Overall and abdominal obesity and prostate cancer risk in a West African population: An analysis of the Ghana Prostate Study.

Obesity has been associated with an increased risk of advanced prostate cancer. However, most studies have been conducted among North American and European populations. Prostate cancer mortality appears elevated in West Africa, yet risk factors for prostate cancer in this region are unknown. We thus examined the relationship between obesity and prostate cancer using a case-control study conducted in Accra, Ghana in 2004 to 2012. Cases and controls were drawn from a population-based sample of 1037 men screened for prostate cancer, yielding 73 cases and 964 controls. An additional 493 incident cases were recruited from the Korle-Bu Teaching Hospital. Anthropometric measurements were taken at enrollment. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR) and prostate cancer, adjusting for potential confounders. The mean BMI was 25.1 kg/m2 for cases and 24.3 kg/m2 for controls. After adjustment, men with BMI ≥ 30 kg/m2 had an increased risk of prostate cancer relative to men with BMI < 25 kg/m2 (OR 1.86, 95% CI 1.11-3.13). Elevated WC (OR 1.76, 95% CI 1.24-2.51) and WHR (OR 1.46, 95% CI 0.99-2.16) were also associated with prostate cancer. Associations were not modified by smoking status and were evident for low- and high-grade disease. These findings indicate that overall and abdominal obesity are positively associated with prostate cancer among men in Ghana, implicating obesity as a potentially modifiable risk factor for prostate cancer in this region.

Usual adult occupation and risk of prostate cancer in West African men: the Ghana Prostate Study.

OBJECTIVES: Established prostate cancer (PCa) risk factors include age, family history of PCa and African ancestry. Studies, mostly among highly screened, predominantly European ancestral populations, suggest that employment in certain occupations (eg, farming, military) may also have an increased risk for PCa. Here, we evaluated the association between usual adult occupation and PCa risk in Ghanaian men, a population with historically low rates of PCa screening. METHODS: The Ghana Prostate Study is a case-control study of PCa that was conducted from 2004 to 2012 in 749 cases and 964 controls. In-person interviews were conducted to collect information from participants, including longest held job. Industrial hygienists classified job titles into occupational categories. Unconditional logistic regression was used to calculate ORs and 95% CIs for the association between longest held job and PCa risk (overall, aggressive (Gleason≥7)), controlling for potential confounders. RESULTS: Risk was increased among men in management (overall PCa OR=2.2, 95% CI 1.4 to 3.2; aggressive PCa OR=2.2, 95% CI 1.3 to 3.5) and military occupations (overall PCa OR=3.4, 95% CI 1.7 to 7.0; aggressive PCa OR=3.5, 95% CI 1.5 to 8.3). Risks were also elevated for management and military-specific jobs based on 3-digit level Standard Occupational Classification definitions. Sensitivity analyses accounting for access to medical care did not show significant differences. CONCLUSIONS: Our study provides some evidence for increased risk of PCa among men in management and military occupations, which is consistent with the published literature. Additional research is needed to clarify the drivers of the associations between these occupations and PCa.

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.

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.

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

Age-adjusted mortality rates for prostate cancer are higher for African-American men compared with those of European ancestry. Recent data suggest that West African men also have elevated risk for prostate cancer relative to European men. Genetic susceptibility to prostate cancer could account for part of this difference. We conducted a genome-wide association study (GWAS) of prostate cancer in West African men in the Ghana Prostate Study. Association testing was performed using multivariable logistic regression adjusted for age and genetic ancestry for 474 prostate cancer cases and 458 population-based controls on the Illumina HumanOmni-5 Quad BeadChip. The most promising association was at 10p14 within an intron of a long non-coding RNA (lncRNA RP11-543F8.2) 360 kb centromeric of GATA3 (p = 1.29E-7). In sub-analyses, SNPs at 5q31.3 were associated with high Gleason score (≥7) cancers, the strongest of which was a missense SNP in PCDHA1 (rs34575154, p = 3.66E-8), and SNPs at Xq28 (rs985081, p = 8.66E-9) and 6q21 (rs2185710, p = 5.95E-8) were associated with low Gleason score (<7) cancers. We sought to validate our findings in silico in the African Ancestry Prostate Cancer GWAS Consortium, but only one SNP, at 10p14, replicated at p < 0.05. Of the 90 prostate cancer loci reported from studies of men of European, Asian or African-American ancestry, we were able to test 81 in the Ghana Prostate Study, and 10 of these replicated at p < 0.05. Further genetic studies of prostate cancer in West African men are needed to confirm our promising susceptibility loci.

Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry.

BACKGROUND: Genetic factors play an important role in prostate cancer (PCa) susceptibility. OBJECTIVE: To discover common genetic variants contributing to the risk of PCa in men of African ancestry. DESIGN, SETTING, AND PARTICIPANTS: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness. RESULTS AND LIMITATIONS: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10-4). CONCLUSIONS: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry. PATIENT SUMMARY: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

Genome and gene alterations by insertions and deletions in the evolution of human and chimpanzee chromosome 22.

