Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa.

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 × 10 −19 for the strongest Correspondence should be addressed to D.R. (reich@genetics.med.harvard.edu). COMPETING INTERESTS STATEMENTThe authors declare no competing financial interests. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript association, and P < 1.5 × 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.We recently carried out an admixture scan in African Americans with prostate cancer 1 , highlighting a 3.8-Mb region of chromosome 8 (125.68-129.48 Mb in build 35 of the reference sequence) as containing risk alleles that are highly differentiated in frequency between West Africans and European Americans ( Fig. 1a and Supplementary Table 1 online). Independently, another group 2 localized the same region via linkage analysis and identified specific variants in a region spanning from 128.54-128.62 Mb (denoted 'region 1') that were associated with increased risk of prostate cancer. We replicated the associations after genotyping the same variants in independent samples 1 . However, our data and analyses indicated that the variants in region 1 are insufficient to explain the magnitude of the admixture signal in African Americans with prostate cancer.To search for additional variants that might also contribute to risk at 8q24, we selected SNPs to capture common genetic variation across the admixture peak based on data from the International HapMap Project (see Methods). We genotyped a total of 1,521 variants (including the alleles of microsatellite DG8S737) in 1,175 African American affected individuals with age at diagnosis <72 years and 837 African American controls (Table 1). We genotyped the same variants in 465 European American cases and 446 European American controls.Analysis of these data identified a cluster of genetic variants that we denote 'region 2' in a span of linkage disequilibrium from 128.14-128.28 Mb. These variants are hundreds of kilobases away from the region 1 described in ref. 2 , and the strongest single-SNP association is significant at P = 6.5 × 10 −7 (Fig. 1b and Supplementary Table 2 online). We followed up by genotyping the most associated SNPs in additional cases and controls from five populations: African Americans, Japanese Americans, Native Hawaiians, Latinos and European Americans (for a total sample size of 4,266 individuals with prostate cancer and 3,252 controls) (see Methods and Supplementary Table 3 online). Analysis...

Clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) was detected using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells (>5–10%) with the same abnormal karyotype (presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rises rapidly to 2–3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions that pinpoint the locations of genes previously associated with hematological cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer prior to DNA sampling, those without a prior diagnosis have an estimated 10-fold higher risk of a subsequent hematological cancer (95% confidence interval = 6–18).

Life span extending mutations in growth signaling pathways protect against age-dependent DNA damage in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian subjects with mutations in the growth hormone receptor gene leading to severe growth hormone receptor (GHR) and IGF-I deficiencies and combined this information with surveys to identify the cause and age of death for subjects who died before this period. The individuals with GHR deficiency (GHRD) exhibited only one non-lethal malignancy and no cases of diabetes, in contrast to 17% cancer and 5% diabetes prevalence in the controls. A possible explanation for the very low incidence of cancer may be revealed by in vitro studies: serum from GHRD subjects reduced DNA breaks but increased apoptosis in human mammary epithelial cells (HMECs) treated with hydrogen peroxide. We also observed reduced insulin concentrations (1.4 μU/ml vs. 4.4μU/ml in unaffected relatives) and a very low homoeostasis model assessment of insulin resistance (HOMA-IR) index (0.34 vs. 0.96 in unaffected relatives) in GHRD individuals, indicating increased insulin sensitivity, which could explain the absence of diabetes in these subjects. Incubation of HMECs with GHRD serum also resulted in reduced expression of RAS, PKA and TOR, and up-regulation of SOD2, changes that promote cellular protection and life span extension in model organisms. These results provide evidence for a role of evolutionarily conserved pathways in promoting aging and diseases in humans and identify a candidate drug target for healthy life span extension.

Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10−8). More than 70 prostate cancer susceptibility loci, explaining ~30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.