Women who carry mutations in BRCA1 and BRCA2 (BRCA1/2) have a substantially increased risk of developing breast and ovarian cancers. There is considerable variability in age at diagnosis and relative incidence of breast and ovarian cancers, even among women with the same mutation, suggestive that additional risk factors modify the age-specific risk. We propose a comprehensive analysis of genes in the insulin-like growth factor (IGF) signaling pathway, a pathway integrally involved in cellular proliferation. We will use powerful new approaches that combine multiple linked variants in a single gene to form haplotypes and that allow evaluation of multiple genes in a single mechanistic pathway. We will utilize the resources of our multi-center cohort, which currently includes 2,000 Caucasian and 76 African-American BRCA1/2 female mutation carriers, and for which collection is ongoing. Few studies have been conducted in African Americans, even though they often have more aggressive breast cancer, present at a younger age, and have histopathology characteristic of BRCA1 tumors. Our overall objective is to identify genetic risk factors that modify breast cancer risk.
Our specific aims are:
Aim 1) to genotype Single Nucleotide Polymorphisms (SNPs) in IGF1, IGF1R, IGFBP1, IGFBP3, IRS1, and SHBG in 100 unrelated Caucasian and African Americans and identify haplotype blocks by linkage disequilibrium analysis. A subset of SNPs (haplotype-tagging SNPs and SNPs with known function) will be selected for Aim 3.
Aim 2) : to continue enrolling BRCAI/2 mutation carriers in order to expand our cohort. This includes extending previously enrolled families carrying mutations; continuing to enroll and screen African-American women with breast cancer and expanding families with deleterious mutations; and obtaining mutation carriers from our multi-center cohort.
Aim 3 : to genotype affected (cases) and unaffected (matched controls) BRCAI/2 mutation carriers for SNPs selected in Aim 1.
Aim 4 : to perform analyses to evaluate the role of the genotypes in breast cancer development, age at diagnosis and stage. Our focus is BRCA1/2 mutation carriers, who because of their higher risk of developing cancer at an early age, are the group for whom these results would be applied. This information can be used to assist women and their physicians in individual risk assessment, as well as to target women for specific prevention or treatment strategies based on their genetic risk factors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA074415-07
Application #
6680035
Study Section
Special Emphasis Panel (ZRG1-SNEM-5 (02))
Program Officer
Seminara, Daniela
Project Start
1998-03-01
Project End
2008-08-31
Budget Start
2003-09-12
Budget End
2004-08-31
Support Year
7
Fiscal Year
2003
Total Cost
$545,271
Indirect Cost
Name
University of California Irvine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Ko, Kwang-Pil; Kim, Shana J; Huzarski, Tomasz et al. (2018) The association between smoking and cancer incidence in BRCA1 and BRCA2 mutation carriers. Int J Cancer 142:2263-2272
Ding, Yuan Chun; Adamson, Aaron W; Steele, Linda et al. (2018) Discovery of mutations in homologous recombination genes in African-American women with breast cancer. Fam Cancer 17:187-195
Kotsopoulos, Joanne; Huzarski, Tomasz; Gronwald, Jacek et al. (2016) Hormone replacement therapy after menopause and risk of breast cancer in BRCA1 mutation carriers: a case-control study. Breast Cancer Res Treat 155:365-73
Gronwald, Jacek; Glass, Karen; Rosen, Barry et al. (2016) Treatment of infertility does not increase the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation. Fertil Steril 105:781-785
Cybulski, Cezary; Lubinski, Jan; Huzarski, Tomasz et al. (2015) Prospective evaluation of alcohol consumption and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 151:435-41
Kotsopoulos, Joanne; Lubinski, Jan; Gronwald, Jacek et al. (2015) Factors influencing ovulation and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers. Int J Cancer 137:1136-46
Segev, Yakir; Rosen, Barry; Lubinski, Jan et al. (2015) Risk factors for endometrial cancer among women with a BRCA1 or BRCA2 mutation: a case control study. Fam Cancer 14:383-91
Kotsopoulos, Joanne; Lubinski, Jan; Neuhausen, Susan L et al. (2015) Weight gain after oophorectomy among women with a BRCA1 or BRCA2 mutation. Womens Health (Lond) 11:453-9
Rebbeck, Timothy R (see original citation for additional authors) (2015) Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA 313:1347-61
Osorio, Ana; Milne, Roger L; Kuchenbaecker, Karoline et al. (2014) DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers. PLoS Genet 10:e1004256

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