LaCreis R. Kidd

Validation of Genome-Wide Prostate Cancer Associations in Men of African Descent

Background: Genome-wide association studies (GWAS) have identified numerous prostate cancer susceptibility alleles, but these loci have been identified primarily in men of European descent. There is limited information about the role of these loci in men of African descent. Methods: We identified 7,788 prostate cancer cases and controls with genotype data for 47 GWAS-identified loci. Results: We identified significant associations for SNP rs10486567 at JAZF1, rs10993994 at MSMB, rs12418451 and rs7931342 at 11q13, and rs5945572 and rs5945619 at NUDT10/11. These associations were in the same direction and of similar magnitude as those reported in men of European descent. Significance was attained at all reported prostate cancer susceptibility regions at chromosome 8q24, including associations reaching genome-wide significance in region 2. Conclusion: We have validated in men of African descent the associations at some, but not all, prostate cancer susceptibility loci originally identified in European descent populations. This may be due to the heterogeneity in genetic etiology or in the pattern of genetic variation across populations. Impact: The genetic etiology of prostate cancer in men of African descent differs from that of men of European descent. Cancer Epidemiol Biomarkers Prev; 20(1); 23–32. ©2011 AACR.

Global Patterns of Prostate Cancer Incidence, Aggressiveness, and Mortality in Men of African Descent

Prostate cancer (CaP) is the leading cancer among men of African descent in the USA, Caribbean, and Sub-Saharan Africa (SSA). The estimated number of CaP deaths in SSA during 2008 was more than five times that among African Americans and is expected to double in Africa by 2030. We summarize publicly available CaP data and collected data from the men of African descent and Carcinoma of the Prostate (MADCaP) Consortium and the African Caribbean Cancer Consortium (AC3) to evaluate CaP incidence and mortality in men of African descent worldwide. CaP incidence and mortality are highest in men of African descent in the USA and the Caribbean. Tumor stage and grade were highest in SSA. We report a higher proportion of T1 stage prostate tumors in countries with greater percent gross domestic product spent on health care and physicians per 100,000 persons. We also observed that regions with a higher proportion of advanced tumors reported lower mortality rates. This finding suggests that CaP is underdiagnosed and/or underreported in SSA men. Nonetheless, CaP incidence and mortality represent a significant public health problem in men of African descent around the world.

miRNAs associated with prostate cancer risk and progression

Prostate cancer is the most common malignancy among men in the US. Though considerable improvement in the diagnosis of prostate cancer has been achieved in the past decade, predicting disease outcome remains a major clinical challenge. Recent expression profiling studies in prostate cancer suggest microRNAs (miRNAs) may serve as potential biomarkers for prostate cancer risk and disease progression. miRNAs comprise a large family of about 22-nucleotide-long non-protein coding RNAs, regulate gene expression post-transcriptionally and participate in the regulation of numerous cellular processes. In this review, we discuss the current status of miRNA in studies evaluating the disease progression of prostate cancer. The discussion highlights key findings from previous studies, which reported the role of miRNAs in risk and progression of prostate cancer, providing an understanding of the influence of miRNA on prostate cancer. Our review indicates that somewhat consistent results exist between these studies and reports on several prostate cancer related miRNAs. Present promising candidates are miR-1, −21, 106b, 141, −145, −205, −221, and −375, which are the most frequently studied and seem to be the most promising for diagnosis and prognosis for prostate cancer. Nevertheless, the findings from previous studies suggest miRNAs may play an important role in the risk and progression of prostate cancer as promising biomarkers.

8q24 sequence variants in relation to prostate cancer risk among men of African descent: A case-control study

BackgroundHuman chromosome 8q24 has been implicated in prostate tumorigenesis.MethodsConsequently, we evaluated seven 8q24 sequence variants relative to prostate cancer (PCA) in a case-control study involving men of African descent. Genetic alterations were detected in germ-line DNA from 195 incident PCA cases and 531 controls using TaqMan polymerase chain reaction (PCR).ResultsInheritance of the 8q24 rs16901979 T allele corresponded to a 2.5-fold increase in the risk of developing PCA for our test group. These findings were validated using multifactor dimensionality reduction (MDR) and permutation testing (p = 0.038). The remaining 8q24 targets were not significantly related to PCA outcomes.ConclusionsAlthough compelling evidence suggests that the 8q24 rs16901979 locus may serve as an effective PCA predictor, our findings require additional evaluation in larger studies.

