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 & 18 others 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

Research output: Contribution to journalArticle

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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 (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.

Original languageEnglish
Pages (from-to)5792-5805
Number of pages14
JournalCancer Research
Volume71
Issue number17
DOIs
StatePublished - Sep 1 2011

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BRCA1 Gene
Ovarian Neoplasms
Haplotypes
Breast Neoplasms
Mutation
Modifier Genes
Neoplasms
Proteins
Genes

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology

Cite this

Rebbeck, T. R., Mitra, N., Domchek, S. M., Wan, F., Friebel, T. M., Tran, T. V., ... 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

Modification of BRCA1-associated breast and ovarian cancer risk by BRCA1-interacting genes. / Rebbeck, Timothy R.; Mitra, Nandita; Domchek, Susan M.; Wan, Fei; Friebel, Tara M.; Tran, Teo V.; Singer, Christian F.; Tea, Muy Kheng Maria; Blum, Joanne L.; Tung, Nadine; Olopade, Olufunmilayo I.; Weitzel, Jeffrey N.; Lynch, Henry T.; Snyder, Carrie L.; Garber, Judy E.; Antoniou, Antonis C.; Peock, Susan; Evans, D. Gareth; Paterson, Joan; Kennedy, M. John; Donaldson, Alan; Dorkins, Huw; Easton, Douglas F.; Rubinstein, Wendy S.; Daly, Mary B.; Isaacs, Claudine; Nevanlinna, Heli; Couch, Fergus J.; Andrulis, Irene L.; Freidman, Eitan; Laitman, Yael; Ganz, Patricia A.; Tomlinson, Gail E.; Neuhausen, Susan L.; Narod, Steven A.; Phelan, Catherine M.; Greenberg, Roger; Nathanson, Katherine L.

In: Cancer Research, Vol. 71, No. 17, 01.09.2011, p. 5792-5805.

Research output: Contribution to journalArticle

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
Rebbeck TR, Mitra N, Domchek SM, Wan F, Friebel TM, Tran TV et al. Modification of BRCA1-associated breast and ovarian cancer risk by BRCA1-interacting genes. Cancer Research. 2011 Sep 1;71(17):5792-5805. https://doi.org/10.1158/0008-5472.CAN-11-0773
Rebbeck, Timothy R. ; Mitra, Nandita ; Domchek, Susan M. ; Wan, Fei ; Friebel, Tara M. ; Tran, Teo V. ; Singer, Christian F. ; Tea, Muy Kheng Maria ; Blum, Joanne L. ; Tung, Nadine ; Olopade, Olufunmilayo I. ; Weitzel, Jeffrey N. ; Lynch, Henry T. ; Snyder, Carrie L. ; Garber, Judy E. ; Antoniou, Antonis C. ; Peock, Susan ; Evans, D. Gareth ; Paterson, Joan ; Kennedy, M. John ; Donaldson, Alan ; Dorkins, Huw ; Easton, Douglas F. ; Rubinstein, Wendy S. ; Daly, Mary B. ; Isaacs, Claudine ; Nevanlinna, Heli ; Couch, Fergus J. ; Andrulis, Irene L. ; Freidman, Eitan ; Laitman, Yael ; Ganz, Patricia A. ; Tomlinson, Gail E. ; Neuhausen, Susan L. ; Narod, Steven A. ; Phelan, Catherine M. ; Greenberg, Roger ; Nathanson, Katherine L. / Modification of BRCA1-associated breast and ovarian cancer risk by BRCA1-interacting genes. In: Cancer Research. 2011 ; Vol. 71, No. 17. pp. 5792-5805.
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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 (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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AU - Tran, Teo V.

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AU - Andrulis, Irene L.

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AU - Tomlinson, Gail E.

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