo V. Tran, Christian F. Singer, Muy Kheng Maria Tea, Joanne L. Blum, Nadine Tung, Olufunmilayo I. Olopade, Jeffrey N. Weitzel, Henry T. Lynch, Carrie L. Snyder, Judy E. Garber, Antonis C. Antoniou, Susan Peock, D. Gareth Evans, Joan Paterson, M. John KennedyAlan Donaldson, Huw Dorkins, Douglas F. Easton, Wendy S. Rubinstein, Mary B. Daly, Claudine Isaacs, Heli Nevanlinna, Fergus J. Couch, Irene L. Andrulis, Eitan Freidman, Yael Laitman, Patricia A. Ganz, Gail E. Tomlinson, Susan L. Neuhausen, Steven A. Narod, Catherine M. Phelan, Roger Greenberg, Katherine L. Nathanson

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Abstract

Inherited BRCA1 mutations confer elevated cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, and TOPBP1, and was associated with time to breast and ovarian cancer diagnosis. Statistically significant false discovery rate (FDR) adjusted P values for overall association of haplotypes (PFDR) with breast cancer were identified at ATM (P_FDR = 0.029), BRCC45 (P_FDR = 0.019), BRIP1 (P_FDR = 0.008), CTIP (P_FDR = 0.017), MERIT40 (P_FDR = 0.019), NBS1 (P_FDR = 0.003), RAD50 (PFDR = 0.014), and TOPBP1 (P_FDR = 0.011). Haplotypes at ABRA1 (P _FDR = 0.007), BRCC45 (P_FDR = 0.016 and PFDR = 0.005 in two haplotype blocks), and RAP80 (P_FDR < 0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.

Original language	English (US)
Pages (from-to)	5792-5805
Number of pages	14
Journal	Cancer research
Volume	71
Issue number	17
DOIs	https://doi.org/10.1158/0008-5472.CAN-11-0773
State	Published - Sep 1 2011

ASJC Scopus subject areas

Oncology
Cancer Research

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Rebbeck, T. R., Mitra, N., Domchek, S. M., Wan, F., Friebel, T. M., Tran, T. V., Singer, C. F., Tea, M. K. M., Blum, J. L., Tung, N., Olopade, O. I., Weitzel, J. N., Lynch, H. T., Snyder, C. L., Garber, J. E., Antoniou, A. C., Peock, S., Evans, D. G., Paterson, J., ... Nathanson, K. L. (2011). Modification of BRCA1-associated breast and ovarian cancer risk by BRCA1-interacting genes. Cancer research, 71(17), 5792-5805. https://doi.org/10.1158/0008-5472.CAN-11-0773

Rebbeck, TR, Mitra, N, Domchek, SM, Wan, F, Friebel, TM, Tran, TV, Singer, CF, Tea, MKM, Blum, JL, Tung, N, Olopade, OI, Weitzel, JN, Lynch, HT, Snyder, CL, Garber, JE, Antoniou, AC, Peock, S, Evans, DG, Paterson, J, Kennedy, MJ, Donaldson, A, Dorkins, H, Easton, DF, Rubinstein, WS, Daly, MB, Isaacs, C, Nevanlinna, H, Couch, FJ, Andrulis, IL, Freidman, E, Laitman, Y, Ganz, PA, Tomlinson, GE, Neuhausen, SL, Narod, SA, Phelan, CM, Greenberg, R & Nathanson, KL 2011, 'Modification of BRCA1-associated breast and ovarian cancer risk by BRCA1-interacting genes', Cancer research, vol. 71, no. 17, pp. 5792-5805. https://doi.org/10.1158/0008-5472.CAN-11-0773

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title = "Modification of BRCA1-associated breast and ovarian cancer risk by BRCA1-interacting genes",

abstract = "Inherited BRCA1 mutations confer elevated cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, and TOPBP1, and was associated with time to breast and ovarian cancer diagnosis. Statistically significant false discovery rate (FDR) adjusted P values for overall association of haplotypes (PFDR) with breast cancer were identified at ATM (PFDR = 0.029), BRCC45 (PFDR = 0.019), BRIP1 (PFDR = 0.008), CTIP (PFDR = 0.017), MERIT40 (PFDR = 0.019), NBS1 (PFDR = 0.003), RAD50 (PFDR = 0.014), and TOPBP1 (PFDR = 0.011). Haplotypes at ABRA1 (P FDR = 0.007), BRCC45 (PFDR = 0.016 and PFDR = 0.005 in two haplotype blocks), and RAP80 (PFDR < 0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.",

