Genetic variation in insulin-like growth factor signaling genes and breast cancer risk among BRCA1 and BRCA2 carriers

Susan L. Neuhausen, Sean Brummel, Yuan C. Ding, Christian F. Singer, Georg Pfeiler, Henry T. Lynch, Katherine L. Nathanson, Timothy R. Rebbeck, Judy E. Garber, Fergus Couch, Jeffrey Weitzel, Steven A. Narod, Patricia A. Ganz, Mary B. Daly, Andrew K. Godwin, Claudine Isaacs, Olufunmilayo I. Olopade, Gail Tomlinson, Wendy S. Rubinstein, Nadine TungJoanne L. Blum, Daniel L. Gillen

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Abstract

Introduction: Women who carry mutations in BRCA1 and BRCA2 have a substantially increased risk of developing breast cancer as compared with the general population. However, risk estimates range from 20 to 80%, suggesting the presence of genetic and/or environmental risk modifiers. Based on extensive in vivo and in vitro studies, one important pathway for breast cancer pathogenesis may be the insulin-like growth factor (IGF) signaling pathway, which regulates both cellular proliferation and apoptosis. BRCA1 has been shown to directly interact with IGF signaling such that variants in this pathway may modify risk of cancer in women carrying BRCA mutations. In this study, we investigate the association of variants in genes involved in IGF signaling and risk of breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations.Methods: A cohort of 1,665 adult, female mutation carriers, including 1,122 BRCA1 carriers (433 cases) and 543 BRCA2 carriers (238 cases) were genotyped for SNPs in IGF1, IGF1 receptor (IGF1R), IGF1 binding protein (IGFBP1, IGFBP2, IGFBP5), and IGF receptor substrate 1 (IRS1). Cox proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was assumed; and for single SNP analyses, no additivity assumptions were made.Results: Among BRCA1 carriers, significant associations were found between risk of breast cancer and LD blocks in IGF1R (global P = 0.011 for LD block 2 and global P = 0.012 for LD block 11). Among BRCA2 carriers, an LD block in IGFBP2 (global P = 0.0145) was found to be associated with the time to breast cancer diagnosis. No significant LD block associations were found for the other investigated genes among BRCA1 and BRCA2 carriers.Conclusions: This is the first study to investigate the role of genetic variation in IGF signaling and breast cancer risk in women carrying deleterious mutations in BRCA1 and BRCA2. We identified significant associations in variants in IGF1R and IRS1 in BRCA1 carriers and in IGFBP2 in BRCA2 carriers. Although there is known to be interaction of BRCA1 and IGF signaling, further replication and identification of causal mechanisms are needed to better understand these associations.

Original languageEnglish
Article numberR76
JournalBreast Cancer Research
Volume11
Issue number5
DOIs
StatePublished - Oct 20 2009

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Somatomedins
Linkage Disequilibrium
Breast Neoplasms
Genes
Mutation
Single Nucleotide Polymorphism
BRCA2 Gene
BRCA1 Gene
Somatomedin Receptors
IGF Type 1 Receptor
Genetic Models
Carrier Proteins
Cell Proliferation
Parturition
Apoptosis
Population
Neoplasms

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Genetic variation in insulin-like growth factor signaling genes and breast cancer risk among BRCA1 and BRCA2 carriers. / Neuhausen, Susan L.; Brummel, Sean; Ding, Yuan C.; Singer, Christian F.; Pfeiler, Georg; Lynch, Henry T.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Garber, Judy E.; Couch, Fergus; Weitzel, Jeffrey; Narod, Steven A.; Ganz, Patricia A.; Daly, Mary B.; Godwin, Andrew K.; Isaacs, Claudine; Olopade, Olufunmilayo I.; Tomlinson, Gail; Rubinstein, Wendy S.; Tung, Nadine; Blum, Joanne L.; Gillen, Daniel L.

In: Breast Cancer Research, Vol. 11, No. 5, R76, 20.10.2009.

