Women who carry mutations in the BRCA1 or BRCA2 tumor suppressor genes are at extreme risk for breast cancer. BRCA1 or BRCA2 mutation carriers are heterozygous, but their breast tumors typically show loss of heterozygosity (LOH), i.e., loss of the wild-type BRCA allele. LOH at the BRCA loci has been thought of as a rare event, occurring in single cells that are the proximate precursors of a tumor. Recent evidence suggests it may occur instead as earlier or more frequent events giving rise to a large population of cells poised for neoplastic transformation - a """"""""field effect"""""""". This study will determine whether LOH at the BRCA loci is typically present in histologically normal or pre-neoplastic breast epithelia of mutation carriers. It is a first step in exploring the potential of LOH at the BRCA loci as a marker for diagnosis or prognosis in mutation carriers, and for new approaches to chemotherapy and chemoprevention that target the DNA repair defects of cells lacking BRCA1 or BRCA2 function.
Specific aims will be: 1. To determine whether LOH at the BRCA loci is typically present in pre-neoplastic and histologically normal tissue outside the margins of breast tumors in mutation carriers. Samples of breast tissue will be micro-dissected and assayed by Pyrosequencing, a high-throughput, micro-sequencing technology for mutation detection and allele quantification. For each patient, an individualized Pyrosequencing assay at the mutation site will be designed for direct quantification of the mutant and wild-type alleles. 2. To determine whether LOH at the BRCA loci can be similarly detected in breast tissue removed in prophylactic mastectomy from BRCA mutation carriers, in advance of any diagnosis of breast cancer. 3. To test the feasibility of detecting LOH at the BRCA loci in breast biopsies of BRCA mutation carriers.

Public Health Relevance

This project will study genetic (DNA) changes in women from certain families that are prone to breast cancer. Understanding how these changes take place in breast tissue may open new approaches to early diagnosis, treatment and prevention for this special, high-risk group of patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA122795-02
Application #
7772323
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Lively, Tracy (LUGO)
Project Start
2009-03-01
Project End
2012-02-28
Budget Start
2010-05-19
Budget End
2012-02-28
Support Year
2
Fiscal Year
2010
Total Cost
$204,375
Indirect Cost
Name
Rutgers University
Department
Genetics
Type
Schools of Arts and Sciences
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Yeung, Percy Luk; Denissova, Natalia G; Nasello, Cara et al. (2012) Promyelocytic leukemia nuclear bodies support a late step in DNA double-strand break repair by homologous recombination. J Cell Biochem 113:1787-99
Kristensen, Colleen N; Bystol, Karin M; Li, Boran et al. (2010) Depletion of DSS1 protein disables homologous recombinational repair in human cells. Mutat Res 694:60-4