author = "Rebbeck, {Timothy R.} and Nandita Mitra and Domchek, {Susan M.} and Fei Wan and Friebel, {Tara M.} and Tran, {Teo V.} and Singer, {Christian F.} and Tea, {Muy Kheng Maria} and Blum, {Joanne L.} and Nadine Tung and Olopade, {Olufunmilayo I.} and Weitzel, {Jeffrey N.} and Lynch, {Henry T.} and Snyder, {Carrie L.} and Garber, {Judy E.} and Antoniou, {Antonis C.} and Susan Peock and Evans, {D. Gareth} and Joan Paterson and Kennedy, {M. John} and Alan Donaldson and Huw Dorkins and Easton, {Douglas F.} and Rubinstein, {Wendy S.} and Daly, {Mary B.} and Claudine Isaacs and Heli Nevanlinna and Couch, {Fergus J.} and Andrulis, {Irene L.} and Eitan Freidman and Yael Laitman and Ganz, {Patricia A.} and Tomlinson, {Gail E.} and Neuhausen, {Susan L.} and Narod, {Steven A.} and Phelan, {Catherine M.} and Roger Greenberg and Nathanson, {Katherine L.}",

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AU - Rebbeck, Timothy R.

AU - Mitra, Nandita

AU - Domchek, Susan M.

AU - Wan, Fei

AU - Friebel, Tara M.

AU - Tran, Teo V.

AU - Singer, Christian F.

AU - Tea, Muy Kheng Maria

AU - Blum, Joanne L.

AU - Tung, Nadine

AU - Olopade, Olufunmilayo I.

AU - Weitzel, Jeffrey N.

AU - Lynch, Henry T.

AU - Snyder, Carrie L.

AU - Garber, Judy E.

AU - Antoniou, Antonis C.

AU - Peock, Susan

AU - Evans, D. Gareth

AU - Paterson, Joan

AU - Kennedy, M. John

AU - Donaldson, Alan

AU - Dorkins, Huw

AU - Easton, Douglas F.

AU - Rubinstein, Wendy S.

AU - Daly, Mary B.

AU - Isaacs, Claudine

AU - Nevanlinna, Heli

AU - Couch, Fergus J.

AU - Andrulis, Irene L.

AU - Freidman, Eitan

AU - Laitman, Yael

AU - Ganz, Patricia A.

AU - Tomlinson, Gail E.

AU - Neuhausen, Susan L.

AU - Narod, Steven A.

AU - Phelan, Catherine M.

AU - Greenberg, Roger

AU - Nathanson, Katherine L.

PY - 2011/9/1

Y1 - 2011/9/1

N2 - Inherited BRCA1 mutations confer elevated cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, and TOPBP1, and was associated with time to breast and ovarian cancer diagnosis. Statistically significant false discovery rate (FDR) adjusted P values for overall association of haplotypes (PFDR) with breast cancer were identified at ATM (PFDR = 0.029), BRCC45 (PFDR = 0.019), BRIP1 (PFDR = 0.008), CTIP (PFDR = 0.017), MERIT40 (PFDR = 0.019), NBS1 (PFDR = 0.003), RAD50 (PFDR = 0.014), and TOPBP1 (PFDR = 0.011). Haplotypes at ABRA1 (P FDR = 0.007), BRCC45 (PFDR = 0.016 and PFDR = 0.005 in two haplotype blocks), and RAP80 (PFDR < 0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.

AB - Inherited BRCA1 mutations confer elevated cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, and TOPBP1, and was associated with time to breast and ovarian cancer diagnosis. Statistically significant false discovery rate (FDR) adjusted P values for overall association of haplotypes (PFDR) with breast cancer were identified at ATM (PFDR = 0.029), BRCC45 (PFDR = 0.019), BRIP1 (PFDR = 0.008), CTIP (PFDR = 0.017), MERIT40 (PFDR = 0.019), NBS1 (PFDR = 0.003), RAD50 (PFDR = 0.014), and TOPBP1 (PFDR = 0.011). Haplotypes at ABRA1 (P FDR = 0.007), BRCC45 (PFDR = 0.016 and PFDR = 0.005 in two haplotype blocks), and RAP80 (PFDR < 0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.

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Modification of BRCA1-associated breast and ovarian cancer risk by BRCA1-interacting genes

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