The majority of breast cancer cases involve the contribution of multiple genes and environmental factors. Several cancers, including breast cancer, have been associated with low DNA repair capacity (DRC). Most of the genes predisposing to breast cancer remain unknown, and the causes of the low DRC in breast cancer patients are poorly understood. The objective of this application is to address the role of inherited genetic polymorphisms in a subset of DNA repair genes in controlling DRC levels and risk of breast cancer. Our central hypothesis is that inter-individual genetic variations in the genes involved in the maintenance of DNA integrity participate in determining DRC and breast cancer risk. In this pilot study, we will focus on the Nucleotide Excision Repair (NER) pathway genes.
In specific aim #1, we will identify single nucleotide polymorphisms (SNPs) in the NER pathway genes that are associated with DRC levels and breast cancer risk. To achieve this goal, we will compare allelic and genotype frequencies in a group of breast cancer patients and controls for which the DNA repair capacity is known. We will investigate single SNP loci, gene-gene interactions and the effect of environmental factors on the SNP associated risk.
Under specific aim#2, we will establish the role of Copy Number Variations (CNVs) in NER candidate genes in genetic susceptibility to breast cancer. We will identify copy number variations in regions encompassing NER genes and correlate CNV data with the DRC and breast cancer phenotypes. This MBRS-SC2 application proposes an integrated and innovative strategy to unveil the role of SNP and CNV genetic factors on the DRC phenotype and the risk of breast cancer. Furthermore, it targets a Hispanic population, which is often underrepresented in most genetic studies. Our findings are expected to improve prevention and detection of breast cancer in at risk women. In addition, the proposed project is expected to have a positive impact on the PI's career by providing the basis for the preparation of high quality manuscripts and by providing preliminary data for the preparation of competitive grant applications. Through this three year program, Dr. Dutil intends to achieve research independence by establishing herself as an expert in managing the genetic risk for breast cancer in Puerto Rico. Dr. Dutil is well trained in molecular genetics and is surrounded by a strong multidisciplinary team: Dr. Matta (PSM) is an expert in DNA repair and will provide the study population of over 570 participants;Dr. Lizardi (Yale University) is an expert in genomics technologies and whole genome rearrangements mapping;Dr Rebecca Sutphen (Moffitt Cancer Center) will provide guidance in TagSNP selection;Dr. Manuel Bayona (PSM) is a biostatistician and epidemiologist who will oversee statistical analyses.
It is estimated that approximately 3 million women in the U.S. are living with breast cancer. Lifestyle and inherited genetic factors are believed to increase the risk that certain women develop breast cancer, but we know very little about these genes. Even less information is available for certain minority population, such as the Hispanics of Puerto Rico. Research has shown that those who are educated about their increased risk of breast cancer are more likely to engage in risk-reducing behaviors and early detection strategies such as monthly self-breast exam, physician visits, mammography and breast MRI screening. Therefore, by identifying the genes that make some women more at risk of developing breast cancer, we expect to improve early detection and prevention strategies, and provide a clinical management of breast cancer risk that is adapted to each population.
| Perez-Mayoral, Julyann; Pacheco-Torres, Alba L; Morales, Luisa et al. (2013) Genetic polymorphisms in RAD23B and XPC modulate DNA repair capacity and breast cancer risk in Puerto Rican women. Mol Carcinog 52 Suppl 1:E127-38 |