Research output: Contribution to journalArticle

Neuhausen, SL, Brummel, S, Ding, YC, Singer, CF, Pfeiler, G, Lynch, HT, Nathanson, KL, Rebbeck, TR, Garber, JE, Couch, F, Weitzel, J, Narod, SA, Ganz, PA, Daly, MB, Godwin, AK, Isaacs, C, Olopade, OI, Tomlinson, G, Rubinstein, WS, Tung, N, Blum, JL & Gillen, DL 2009, 'Genetic variation in insulin-like growth factor signaling genes and breast cancer risk among BRCA1 and BRCA2 carriers', Breast Cancer Research, vol. 11, no. 5, R76. https://doi.org/10.1186/bcr2414
Neuhausen, Susan L. ; Brummel, Sean ; Ding, Yuan C. ; Singer, Christian F. ; Pfeiler, Georg ; Lynch, Henry T. ; Nathanson, Katherine L. ; Rebbeck, Timothy R. ; Garber, Judy E. ; Couch, Fergus ; Weitzel, Jeffrey ; Narod, Steven A. ; Ganz, Patricia A. ; Daly, Mary B. ; Godwin, Andrew K. ; Isaacs, Claudine ; Olopade, Olufunmilayo I. ; Tomlinson, Gail ; Rubinstein, Wendy S. ; Tung, Nadine ; Blum, Joanne L. ; Gillen, Daniel L. / Genetic variation in insulin-like growth factor signaling genes and breast cancer risk among BRCA1 and BRCA2 carriers. In: Breast Cancer Research. 2009 ; Vol. 11, No. 5.
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title = "Genetic variation in insulin-like growth factor signaling genes and breast cancer risk among BRCA1 and BRCA2 carriers",
abstract = "Introduction: Women who carry mutations in BRCA1 and BRCA2 have a substantially increased risk of developing breast cancer as compared with the general population. However, risk estimates range from 20 to 80{\%}, suggesting the presence of genetic and/or environmental risk modifiers. Based on extensive in vivo and in vitro studies, one important pathway for breast cancer pathogenesis may be the insulin-like growth factor (IGF) signaling pathway, which regulates both cellular proliferation and apoptosis. BRCA1 has been shown to directly interact with IGF signaling such that variants in this pathway may modify risk of cancer in women carrying BRCA mutations. In this study, we investigate the association of variants in genes involved in IGF signaling and risk of breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations.Methods: A cohort of 1,665 adult, female mutation carriers, including 1,122 BRCA1 carriers (433 cases) and 543 BRCA2 carriers (238 cases) were genotyped for SNPs in IGF1, IGF1 receptor (IGF1R), IGF1 binding protein (IGFBP1, IGFBP2, IGFBP5), and IGF receptor substrate 1 (IRS1). Cox proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was assumed; and for single SNP analyses, no additivity assumptions were made.Results: Among BRCA1 carriers, significant associations were found between risk of breast cancer and LD blocks in IGF1R (global P = 0.011 for LD block 2 and global P = 0.012 for LD block 11). Among BRCA2 carriers, an LD block in IGFBP2 (global P = 0.0145) was found to be associated with the time to breast cancer diagnosis. No significant LD block associations were found for the other investigated genes among BRCA1 and BRCA2 carriers.Conclusions: This is the first study to investigate the role of genetic variation in IGF signaling and breast cancer risk in women carrying deleterious mutations in BRCA1 and BRCA2. We identified significant associations in variants in IGF1R and IRS1 in BRCA1 carriers and in IGFBP2 in BRCA2 carriers. Although there is known to be interaction of BRCA1 and IGF signaling, further replication and identification of causal mechanisms are needed to better understand these associations.",
author = "Neuhausen, {Susan L.} and Sean Brummel and Ding, {Yuan C.} and Singer, {Christian F.} and Georg Pfeiler and Lynch, {Henry T.} and Nathanson, {Katherine L.} and Rebbeck, {Timothy R.} and Garber, {Judy E.} and Fergus Couch and Jeffrey Weitzel and Narod, {Steven A.} and Ganz, {Patricia A.} and Daly, {Mary B.} and Godwin, {Andrew K.} and Claudine Isaacs and Olopade, {Olufunmilayo I.} and Gail Tomlinson and Rubinstein, {Wendy S.} and Nadine Tung and Blum, {Joanne L.} and Gillen, {Daniel L.}",
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TY - JOUR

T1 - Genetic variation in insulin-like growth factor signaling genes and breast cancer risk among BRCA1 and BRCA2 carriers

AU - Neuhausen, Susan L.

AU - Brummel, Sean

AU - Ding, Yuan C.

AU - Singer, Christian F.

AU - Pfeiler, Georg

AU - Lynch, Henry T.

AU - Nathanson, Katherine L.

AU - Rebbeck, Timothy R.

AU - Garber, Judy E.

