The Carolina Breast Cancer Study (CBCS) is a comprehensive, interdisciplinary investigation into the causes of breast cancer in African American and white women. CBCS focuses on understanding how genetic and environmental factors interact to cause breast cancer. From 1993-2001, CBCS enrolled 2311 cases of in- situ and invasive breast cancer and 2022 frequency-matched controls from a defined geographic region of eastern and central North Carolina. 40% of CBCS participants are African-American. Over 70 peer-review publications have resulted. During the last SPORE funding cycle (2001-2006), we used previously collected DMA samples to conduct genotyping for polymorphisms in DMA repair genes. Genotypes at multiple genetic loci were combined to create """"""""pathway"""""""" genotypes. We observed interactions between combinations of single nucleotide polymorphisms (SNPs) in the double strand break DNA repair pathway and radiation exposure, and combined genotypes in the nucleotide excision DNA repair pathway and smoking. The data rich CBCS attracted biostatistics collaborators who developed statistical methods to estimate haplotypes at the individual level and to use haplotypes to evaluate gene-gene and gene-environment interactions. We propose to expand our previous investigations by conducting a comprehensive study of haplotypes in genes involved in DNA repair, damage recognition, cell cycle control and cellular proliferation, hormone biosynthesis and metabolism, and oxidative metabolism. The advent of multiplex genotyping and identification of haplotype-tagging SNPs now makes it possible to capture the principal sources of genetic variation in the candidate genes in African Americans and whites. With newly-developed statistical methods, haplotypes will be used to evaluate gene-gene as well as gene-environment interactions. Monte Carlo simulation and applied Bayesian analysis will be used to address multiple hypothesis testing. We will also genotype 100 SNPs that serve as ancestry informative markers in order to adjust for population stratification. We used tumor blocks from CBCS cases to determine the prevalence of specific subtypes of breast cancer. The subtypes were codified using gene expression profiling. In the CBCS, the estrogen-receptor positive forms of breast cancer, Luminal A and B, were found at highest frequency in white women and older African American women, while the estrogen-receptor negative forms, including Basal-like breast cancer, were at highest frequency in younger African American women. CBCS patients with Basal-like breast cancer had lower disease-specific survival than patients with Luminal A or B. Our preliminary data suggest that combinations of genetic and environmental exposures lead to increased risk of specific subtypes of breast cancer. We will expand our investigation of genetic susceptibility to candidate genes for breast cancer subtypes, including newly-discovered polymorphisms in genes that show differential expression in breast cancer subtypes. Positive findings (including main effects and associations with breast cancer subtypes) will be repeated using DNA samples collected from a large population-based study in Norway.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA058223-18
Application #
8135444
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
18
Fiscal Year
2010
Total Cost
$272,840
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Tanioka, Maki; Fan, Cheng; Parker, Joel S et al. (2018) Integrated Analysis of RNA and DNA from the Phase III Trial CALGB 40601 Identifies Predictors of Response to Trastuzumab-Based Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer. Clin Cancer Res 24:5292-5304
Mundt, Filip; Rajput, Sandeep; Li, Shunqiang et al. (2018) Mass Spectrometry-Based Proteomics Reveals Potential Roles of NEK9 and MAP2K4 in Resistance to PI3K Inhibition in Triple-Negative Breast Cancers. Cancer Res 78:2732-2746
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Echavarria, Isabel; López-Tarruella, Sara; Picornell, Antoni et al. (2018) Pathological Response in a Triple-Negative Breast Cancer Cohort Treated with Neoadjuvant Carboplatin and Docetaxel According to Lehmann's Refined Classification. Clin Cancer Res 24:1845-1852
Cai, Ling; Tsai, Yi-Hsuan; Wang, Ping et al. (2018) ZFX Mediates Non-canonical Oncogenic Functions of the Androgen Receptor Splice Variant 7 in Castrate-Resistant Prostate Cancer. Mol Cell 72:341-354.e6
Bensen, Jeannette T; Graff, Mariaelisa; Young, Kristin L et al. (2018) A survey of microRNA single nucleotide polymorphisms identifies novel breast cancer susceptibility loci in a case-control, population-based study of African-American women. Breast Cancer Res 20:45
Puvanesarajah, Samantha; Nyante, Sarah J; Kuzmiak, Cherie M et al. (2018) PAM50 and Risk of Recurrence Scores for Interval Breast Cancers. Cancer Prev Res (Phila) 11:327-336
Knott, Simon R V; Wagenblast, Elvin; Khan, Showkhin et al. (2018) Asparagine bioavailability governs metastasis in a model of breast cancer. Nature 554:378-381

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