Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals.

Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Abstract: Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence

Allergies and risk of pancreatic cancer : a pooled analysis from the Pancreatic Cancer Case-Control Consortium

In order to quantify the risk of pancreatic cancer associated with history of any allergy and specific allergies, to investigate differences in the association with risk according to age, gender, smoking status, or body mass index, and to study the influence of age at onset, we pooled data from 10 case-control studies. In total, there were 3,567 cases and 9,145 controls. Study-specific odds ratios and 95% confidence intervals were calculated by using unconditional logistic regression adjusted for age, gender, smoking status, and body mass index. Between-study heterogeneity was assessed by using the Cochran Q statistic. Study-specific odds ratios were pooled by using a random-effects model. The odds ratio for any allergy was 0.79 (95% confidence interval (CI): 0.62, 1.00) with heterogeneity among studies (P < 0.001). Heterogeneity was attributable to one study; with that study excluded, the pooled odds ratio was 0.73 (95% CI: 0.64, 0.84) (Pheterogeneity = 0.23). Hay fever (odds ratio = 0.74, 95% CI: 0.56, 0.96) and allergy to animals (odds ratio = 0.62, 95% CI: 0.41, 0.94) were related to lower risk, while there was no statistically significant association with other allergies or asthma. There were no major differences among subgroups defined by age, gender, smoking status, or body mass index. Older age at onset of allergies was slightly more protective than earlier age

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers.

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence