Genetic variation in IGF2 and HTRA1 and breast cancer risk among BRCA1 and BRCA2 carriers

Susan L. Neuhausen, Sean Brummel, Yuan Chun Ding, Linda Steele, Katherine L. Nathanson, Susan Domchek, Timothy R. Rebbeck, Christian F. Singer, Georg Pfeiler, Henry T. Lynch, Judy E. Garber, Fergus Couch, Jeffrey N. Weitzel, Andrew Godwin, Steven A. Narod, Patricia A. Ganz, Mary B. Daly, Claudine Isaacs, Olufunmilayo I. Olopade, Gail E. Tomlinson & 4 others Wendy S. Rubinstein, Nadine Tung, Joanne L. Blum, Daniel L. Gillen

Research output: Contribution to journalArticle

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Abstract

Background: BRCA1 and BRCA2 mutation carriers have a lifetime breast cancer risk of 40% to 80%, suggesting the presence of risk modifiers. We previously identified significant associations in genetic variants in the insulin-like growth factor (IGF) signaling pathway. Here, we investigate additional IGF signaling genes as risk modifiers for breast cancer development in BRCA carriers. Methods: A cohort of 1,019 BRCA1 and 500 BRCA2 mutation carriers were genotyped for 99 singlenucleotide polymorphisms (SNP) in 13 genes. 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 used. For an SNP analysis, no additivity assumptions were made. Results: Significant associations were found between risk of breast cancer and LD blocks in IGF2 for BRCA1 and BRCA2 mutation carriers (global P values of 0.009 for BRCA1 and 0.007 for BRCA2), HTRA1 for BRCA1 carriers (global P value of 0.005), and MMP3 for BRCA2 carriers (global P = 0.0000007 for BRCA2). Conclusions: We identified significant associations of genetic variants involved in IGF signaling. With the known interaction of BRCA1 and IGF signaling and the loss of PTEN in a majority of BRCA1 tumors, this suggests that signaling through AKT may modify breast cancer risk in BRCA1 carriers. Impact: These results suggest potential avenues for future research targeting the IGF signaling pathway in modifying risk in BRCA1and BRCA2 mutation carriers.

Original languageEnglish
Pages (from-to)1690-1702
Number of pages13
JournalCancer Epidemiology Biomarkers and Prevention
Volume20
Issue number8
DOIs
StatePublished - Aug 2011

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Somatomedins
Breast Neoplasms
Mutation
Linkage Disequilibrium
Genetic Models
Genes
Single Nucleotide Polymorphism
Parturition
Neoplasms

All Science Journal Classification (ASJC) codes

  • Epidemiology
  • Oncology

Cite this

Neuhausen, S. L., Brummel, S., Ding, Y. C., Steele, L., Nathanson, K. L., Domchek, S., ... Gillen, D. L. (2011). Genetic variation in IGF2 and HTRA1 and breast cancer risk among BRCA1 and BRCA2 carriers. Cancer Epidemiology Biomarkers and Prevention, 20(8), 1690-1702. https://doi.org/10.1158/1055-9965.EPI-10-1336

Genetic variation in IGF2 and HTRA1 and breast cancer risk among BRCA1 and BRCA2 carriers. / Neuhausen, Susan L.; Brummel, Sean; Ding, Yuan Chun; Steele, Linda; Nathanson, Katherine L.; Domchek, Susan; Rebbeck, Timothy R.; Singer, Christian F.; Pfeiler, Georg; Lynch, Henry T.; Garber, Judy E.; Couch, Fergus; Weitzel, Jeffrey N.; Godwin, Andrew; Narod, Steven A.; Ganz, Patricia A.; Daly, Mary B.; Isaacs, Claudine; Olopade, Olufunmilayo I.; Tomlinson, Gail E.; Rubinstein, Wendy S.; Tung, Nadine; Blum, Joanne L.; Gillen, Daniel L.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 20, No. 8, 08.2011, p. 1690-1702.