Toll-like receptor-associated sequence variants and prostate cancer risk among men of African descent

Recent advances demonstrate a relationship between chronic/recurrent inflammation and prostate cancer (PCA). Among inflammatory regulators, toll-like receptors (TLRs) have a critical role in innate immune responses. However, it remains unclear whether variant TLR genes influence PCA risk among men of African descent. Therefore, we evaluated the impact of 32 TLR-associated single-nucleotide polymorphisms (SNPs) on PCA risk among African Americans and Jamaicans. SNP profiles of 814 subjects were evaluated using Illumina’s Veracode genotyping platform. Single and combined effects of SNPs in relation to PCA risk were assessed using age-adjusted logistic regression and entropy-based multifactor dimensionality reduction (MDR) models. Seven sequence variants detected in TLR6, TOLLIP (Toll-interacting protein), IRAK4 (interleukin-1 receptor-associated kinase 4) and IRF3 (interferon regulatory factor 3) were marginally related to PCA. However, none of these effects remained significant after adjusting for multiple hypothesis testing. Nevertheless, MDR modeling revealed a complex interaction between IRAK4 rs4251545 and TLR2 rs1898830 as a significant predictor of PCA risk among US men (permutation testing P-value=0.001). However, these findings require further assessment and validation.

Chemokine Ligand 5 (CCL5) and chemokine receptor (CCR5) genetic variants and prostate cancer risk among men of African Descent:a case-control study

BackgroundChemokine and chemokine receptors play an essential role in tumorigenesis. Although chemokine-associated single nucleotide polymorphisms (SNPs) are associated with various cancers, their impact on prostate cancer (PCA) among men of African descent is unknown. Consequently, this study evaluated 43 chemokine-associated SNPs in relation to PCA risk. We hypothesized inheritance of variant chemokine-associated alleles may lead to alterations in PCA susceptibility, presumably due to variations in antitumor immune responses.MethodsSequence variants were evaluated in germ-line DNA samples from 814 African-American and Jamaican men (279 PCA cases and 535 controls) using Illumina’s Goldengate genotyping system.ResultsInheritance of CCL5 rs2107538 (AA, GA+AA) and rs3817655 (AA, AG, AG+AA) genotypes were linked with a 34-48% reduction in PCA risk. Additionally, the recessive and dominant models for CCR5 rs1799988 and CCR7 rs3136685 were associated with a 1.52-1.73 fold increase in PCA risk. Upon stratification, only CCL5 rs3817655 and CCR7 rs3136685 remained significant for the Jamaican and U.S. subgroups, respectively.ConclusionsIn summary, CCL5 (rs2107538, rs3817655) and CCR5 (rs1799988) sequence variants significantly modified PCA susceptibility among men of African descent, even after adjusting for age and multiple comparisons. Our findings are only suggestive and require further evaluation and validation in relation to prostate cancer risk and ultimately disease progression, biochemical/disease recurrence and mortality in larger high-risk subgroups. 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.

IRAK4 and TLR3 Sequence Variants may Alter Breast Cancer Risk among African-American Women

Mounting evidence suggests that imbalances in immune regulation contribute to cell transformation. Women of African descent are an understudied group at high risk for developing aggressive breast cancer (BrCa). Therefore, we examined the role of 16 innate immune single nucleotide polymorphisms (SNPs) in relation to BrCa susceptibility among 174 African-American women in Atlanta, GA, USA. SNPs were examined in germ-line DNA collected from 102 BrCa patients and 72 women with benign nodules using SNPstream methodology. Inheritance of the TLR3 rs10025405 GG genotype was associated with an 82% decrease in BrCa risk. In contrast, individuals who possessed at least one IRAK4 rs4251545 T allele had a 1.68- to 4.99-fold increase in the risk of developing BrCa relative to those with the referent genotype (OR = 4.99; 95% CI = 1.00, 25.00; p = 0.0605). However, the IRAK4 rs4251545 locus was only significant under the additive genetic model (p trend = 0.0406). In silico predictions suggest IRAK4 rs4251545 SNP falls within a transcription enhancer/silencer region of the gene and codes for an Ala428Thr amino acid change. This missense mutation introduces a potential phosphorylation site in the extreme carboxy terminus (XCT) of the IRAK4 kinase domain. Preliminary molecular modeling predicts that this SNP stabilizes two alpha helices within the XCT on the surface of the IRAK4 kinase domain and increases the size of the groove between them. Our in silico results, combined with previous reports noting the presence of IRAK4 and XCT fragments in mouse and human serum, suggest the possibility that the XCT subdomain of IRAK4 possesses biological function. These findings require further evaluation and validation in larger populations, additional molecular modeling as well as functional studies to explore the role of IRAK4 and its XCT in cell transformation and innate immunity.

