Ann Truelove

Two susceptibility loci identified for prostate cancer aggressiveness

Most men diagnosed with prostate cancer will experience indolent disease; hence discovering genetic variants that distinguish aggressive from non-aggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49×10-9) and rs78943174 at 3q26.31 (NAALADL2, P=4.18×10-8). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85×10-5) with no association for non-aggressive prostate cancer compared to controls (P=0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation.

Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions

Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genome-encoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10(-4)-5.6 × 10(-3)) and in 30 regions we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10(-6)) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.

Prostate cancer susceptibility in men of African ancestry at 8q24

The 8q24 region harbors multiple risk variants for distinct cancers, including >8 for prostate cancer. In this study, we conducted fine mapping of the 8q24 risk region (127.8-128.8Mb) in search of novel associations with common and rare variation in 4853 prostate cancer case patients and 4678 control subjects of African ancestry. All statistical tests were two-sided. We identified three independent associations at P values of less than 5.00×10(-8), all of which were replicated in studies from Ghana and Uganda (combined sample = 5869 case patients, 5615 control subjects; rs114798100: risk allele frequency [RAF] = 0.04, per-allele odds ratio [OR] = 2.31, 95% confidence interval [CI] = 2.04 to 2.61, P = 2.38×10(-40); rs72725879: RAF = 0.33, OR = 1.37, 95% CI = 1.30 to 1.45, P = 3.04×10(-27); and rs111906932: RAF = 0.03, OR = 1.79, 95% CI = 1.53 to 2.08, P = 1.39×10(-13)). Risk variants rs114798100 and rs111906923 are only found in men of African ancestry, with rs111906923 representing a novel association signal. The three variants are located within or near a number of prostate cancer-associated long noncoding RNAs (lncRNAs), including PRNCR1, PCAT1, and PCAT2. These findings highlight ancestry-specific risk variation and implicate prostate-specific lncRNAs at the 8q24 prostate cancer susceptibility region.

Two Novel Susceptibility Loci for Prostate Cancer in Men of African Ancestry

Abstract Prostate cancer incidence is 1.6-fold higher in African Americans than in other populations. The risk factors that drive this disparity are unknown and potentially consist of social, environmental, and genetic influences. To investigate the genetic basis of prostate cancer in men of African ancestry, we performed a genome-wide association meta-analysis using two-sided statistical tests in 10 202 case subjects and 10 810 control subjects. We identified novel signals on chromosomes 13q34 and 22q12, with the risk-associated alleles found only in men of African ancestry (13q34: rs75823044, risk allele frequency = 2.2%, odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.37 to 1.76, P = 6.10 × 10−12; 22q12.1: rs78554043, risk allele frequency = 1.5%, OR = 1.62, 95% CI = 1.39 to 1.89, P = 7.50 × 10−10). At 13q34, the signal is located 5’ of the gene IRS2 and 3’ of a long noncoding RNA, while at 22q12 the candidate functional allele is a missense variant in the CHEK2 gene. These findings provide further support for the role of ancestry-specific germline variation in contributing to population differences in prostate cancer risk.

TMPRSS2:ERG Gene Fusions in Prostate Cancer of West African Men and a Meta-Analysis of Racial Differences

The prevalence of fusions of the transmembrane protease, serine 2, gene (TMPRSS2) with the erythroblast transformation-specific-related gene (ERG), or TMPRSS2:ERG, in prostate cancer varies by race. However, such somatic aberration and its association with prognostic factors have neither been studied in a West African population nor been systematically reviewed in the context of racial differences. We used immunohistochemistry to assess oncoprotein encoded by the ERG gene as the established surrogate of ERG fusion genes among 262 prostate cancer biopsies from the Ghana Prostate Study (2004-2006). Poisson regression with robust variance estimation provided prevalence ratios and 95% confidence intervals of ERG expression in relation to patient characteristics. We found that 47 of 262 (18%) prostate cancers were ERG-positive, and being negative for ERG staining was associated with higher Gleason score. We further conducted a systematic review and meta-analysis of TMPRSS2:ERG fusions in relation to race, Gleason score, and tumor stage, combining results from Ghana with 40 additional studies. Meta-analysis showed the prevalence of TMPRSS2:ERG fusions in prostate cancer to be highest in men of European descent (49%), followed by men of Asian (27%) and then African (25%) descent. The lower prevalence of TMPRSS2:ERG fusions in men of African descent implies that alternative genomic mechanisms might explain the disproportionately high prostate cancer burden in such populations.

