The DNA repair pathways and the signaling networks that link DNA repair to cell cycle regulation, known as the DNA damage response (DDR), constitute a central mechanism in the development of cancer. The genes underlying DNA repair and DDR have been shown to be key players in genetic predisposition to breast cancer and subsequent tumor progression. The overall objective of the research described in this proposal is to identify the germline and somatic genetic changes in DNA damage response genes that underlie the risk of breast cancer, specifically in the population of Puerto Rico. The overall hypothesis is that the germ-line and tumor genetic factors underlying breast cancer susceptibility in Puerto Rico may differ qualitatively or quantitatively from those in Caucasian women.
In specific aim #1, we will determine the prevalence of germline changes in the genes involved in breast cancer risk. We will perform a comprehensive screening of a panel 21 candidate genes that have been implicated in breast cancer predisposition in the general population. Several of those genes are involved in the cellular response to DNA damage. We will accomplish this aim using capture technology coupled with massively parallel sequencing. We expect to determine whether the genes that were previously implicated in breast cancer predisposition are also determinants of breast cancer risk in the Puerto Rican population.
In specific aim #2, we propose to determine the prevalence of somatic changes in genes involved in DNA repair and DDR. This will be accomplished by the library preparation from tumor samples and full exome capture hybridization followed by massively parallel sequencing. The identification of somatic changes in DNA repair and DDR genes is expected to reveal key genes that are mutated in tumorigenesis in the Puerto Rican population. This project proposes to examine both germline and somatic changes, thereby providing an integrated picture of the role of genetic variants in DNA repair and DDR genes in breast cancer risk and development. It targets a Hispanic population, which is often underrepresented in genetic studies. Our findings may uncover genetic changes specific to this population that will allow for the development of custom-designed predisposition tests. Importantly, these data will serve the basis for a vision of personalized medicine that takes into account natural differences in populations to maximize the identification of individuals at risk and the efficacy of therapeutic regimens. This project supports the overall U54 application by fostering the close collaboration between PSM and MCC investigators while gathering knowledge that will directly improve cancer prevention and treatment in Puerto Rico.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA163071-03
Application #
8728153
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2014-09-01
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ponce School of Medicine
Department
Type
DUNS #
City
Ponce
State
PR
Country
United States
Zip Code
00732
Matta, Jaime; Morales, Luisa; Ortiz, Carmen et al. (2016) Estrogen Receptor Expression Is Associated with DNA Repair Capacity in Breast Cancer. PLoS One 11:e0152422
de Jesus, Edelmarie Rivera; Isidro, Raymond A; Cruz, Myrella L et al. (2016) Adoptive Transfer of Dendritic Cells Expressing Fas Ligand Modulates Intestinal Inflammation in a Model of Inflammatory Bowel Disease. J Clin Cell Immunol 7:
Rivera, Y M; Vélez, H; Canales, J et al. (2016) When a Common Language Is Not Enough: Transcreating Cancer 101 for Communities in Puerto Rico. J Cancer Educ 31:776-783
Lynce, Filipa; Graves, Kristi D; Jandorf, Lina et al. (2016) Genomic Disparities in Breast Cancer Among Latinas. Cancer Control 23:359-372
Abreu-Delgado, Yamilka; Isidro, Raymond A; Torres, Esther A et al. (2016) Serum vitamin D and colonic vitamin D receptor in inflammatory bowel disease. World J Gastroenterol 22:3581-91
Encarnación, Jarline; Ortiz, Carmen; Vergne, Ralphdy et al. (2016) High DRC Levels Are Associated with Let-7b Overexpression in Women with Breast Cancer. Int J Mol Sci 17:
Castro, Eida M; Jiménez, Julio C; Quinn, Gwendolyn et al. (2015) Identifying clinical and support service resources and network practices for cancer patients and survivors in southern Puerto Rico. Support Care Cancer 23:967-75
Isidro, Raymond A; Isidro, Angel A; Cruz, Myrella L et al. (2015) Double immunofluorescent staining of rat macrophages in formalin-fixed paraffin-embedded tissue using two monoclonal mouse antibodies. Histochem Cell Biol 144:613-21
Sosa-García, Bernadette; Vázquez-Rivera, Viviana; González-Flores, Jonathan N et al. (2015) The Retinoblastoma Tumor Suppressor Transcriptionally Represses Pak1 in Osteoblasts. PLoS One 10:e0142406
Dutil, Julie; Golubeva, Volha A; Pacheco-Torres, Alba L et al. (2015) The spectrum of BRCA1 and BRCA2 alleles in Latin America and the Caribbean: a clinical perspective. Breast Cancer Res Treat 154:441-53

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