Abstract A70: Chemokine-associated genetic variants as predictors of prostate cancer outcomes among men of African descent

Abstract

Abstract Background: African-American men in the U.S. are 1.6 and 2-fold more likely to receive a prostate cancer (PCA) diagnosis and die from the disease relative to their Caucasian counterparts, respectively. This health disparity extends beyond the U.S. For instance, men from Kingston, Jamaica have higher cancer mortality and morbidity rates compared to African-Americans. Reasons for these disparities may be attributed to differences in cancer screening practices, lifestyle factors, clinical management of the disease, detection of aggressive/advance tumors that are not responsive to available treatments, and genetic susceptibilities. Recent research efforts have focused on the identification of genetic determinants of PCA. Emphasis has been placed on genes that encode chemokines and their receptors, since they play an essential role in tumorigenesis. For instance, over expression of CCR6 is associated with lung, pancreatic, and PCA, presumably by triggering leukocyte production and promoting cell survival and metastasis. Moreover sequence variants detected in CCL5 (rs2280078, rs2107538 at positions −28 and −403, respectively) and CCR6 (rs9459883, rs3798315) were significantly associated with oral cancer, lymphoma or brain cancer in three independent studies. Research Goal and Objective: With the ultimate goal of improving PCA detection/prognosis predictions and clinical management practices, this study seeks to systematically evaluate the individual and combined effects of 41 single nucleotide polymorphisms (SNPs) in chemokine associated genes in relation to PCA risk and disease progression among 1,237 African-American, African and Caribbean men. Hypothesis: We hypothesized that individuals inheriting one or multiple chemokine associated loci (linked to increased inflammation, immune response surveillance, metastasis and cell survival) will have an increased risk of developing PCA relative to those of referent genotypes. Materials and Methods: Forty-one sequence variants detected in chemokine associated genes will be evaluated in germ-line DNA samples collected from 420 PCA cases and 735 controls using Illumina's Veracode genotyping system. Study participants were recruited from cancer screening programs, hospitals, or cancer centers located in the Washington D.C., South Carolina, and Kingston, Jamaica. Main effects and complex SNP interactions will be evaluated using logistic regression analysis and multi-factor dimensionality reduction (MDR), respectively. All risk models will be adjusted for potential confounders (i.e., age and West African Ancestry) and multiple hypothesis testing. Results: In a pilot study, four SNPs detected in CCR6, CCL5, and CCR4 were significantly associated with PCA among 230 men of African Descent from the United States (124 PCA cases, 106 controls). Inheritance of at least one minor CCR6 rs2023305 A allele was associated with a 1.92 fold increase in the risk of developing PCA. However, a 48–63% decrease in PCA was observed among carriers of the CCL5 (rs2107538 AG+AA, rs3817655 AT+AA) and CCR4 rs6550178 AG. With the exception of the CCR4 marker, these markers remained statistically after adjusting for age and West African ancestry. Discussion: In summary, polymorphisms in chemokine associated genes modify PCA susceptibility among men of African descent in the current study. Our findings will undergo further evaluation and validation in a larger and ethnically diverse study population, including 420 PCA cases and 735 controls from the U.S. and Jamaica. Such efforts will help to identify genetic markers capable of explaining disproportionately high prostate cancer incidence, mortality, and morbidity rates among men of African descent. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A70.