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.

Analgesic use and risk of renal cell carcinoma: A case-control, cohort and meta-analytic assessment.

Analgesics are the most commonly consumed drugs worldwide. Evidence that analgesics increase kidney cancer risk has been mixed. We investigated the association between renal cell carcinoma (RCC) and analgesic use in a large population-based case-control study and a post-trial observational cohort study. Findings were used to update a recent meta-analytic review. We analyzed data from 1,217 RCC cases and 1,235 controls in the US Kidney Cancer Study and 98,807 participants in the US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO: n = 137 RCCs). Self-reported acetaminophen, aspirin and nonsteroid anti-inflammatory drug (NSAID) use and duration information was assessed in relation to RCC. For the US Kidney Cancer Study, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression. For PLCO, we computed hazard ratios (HRs) and 95%CIs using Cox regression. Among case-control participants, RCC risk was associated with over-the-counter acetaminophen use (OR = 1.35, 95%CI = 1.01-1.83). There was a positive trend with increasing duration (p-trend = 0.01), with a two-fold risk for use ≥10 years (OR = 2.01, 95%CI = 1.30-3.12). No association with prescription acetaminophen use was detected. In PLCO, acetaminophen use was also associated with increased RCC risk (HR = 1.68, 95%CI = 1.19-2.39), although elevated risk was absent among the few long-term users. No association with RCC risk was detected for aspirin or NSAIDs use in either study. An association between acetaminophen use and kidney cancer was supported by meta-analytic cohort (n = 4; summary relative risk = 1.34; 95%CI = 1.13-1.59; p-heterogeneity = 0.40) and case-control (n = 9, summary OR = 1.20; 95%CI = 1.01-1.42; p-heterogeneity = 0.05) findings. In brief, acetaminophen use may increase the risk of developing RCC.

Is repeat prostate biopsy associated with a greater risk of hospitalization? Data from SEER-Medicare.

PURPOSE: We recently reported an increasing risk over time of hospitalization among Medicare participants after undergoing an initial prostate biopsy. Less is known about the relative risks of repeat prostate biopsies, which are frequently performed in prostate cancer screening and in active surveillance programs. We determined whether repeat biopsies are associated with an increased risk of hospitalization compared to the initial biopsy. MATERIALS AND METHODS: Using SEER (Surveillance, Epidemiology and End Results)-Medicare linked data from 1991 to 2007 we identified 13,883 men who underwent a single prostate biopsy and 3,640 who had multiple biopsies. The 30-day hospitalization rates were compared between these groups, and with a randomly selected control population of 134,977. ICD-9 codes were then used to examine the frequency of serious infectious and noninfectious urological complications as the primary diagnosis for hospital admissions. RESULTS: Initial and repeat biopsies were associated with a significantly increased risk of hospitalization within a 30-day period compared to randomly selected controls (p <0.0001). However, the repeat biopsy session was not associated with a greater risk of infectious (OR 0.81, 95% 0.49-1.32, p = 0.39) or serious noninfectious urological complications (OR 0.94, 95% CI 0.54-1.62, p = 0.82) compared to the initial biopsy. CONCLUSIONS: Each biopsy was associated with a significant risk of complications compared to randomly selected controls. However, the repeat biopsy procedure itself was not associated with a greater risk of serious complications requiring hospital admission compared to the initial biopsy.

Complications after prostate biopsy: data from SEER-Medicare.

PURPOSE: More than 1 million prostate biopsies are performed annually among Medicare beneficiaries. We determined the risk of serious complications requiring hospitalization. We hypothesized that with emerging multidrug resistant organisms there may be an increasing risk of infectious complications. MATERIALS AND METHODS: In a 5% random sample of Medicare participants in SEER (Surveillance, Epidemiology and End Results) regions from 1991 to 2007 we compared 30-day hospitalization rates and ICD-9 primary diagnosis codes for admissions between 17,472 men who underwent prostate biopsy and a random sample of 134,977 controls. Multivariate logistic and Poisson regression were used to examine the risk and predictors of serious infectious and noninfectious complications with time. RESULTS: The 30-day hospitalization rate was 6.9% within 30 days of prostate biopsy, which was substantially higher than the 2.7% in the control population. After adjusting for age, race, SEER region, year and comorbidities prostate biopsy was associated with a 2.65-fold (95% CI 2.47-2.84) increased risk of hospitalization within 30 days compared to the control population (p <0.0001). The risk of infectious complications requiring hospitalization after biopsy was significantly greater in more recent years (p(trend) = 0.001). Among men undergoing biopsy, later year, nonwhite race and higher comorbidity scores were significantly associated with an increased risk of infectious complications. CONCLUSIONS: The risk of hospitalization within 30 days of prostate biopsy was significantly higher than in a control population. Infectious complications after prostate biopsy have increased in recent years while the rate of serious noninfectious complications is relatively stable. Careful patient selection for prostate biopsy is essential to minimize the potential harms.

Comprehensive assessment of genetic variation of catechol-O-methyltransferase and breast cancer risk.

Because catechol-O-methyltransferase (COMT) catalyzes the addition of methyl groups to stabilize catechol estrogens that may induce DNA damage, genetic variants could influence breast cancer risk. To comprehensively characterize genetic variation in this gene, we selected haplotype-tagging single nucleotide polymorphisms (htSNP) in COMT. A total of 11 htSNPs (including COMT Val(158)Met) were selected based on the resequencing and dense genotyping approach of the Breast and Prostate Cancer Cohort Consortium. htSNPs were genotyped in a population-based, case-control study in Poland (1,995 cases and 2,296 controls). Individual SNPs were not significantly associated with risk. Haplotypes were estimated using the expectation-maximization algorithm. Overall differences in the haplotype distribution between cases and controls were assessed using a global score test. The TGAG haplotype (frequent in 4.3% of controls), in a linkage disequilibrium (LD) block that included the 3' untranslated region (UTR) of COMT, was associated with breast cancer risk (odds ratio, 1.29; 95% confidence interval, 1.06-1.58) compared with the most common haplotype TGAA; however, the global test for haplotype associations was not significant (P = 0.09). Haplotypes in another LD block, which included COMT Val(158)Met, were not associated with breast cancer risk (global P = 0.76). Haplotype-breast cancer risk associations were not significantly modified by hormonally related risk factors, family history of breast cancer, or tumor characteristics. In summary, our data does not support a substantial overall association between COMT haplotypes and breast cancer. The suggestion of increased risk associated with a haplotype in the 3' UTR of COMT needs to be confirmed in independent study populations.