The impact of genetic variants in inflammatory-related genes on prostate cancer risk among men of African Descent: a case control study

PurposeAlthough case–control studies have evaluated the role of variant inflammatory-related loci in prostate cancer, their impact is virtually unknown among men of African descent. To address this, we evaluated the impact of inflammatory cytokine single nucleotide polymorphisms (SNPs) on prostate cancer risk for men of African descent.MethodsForty-four SNPs in inflammatory cytokine-associated genes were evaluated among 814 African-American and Jamaican men (279 prostate cancer cases and 535 controls) using Illumina’s Golden gate genotyping system. Individual SNP effects were evaluated using logistic regression analysis.ResultsFour SNPs were modestly associated with prostate cancer after adjusting for age. In the total population, inheritance of the IL1R2 rs11886877 AA, IL8RB rs11574752 AA, TNF rs1800629 GA + AA, and TNF rs673 GA genotypes modestly increased prostate cancer risk by 1.45 to 11.7-fold relative to the referent genotype. Among U.S. men, age-adjusted dominant, recessive and additive genetic models for the IL1R2 rs11886877 locus were linked to an increase in prostate cancer susceptibility. However, these main effects did not persist after adjusting for multiple hypothesis testing.ConclusionOur preliminary data does not strongly support the hypothesis that inflammatory-related sequence variants influence prostate cancer risk among men of African descent. However, further evaluation is needed to assess whether other variant inflammatory-related genes may contribute to prostate cancer risk and disease progression in larger and ethnically diverse multi-center studies.

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

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 Illumina9s 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.

Inflammation polymorphisms and prostate cancer risk in Jamaican men: Role of obesity/body size

African ancestry and obesity are associated with higher risk of prostate cancer (PC). In a pilot study, we explored interactions between obesity (as measured by waist to hip ratio (WHR)) and inflammatory SNPs in relation to PC risk among Jamaican men. This study evaluated 87 chemokine and cytokine associated SNPs in obese and normal weight cases (N=109) and controls (N=102) using a stepwise penalized logistic regression approach in multivariable analyses. Upon stratification by WHR (normal weight (WHR<0.90) or obese (WHR≥0.90)), inheritance of CCR6 rs2023305 AG+GG (OR=1.75, p=0.007), CCR9 rs7613548 AG+GG (OR=1.71, p=0.012) and IL10ra rs2229113 AG+GG (OR=1.45, p=0.01) genotypes was associated with increase in overall or low grade (Gleason score<7) PC risk among normal weight men. These odds were elevated among obese men who possessed the CCR5 rs1799987 AG+GG (OR=1.95, p=0.003) and RNASEL rs12135247 CT+TT genotypes (OR=1.59, p=0.05). CCR7 rs3136685 AG+GG (p=0.032) was associated with a 1.52-1.70 fold increase in the risk of high grade cancer (Gleason score≥7) among obese men. CCR7 variant emerged as an important factor associated with high grade PC risk among obese men in our analyses. Overall, genetic loci found significant in normal weight men were not significant in obese men and vice-versa, partially explaining the role of obesity on PC risk among black men. Also, older age was an important risk factor both in normal weight and obese men but only with regard to low grade PC. Associations of inflammatory SNPs with obesity are suggestive and require further validation in larger cohorts to help develop an understanding of PC risk among obese and non-obese men of African descent.