Research output: Contribution to journalArticle

Neuhausen, SL, Brummel, S, Ding, YC, Steele, L, Nathanson, KL, Domchek, S, Rebbeck, TR, Singer, CF, Pfeiler, G, Lynch, HT, Garber, JE, Couch, F, Weitzel, JN, Godwin, A, Narod, SA, Ganz, PA, Daly, MB, Isaacs, C, Olopade, OI, Tomlinson, GE, Rubinstein, WS, Tung, N, Blum, JL & Gillen, DL 2011, 'Genetic variation in IGF2 and HTRA1 and breast cancer risk among BRCA1 and BRCA2 carriers', Cancer Epidemiology Biomarkers and Prevention, vol. 20, no. 8, pp. 1690-1702. https://doi.org/10.1158/1055-9965.EPI-10-1336
Neuhausen, Susan L. ; Brummel, Sean ; Ding, Yuan Chun ; Steele, Linda ; Nathanson, Katherine L. ; Domchek, Susan ; Rebbeck, Timothy R. ; Singer, Christian F. ; Pfeiler, Georg ; Lynch, Henry T. ; Garber, Judy E. ; Couch, Fergus ; Weitzel, Jeffrey N. ; Godwin, Andrew ; Narod, Steven A. ; Ganz, Patricia A. ; Daly, Mary B. ; Isaacs, Claudine ; Olopade, Olufunmilayo I. ; Tomlinson, Gail E. ; Rubinstein, Wendy S. ; Tung, Nadine ; Blum, Joanne L. ; Gillen, Daniel L. / Genetic variation in IGF2 and HTRA1 and breast cancer risk among BRCA1 and BRCA2 carriers. In: Cancer Epidemiology Biomarkers and Prevention. 2011 ; Vol. 20, No. 8. pp. 1690-1702.
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abstract = "Background: BRCA1 and BRCA2 mutation carriers have a lifetime breast cancer risk of 40{\%} to 80{\%}, suggesting the presence of risk modifiers. We previously identified significant associations in genetic variants in the insulin-like growth factor (IGF) signaling pathway. Here, we investigate additional IGF signaling genes as risk modifiers for breast cancer development in BRCA carriers. Methods: A cohort of 1,019 BRCA1 and 500 BRCA2 mutation carriers were genotyped for 99 singlenucleotide polymorphisms (SNP) in 13 genes. 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 used. For an SNP analysis, no additivity assumptions were made. Results: Significant associations were found between risk of breast cancer and LD blocks in IGF2 for BRCA1 and BRCA2 mutation carriers (global P values of 0.009 for BRCA1 and 0.007 for BRCA2), HTRA1 for BRCA1 carriers (global P value of 0.005), and MMP3 for BRCA2 carriers (global P = 0.0000007 for BRCA2). Conclusions: We identified significant associations of genetic variants involved in IGF signaling. With the known interaction of BRCA1 and IGF signaling and the loss of PTEN in a majority of BRCA1 tumors, this suggests that signaling through AKT may modify breast cancer risk in BRCA1 carriers. Impact: These results suggest potential avenues for future research targeting the IGF signaling pathway in modifying risk in BRCA1and BRCA2 mutation carriers.",
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T1 - Genetic variation in IGF2 and HTRA1 and breast cancer risk among BRCA1 and BRCA2 carriers

AU - Neuhausen, Susan L.

AU - Brummel, Sean

AU - Ding, Yuan Chun

AU - Steele, Linda

AU - Nathanson, Katherine L.

AU - Domchek, Susan

AU - Rebbeck, Timothy R.

AU - Singer, Christian F.

AU - Pfeiler, Georg

AU - Lynch, Henry T.

AU - Garber, Judy E.

AU - Couch, Fergus

AU - Weitzel, Jeffrey N.

AU - Godwin, Andrew

AU - Narod, Steven A.

AU - Ganz, Patricia A.

AU - Daly, Mary B.

AU - Isaacs, Claudine

AU - Olopade, Olufunmilayo I.

AU - Tomlinson, Gail E.

AU - Rubinstein, Wendy S.

AU - Tung, Nadine

AU - Blum, Joanne L.

AU - Gillen, Daniel L.

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N2 - Background: BRCA1 and BRCA2 mutation carriers have a lifetime breast cancer risk of 40% to 80%, suggesting the presence of risk modifiers. We previously identified significant associations in genetic variants in the insulin-like growth factor (IGF) signaling pathway. Here, we investigate additional IGF signaling genes as risk modifiers for breast cancer development in BRCA carriers. Methods: A cohort of 1,019 BRCA1 and 500 BRCA2 mutation carriers were genotyped for 99 singlenucleotide polymorphisms (SNP) in 13 genes. 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 used. For an SNP analysis, no additivity assumptions were made. Results: Significant associations were found between risk of breast cancer and LD blocks in IGF2 for BRCA1 and BRCA2 mutation carriers (global P values of 0.009 for BRCA1 and 0.007 for BRCA2), HTRA1 for BRCA1 carriers (global P value of 0.005), and MMP3 for BRCA2 carriers (global P = 0.0000007 for BRCA2). Conclusions: We identified significant associations of genetic variants involved in IGF signaling. With the known interaction of BRCA1 and IGF signaling and the loss of PTEN in a majority of BRCA1 tumors, this suggests that signaling through AKT may modify breast cancer risk in BRCA1 carriers. Impact: These results suggest potential avenues for future research targeting the IGF signaling pathway in modifying risk in BRCA1and BRCA2 mutation carriers.

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