Abstract LB-371: ERG protein expression in diagnostic prostate cancer tissues among West African men

Background: Fusion of androgen regulated TMPRSS2 gene and the ERG oncogene is a common recurrent chromosomal aberration in prostate cancer, which leads to elevated expression of ERG oncoprotein. ERG expression detected by immunohistochemistry (IHC) has been validated as a proxy of TMPRSS2-ERG gene fusion. The prevalence of TMPRSS2-ERG gene fusion has been shown to vary by race being highest in Caucasian prostate cancer patients, followed by African American and then Asian. However, the prevalence of TMPRSS2-ERG gene fusion in African prostate cancer populations remains to be determined. Methods and Materials: There were 428 prostate cancer patients diagnosed during 2004-2012 in the Ghana Prostate Study who had formalin-fixed paraffin-embedded needle biopsy tissues available for analysis. Pathologists centrally scored 262 tissue samples for ERG expression and Gleason patterns, after excluding 166 without sufficient tissues. ERG-positive nuclear immunostaining of normal endothelial cells was used as an internal control and only nuclear immunostaining of prostate cancer cells was deemed ERG-positive. We evaluated ERG expression status in relation to clinicopathological characteristics using logistic regression models. To assess potential selection bias, we performed sensitivity analyses comparing clinicopathological characteristics extracted from medical records by inclusion/exclusion status. Results: We found 47 (18%) tissue samples were ERG-positive. Since recently preserved tissues appeared more likely to be ERG-negative (P = 0.044), all logistic regression models were adjusted for calendar year of diagnosis. Negative ERG staining was significantly associated with higher Gleason score (P = 0.035), in particular with higher primary Gleason grade (P = 0.028). Age at diagnosis, PSA concentration at diagnosis, and tribal group were not significantly associated with ERG expression status. Sensitivity analyses revealed that excluded tissues were more likely to be preserved in earlier years (P = 0.033) and to have lower Gleason scores (P = 0.003). Conclusions: This first study of ERG expression in an African prostate cancer population indicates that the prevalence of TMPRSS2-ERG gene fusion is similar to that of African American patients but lower than those with European ancestry. Whether this lower proportion of TMPRSS2-ERG gene fusion leads to a greater proportion of aggressive prostate cancer in African men or is the result of diagnostic selection of a higher proportion of symptomatic, high Gleason score prostate cancers in such populations remains unknown. Citation Format: Cindy Ke Zhou, Denise Young, Edward D. Yeboah, Richard B. Biritwum, Andrew A. Adjei, Yao Tettey, Evelyn Tay, Shelley Niwa, Ann L. Truelove, Isabell A. Sesterhenn, Shiv Srivastava, Robert N. Hoover, Ann W. Hsing, Michael B. Cook. ERG protein expression in diagnostic prostate cancer tissues among West African men. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-371.

Abstract 2552: A genome-wide association study of prostate cancer in West African men.

Age-adjusted mortality rates for prostate cancer are higher for Africa compared with North America or Western Europe. In addition, African American men are noted to have higher age-adjusted incidence rates of this malignancy than European American men. Coupled with the fact that West Africa is the principal ancestral region of African-American men has led to the hypothesis that there may exist distinct ancestral genetic profiles which mediate prostate cancer risk. In addition, advantages of conducting a genome-wide association study (GWAS) of prostate cancer in African men include a more discrete linkage disequilibrium (LD) structure, a higher number of private single nucleotide polymorphisms (SNPs), the predominance of symptomatic disease, and assessment of unique exposures. The Ghana Prostate Study was conducted collaboratively involving the US National Cancer Institute (NCI) and the University of Ghana during 2006-2012. The NCI Cancer Genomics Research Laboratory genotyped 494 prostate cancer cases and 498 population controls using the Illumina HumanOmni5-Quad BeadChip. Associations were assessed using multivariate logistic regression adjusted for age and genetic ancestry. We sought to validate the 30 most promising SNP associations with prostate cancer through the African American Prostate Cancer GWAS Consortium. A novel locus at 10p14 for prostate cancer risk was the strongest signal detected, and the 8 SNPs at this locus were in LD. This locus is located 360 kb 5’ of GATA3 and the 8 SNPs reside within an intron of LincRNA gene RP11-543F8.2. Analysis of African 1000 Genomes Project data did not indicate LD between 10p14 SNPs and splice or exonic SNPs of this gene, while HaploReg found no significant enrichment of enhancer elements. None of the most promising 30 SNPs replicated in the African American Prostate Cancer GWAS Consortium. This may be due to chance or differences in population genetics, environment, and/or proportion of symptomatic disease. Further genetic studies of prostate cancer in African men are needed to validate the 10p14 susceptibility locus. Citation Format: Michael B. Cook, Zhaoming Wang, Edward D. Yeboah, Andrew A. Adjei, Yao Tettey, Richard B. Biritwum, Evelyn Tay, Ann Truelove, Shelley Niwa, Lisa Chu, Meredith Yeager, Amy Hutchinson, Kai Yu, Christopher A. Haiman, African American Prostate Cancer GWAS Consortium, Robert N. Hoover, Ann Hsing, Stephen J. Chanock. A genome-wide association study of prostate cancer in West African men. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2552. doi:10.1158/1538-7445.AM2013-2552