BACKGROUND: Understanding structure and function of human genome requires knowledge of genomes of our closest living relatives, the primates. Nucleotide insertions and deletions (indels) play a significant role in differentiation that underlies phenotypic differences between humans and chimpanzees. In this study, we evaluated distribution, evolutionary history, and function of indels found by comparing syntenic regions of the human and chimpanzee genomes. RESULTS: Specifically, we identified 6,279 indels of 10 bp or greater in a ~33 Mb alignment between human and chimpanzee chromosome 22. After the exclusion of those in repetitive DNA, 1,429 or 23% of indels still remained. This group was characterized according to the local or genome-wide repetitive nature, size, location relative to genes, and other genomic features. We defined three major classes of these indels, using local structure analysis: (i) those indels found uniquely without additional copies of indel sequence in the surrounding (10 Kb) region, (ii) those with at least one exact copy found nearby, and (iii) those with similar but not identical copies found locally. Among these classes, we encountered a high number of exactly repeated indel sequences, most likely due to recent duplications. Many of these indels (683 of 1,429) were in proximity of known human genes. Coding sequences and splice sites contained significantly fewer of these indels than expected from random expectations, suggesting that selection is a factor in limiting their persistence. A subset of indels from coding regions was experimentally validated and their impacts were predicted based on direct sequencing in several human populations as well as chimpanzees, bonobos, gorillas, and two subspecies of orangutans. CONCLUSION: Our analysis demonstrates that while indels are distributed essentially randomly in intergenic and intronic genomic regions, they are significantly under-represented in coding sequences. There are substantial differences in representation of indel classes among genomic elements, most likely caused by differences in their evolutionary histories. Using local sequence context, we predicted origins and phylogenetic relationships of gene-impacting indels in primate species. These results suggest that genome plasticity is a major force behind speciation events separating the great ape lineages.

Evaluation of IL10, IL19 and IL20 gene polymorphisms and chronic hepatitis B infection outcome.

Hepatitis B virus (HBV) infection remains a serious global health problem despite the availability of a highly effective vaccine. Approximately 5% of HBV-infected adults develop chronic hepatitis B, which may result in liver cirrhosis or hepatocellular carcinoma. Variants of interleukin-10 (IL10) have been previously associated with chronic hepatitis B infection and progression to hepatocellular carcinoma. Single nucleotide polymorphisms (SNP; n = 42) from the IL10, IL19 and IL20 gene regions were examined for an association with HBV infection outcome, either chronic or recovered, in a nested case-control study of African Americans and European Americans. Among African Americans, three nominally statistically significant SNP associations in IL10, two in IL20, and one haplotype association were observed with different HBV infection outcomes (P = 0.005-0.04). A SNP (rs1518108) in IL20 deviated significantly from Hardy-Weinberg equilibrium in African Americans, with a large excess of heterozygotes in chronic HBV-infected cases (P = 0.0006), which suggests a strong genetic effect. Among European Americans, a nominally statistically significant SNP association in IL20 and an IL20 haplotype were associated with HBV recovery (P = 0.01-0.04). These results suggest that IL10 and IL20 gene variants influence HBV infection outcome and encourage the pursuit of further studies of these cytokines in HBV pathogenesis.

Next steps in studying the human microbiome and health in prospective studies, Bethesda, MD, May 16-17, 2017.

The National Cancer Institute (NCI) sponsored a 2-day workshop, "Next Steps in Studying the Human Microbiome and Health in Prospective Studies," in Bethesda, Maryland, May 16-17, 2017. The workshop brought together researchers in the field to discuss the challenges of conducting microbiome studies, including study design, collection and processing of samples, bioinformatics and statistical methods, publishing results, and ensuring reproducibility of published results. The presenters emphasized the great potential of microbiome research in understanding the etiology of cancer. This report summarizes the workshop and presents practical suggestions for conducting microbiome studies, from workshop presenters, moderators, and participants.

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

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.

Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

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.

A high-density admixture map for disease gene discovery in african americans.

Admixture mapping (also known as "mapping by admixture linkage disequilibrium," or MALD) provides a way of localizing genes that cause disease, in admixed ethnic groups such as African Americans, with approximately 100 times fewer markers than are required for whole-genome haplotype scans. However, it has not been possible to perform powerful scans with admixture mapping because the method requires a dense map of validated markers known to have large frequency differences between Europeans and Africans. To create such a map, we screened through databases containing approximately 450000 single-nucleotide polymorphisms (SNPs) for which frequencies had been estimated in African and European population samples. We experimentally confirmed the frequencies of the most promising SNPs in a multiethnic panel of unrelated samples and identified 3011 as a MALD map (1.2 cM average spacing). We estimate that this map is approximately 70% informative in differentiating African versus European origins of chromosomal segments. This map provides a practical and powerful tool, which is freely available without restriction, for screening for disease genes in African American patient cohorts. The map is especially appropriate for those diseases that differ in incidence between the parental African and European populations.