Haiman, C.A. et al. Multiple regions within 8q24 independently affect risk for prostate cancer. Nat. Genet. 39, 638-644

Harvard University, Cambridge, Massachusetts, United States
Nature Genetics (Impact Factor: 29.35). 05/2007; 39(5):638-44. DOI: 10.1038/ng2015
Source: PubMed


After the recent discovery that common genetic variation in 8q24 influences inherited risk of prostate cancer, we genotyped 2,973 SNPs in up to 7,518 men with and without prostate cancer from five populations. We identified seven risk variants, five of them previously undescribed, spanning 430 kb and each independently predicting risk for prostate cancer (P = 7.9 x 10(-19) for the strongest association, and P < 1.5 x 10(-4) for five of the variants, after controlling for each of the others). The variants define common genotypes that span a more than fivefold range of susceptibility to cancer in some populations. None of the prostate cancer risk variants aligns to a known gene or alters the coding sequence of an encoded protein.

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    • "Two loci, rs4242382 at 8q24 and rs 10486567 at 7p15.2, with genotypes AA, GA, and GG, were selected for the analysis for the reasons outlined above. The risk allele A of rs4242382 at 8q24 has been previously reported to be associated with an aggressive PrCa [2], [8], [19]–[24]. The risk allele G of rs 10486567 at 7p15.2 on the intron 2 of the JAZF zinc finger1 gene (JAZF1) is commonly observed in the Europeans [9]. "
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    ABSTRACT: Understanding the impact of multiple genetic variants and their interactions on the disease penetrance of familial multiple prostate cancer is very relevant to the overall understanding of carcinogenesis. We assessed the joint effect of two loci on rs4242382 at 8q24 and rs10486567 at 7p15.2 to this end. We analyzed the data from a Finnish family-based genetic study, which was composed of 947 men including 228 cases in 75 families, to evaluate the respective effects of the two loci on the disease penetrance; in particular, the occurrence and number of prostate cancer cases within a family were utilized to evaluate the interactions between the two loci under the additive and multiplicative Poisson regression models. The risk alleles A at rs4242382 (OR = 1.14, 95% CI 1.08-1.19, P<0.0001) and a risk allele A at rs10486567 (OR = 1.06, 96%CI 1.01-1.11, P = 0.0208) were found to be associated with an increased risk of familial PrCa, especially with four or more cases within a family. A multiplicative model fitted the joint effect better than an additive model (likelihood ratio test X(2) = 13.89, P<0.0001). The influence of the risk allele A at rs10486567 was higher in the presence of the risk allele A at rs4242382 (OR = 1.09 (1.01-1.18) vs. 1.01 (0.95-1.07)). Similar findings were observed in non-aggressive PrCa, but not in aggressive PrCa. We demonstrated that two loci (rs4242382 and rs10486567) are highly associated with familial multiple PrCa, and the gene-gene interaction or statistical epistasis was consistent with the Fisher's multiplicative model. These loci's association and epistasis were observed for non-aggressive but not for aggressive tumors. The proposed statistical model can be further developed to accommodate multi-loci interactions to provide further insights into epistasis.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "All SNPs reported to reach genome-wide significance, defined here as a P-value < 1x10-6, and published prior to April 2010 were included in our preliminary stage 1 analysis (44 SNPs; Figure 1 and Additional file 1: Table S1). Two additional SNPs included, Bd11934905 (8q24 region 2), which did not achieve genome-wide significance (P-value = 1.5x10-4) in the discovery target study, but was unique in the African American population [24] and rs7210100 (17q21), which achieved genome-wide significance in the first published African American prostate cancer GWAS (P-value = 3.4x10-13), but was published after the stage 1 publication deadline [18]. "
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    ABSTRACT: Although African ancestry represents a significant risk factor for prostate cancer, few studies have investigated the significance of prostate cancer and relevance of previously defined genetic and epidemiological prostate cancer risk factors within Africa. We recently established the Southern African Prostate Cancer Study (SAPCS), a resource for epidemiological and genetic analysis of prostate cancer risk and outcomes in Black men from South Africa. Biased towards highly aggressive prostate cancer disease, this is the first reported data analysis. The SAPCS is an ongoing population-based study of Black men with or without prostate cancer. Pilot analysis was performed for the first 837 participants, 522 cases and 315 controls. We investigate 46 pre-defined prostate cancer risk alleles and up to 24 epidemiological measures including demographic, lifestyle and environmental factors, for power to predict disease status and to drive on-going SAPCS recruitment, sampling procedures and research direction. Preliminary results suggest that no previously defined risk alleles significantly predict prostate cancer occurrence within the SAPCS. Furthermore, genetic risk profiles did not enhance the predictive power of prostate specific antigen (PSA) testing. Our study supports several lifestyle/environmental factors contributing to prostate cancer risk including a family history of cancer, diabetes, current sexual activity and erectile dysfunction, balding pattern, frequent aspirin usage and high PSA levels. Despite a clear increased prostate cancer risk associated with an African ancestry, experimental data is lacking within Africa. This pilot study is therefore a significant contribution to the field. While genetic risk factors (largely European-defined) show no evidence for disease prediction in the SAPCS, several epidemiological factors were associated with prostate cancer status. We call for improved study power by building on the SAPCS resource, further validation of associated factors in independent African-based resources, and genome-wide approaches to define African-specific risk alleles.
    Full-text · Article · Dec 2013 · BMC Urology
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    • "Although genome-wide association studies (GWAS) have identified more than a dozen PCa risk loci [5], elucidating the biological basis for these associations is challenging [6]. Identified risk loci include the noncoding variants, such as those located in the 8q24 region [7], as well as polymorphisms in the coding regions (genes) that either alter, or are predicted to alter, the protein expression (such as HNF1B [8], TERT [5], and RNASEL [9]). The post-GWAS studies are increasingly suggestive of the interaction between genetic variants and environmental risk factors [10] for which our understanding is still largely inadequate [11]. "
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    ABSTRACT: Background. Prostate cancer (PCa) racial disparity is multifactorial, involving biological, sociocultural, and lifestyle determinants. We investigated the association between selected potentially functional polymorphisms (SNPs) and prostate cancer (PCa) risk in Black (AAM) and White (EAM) men. We further explored if these associations varied by the body mass index (BMI) and height. Methods. Age-matched DNA samples from 259 AAM and 269 EAM were genotyped for 10 candidate SNPs in 7 genes using the TaqMan allelic differentiation analysis. The dominant, recessive, and additive age-adjusted unconditional logistic regression models were fitted. Results. Three SNPs showed statistically significant associations with PCa risk: in AAM, HNF1B rs7501939 (OR = 2.42, P = 0.0046) and rs4430796 (OR = 0.57, P = 0.0383); in EAM, CTBP2 rs4962416 (OR = 1.52, P = 0.0384). In addition, high BMI in AAM (OR = 1.06, P = 0.022) and height in EAM (OR = 0.92, P = 0.0434) showed significant associations. Interestingly, HNF1B rs7501939 was associated with PCa exclusively in obese AAM (OR = 2.14, P = 0.0103). Conclusion. Our results suggest that variation in the HNF1B may influence PCa risk in obese AAM.
    Full-text · Article · Dec 2013
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