AU - Couch, Fergus

AU - Weitzel, Jeffrey

AU - Narod, Steven A.

AU - Ganz, Patricia A.

AU - Daly, Mary B.

AU - Godwin, Andrew K.

AU - Isaacs, Claudine

AU - Olopade, Olufunmilayo I.

AU - Tomlinson, Gail

AU - Rubinstein, Wendy S.

AU - Tung, Nadine

AU - Blum, Joanne L.

AU - Gillen, Daniel L.

PY - 2009/10/20

Y1 - 2009/10/20

N2 - Introduction: Women who carry mutations in BRCA1 and BRCA2 have a substantially increased risk of developing breast cancer as compared with the general population. However, risk estimates range from 20 to 80%, suggesting the presence of genetic and/or environmental risk modifiers. Based on extensive in vivo and in vitro studies, one important pathway for breast cancer pathogenesis may be the insulin-like growth factor (IGF) signaling pathway, which regulates both cellular proliferation and apoptosis. BRCA1 has been shown to directly interact with IGF signaling such that variants in this pathway may modify risk of cancer in women carrying BRCA mutations. In this study, we investigate the association of variants in genes involved in IGF signaling and risk of breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations.Methods: A cohort of 1,665 adult, female mutation carriers, including 1,122 BRCA1 carriers (433 cases) and 543 BRCA2 carriers (238 cases) were genotyped for SNPs in IGF1, IGF1 receptor (IGF1R), IGF1 binding protein (IGFBP1, IGFBP2, IGFBP5), and IGF receptor substrate 1 (IRS1). Cox proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was assumed; and for single SNP analyses, no additivity assumptions were made.Results: Among BRCA1 carriers, significant associations were found between risk of breast cancer and LD blocks in IGF1R (global P = 0.011 for LD block 2 and global P = 0.012 for LD block 11). Among BRCA2 carriers, an LD block in IGFBP2 (global P = 0.0145) was found to be associated with the time to breast cancer diagnosis. No significant LD block associations were found for the other investigated genes among BRCA1 and BRCA2 carriers.Conclusions: This is the first study to investigate the role of genetic variation in IGF signaling and breast cancer risk in women carrying deleterious mutations in BRCA1 and BRCA2. We identified significant associations in variants in IGF1R and IRS1 in BRCA1 carriers and in IGFBP2 in BRCA2 carriers. Although there is known to be interaction of BRCA1 and IGF signaling, further replication and identification of causal mechanisms are needed to better understand these associations.

AB - Introduction: Women who carry mutations in BRCA1 and BRCA2 have a substantially increased risk of developing breast cancer as compared with the general population. However, risk estimates range from 20 to 80%, suggesting the presence of genetic and/or environmental risk modifiers. Based on extensive in vivo and in vitro studies, one important pathway for breast cancer pathogenesis may be the insulin-like growth factor (IGF) signaling pathway, which regulates both cellular proliferation and apoptosis. BRCA1 has been shown to directly interact with IGF signaling such that variants in this pathway may modify risk of cancer in women carrying BRCA mutations. In this study, we investigate the association of variants in genes involved in IGF signaling and risk of breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations.Methods: A cohort of 1,665 adult, female mutation carriers, including 1,122 BRCA1 carriers (433 cases) and 543 BRCA2 carriers (238 cases) were genotyped for SNPs in IGF1, IGF1 receptor (IGF1R), IGF1 binding protein (IGFBP1, IGFBP2, IGFBP5), and IGF receptor substrate 1 (IRS1). Cox proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was assumed; and for single SNP analyses, no additivity assumptions were made.Results: Among BRCA1 carriers, significant associations were found between risk of breast cancer and LD blocks in IGF1R (global P = 0.011 for LD block 2 and global P = 0.012 for LD block 11). Among BRCA2 carriers, an LD block in IGFBP2 (global P = 0.0145) was found to be associated with the time to breast cancer diagnosis. No significant LD block associations were found for the other investigated genes among BRCA1 and BRCA2 carriers.Conclusions: This is the first study to investigate the role of genetic variation in IGF signaling and breast cancer risk in women carrying deleterious mutations in BRCA1 and BRCA2. We identified significant associations in variants in IGF1R and IRS1 in BRCA1 carriers and in IGFBP2 in BRCA2 carriers. Although there is known to be interaction of BRCA1 and IGF signaling, further replication and identification of causal mechanisms are needed to better understand these associations.

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