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Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 ( BRCA1/2 ) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1 . These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual., (©2019 American Association for Cancer Research.)

Background: Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer, but very few studies have examined these effects in BRCA1 and BRCA2 mutation carriers. Given the high breast cancer risk for mutation carriers and the importance of BRCA1 and BRCA2 in DNA repair, better evidence on the associations of these lifestyle factors with breast cancer risk is essential., Methods: Using a large international pooled cohort of BRCA1 and BRCA2 mutation carriers, we conducted retrospective (5,707 BRCA1 mutation carriers and 3,525 BRCA2 mutation carriers) and prospective (2,276 BRCA1 mutation carriers and 1,610 BRCA2 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models., Results: For both BRCA1 and BRCA2 mutation carriers, none of the smoking-related variables was associated with breast cancer risk, except smoking for more than 5 years before a first full-term pregnancy (FFTP) when compared with parous women who never smoked. For BRCA1 mutation carriers, the HR from retrospective analysis (HR R ) was 1.19 [95% confidence interval (CI), 1.02-1.39] and the HR from prospective analysis (HR P ) was 1.36 (95% CI, 0.99-1.87). For BRCA2 mutation carriers, smoking for more than 5 years before an FFTP showed an association of a similar magnitude, but the confidence limits were wider (HR R = 1.25; 95% CI, 1.01-1.55 and HR P = 1.30; 95% CI, 0.83-2.01). For both carrier groups, alcohol consumption was not associated with breast cancer risk., Conclusions: The finding that smoking during the prereproductive years increases breast cancer risk for mutation carriers warrants further investigation., Impact: This is the largest prospective study of BRCA mutation carriers to assess these important risk factors., (©2019 American Association for Cancer Research.)

Prospective cohort studies have provided some evidence that circulating vitamin D is associated with risk of, and survival from, renal cell carcinoma (RCC), but it is unclear whether concentrations of vitamin D at the time of diagnosis of RCC are associated with prognosis. We conducted a case-cohort study of 630 RCC cases, including 203 deaths, from a multicenter case-control study in Eastern Europe. Vitamin D was assessed as 25-hydroxyvitamin D3 [25(OH)D3], and we used weighted Cox models to estimate hazard ratios (HR) and 95% confidence intervals (CI) by categories of season-adjusted 25(OH)D3. Higher concentrations of 25(OH)D3 were associated with lower risk of death after adjusting for stage, age, sex, and country (HR highest vs. lowest category 0.57; 95% CI, 0.34-0.97). The inverse associations of 25(OH)D3 with death were most notable among those who died from non-RCC causes and those diagnosed with early-stage disease. In summary, 25(OH)D3 concentration at diagnosis of RCC was inversely associated with all-cause mortality rates, but not specifically with RCC outcome., (©2015 American Association for Cancer Research.)

Trichloroethylene (TCE) is a suspected renal carcinogen. TCE-associated renal genotoxicity occurs predominantly through glutathione S-transferase (GST) conjugation and bioactivation by renal cysteine beta-lyase (CCBL1). We conducted a case-control study in Central Europe (1,097 cases and 1,476 controls) specifically designed to assess risk associated with occupational exposure to TCE through analysis of detailed job histories. All jobs were coded for organic/chlorinated solvent and TCE exposure (ever/never) as well as the frequency and intensity of exposure based on detailed occupational questionnaires, specialized questionnaires, and expert assessments. Increased risk was observed among subjects ever TCE exposed [odds ratio (OR) = 1.63; 95% confidence interval (95% CI), 1.04-2.54]. Exposure-response trends were observed among subjects above and below the median exposure [average intensity (OR = 1.38; 95% CI, 0.81-2.35; OR = 2.34; 95% CI, 1.05-5.21; P(trend) = 0.02)]. A significant association was found among TCE-exposed subjects with at least one intact GSTT1 allele (active genotype; OR = 1.88; 95% CI, 1.06-3.33) but not among subjects with two deleted alleles (null genotype; OR = 0.93; 95% CI, 0.35-2.44; P(interaction) = 0.18). Similar associations for all exposure metrics including average intensity were observed among GSTT1-active subjects (OR = 1.56; 95% CI, 0.79-3.10; OR = 2.77; 95% CI, 1.01-7.58; P(trend) = 0.02) but not among GSTT1 nulls (OR = 0.81; 95% CI, 0.24-2.72; OR = 1.16; 95% CI, 0.27-5.04; P(trend) = 1.00; P(interaction) = 0.34). Further evidence of heterogeneity was seen among TCE-exposed subjects with >or=1 minor allele of several CCBL1-tagging single nucleotide polymorphisms: rs2293968, rs2280841, rs2259043, and rs941960. These findings provide the strongest evidence to date that TCE exposure is associated with increased renal cancer risk, particularly among individuals carrying polymorphisms in genes that are important in the reductive metabolism of this chemical, and provides biological plausibility of the association in humans., ((c)2010 AACR.)

Lipid peroxidation is considered a unifying mechanistic pathway through which known risk factors induce renal cell carcinoma (RCC). We hypothesized that genes selected a priori for their role in lipid peroxidation would modify cancer risk. We genotyped 635 single nucleotide polymorphisms (SNP) in 38candidate genes in 777 Caucasian RCC cases and 1,035 controls enrolled in a large European case-control study. Top candidate SNPs were confirmed among 718 Caucasian cases and 615 controls in a second study in the United States. Two of the three SNPs (rs8106822 and rs405509) that replicated in the U.S. study were within a regulatory region of the APOE promoter. The OR for rs8106822 A>G variant was 1.22(AG) and 1.41(GG) (P(trend) = 0.01) in the European study, 1.05(AG) and 1.51(GG) (P(trend) = 0.03) in the U.S. study, and 1.15(AG) and 1.44(GG) (P(trend) = 0.001) among 1,485 cases and 1,639 controls combined. The rs405509 G>T variant was associated with risk in the European (OR, 0.87(TG); OR, 0.71(TT); P(trend) = 0.02), the U.S. (OR, 0.68(TG); OR, 0.71(TT); P(trend) = 0.02), and both studies combined (OR(TG), 0.79; OR(TT), 0.71; P(trend) = 0.001), as was the G-G haplotype (r(2) = 0.64; P= 4.7 x 10(-4)). This association is biologically plausible as SNP rs405509 was shown to modify protein binding and transcriptional activity of the APOE protein in vitro and is in linkage disequilibrium with key known variants defining the e2, e3, and e4 alleles that modify risk of atherosclerosis, Alzheimer's disease risk, and progression to AIDS. In two large case-control studies, our findings further define a functional region of interest at the APOE locus that increases RCC susceptibility.

An elevated familial relative risk may indicate either an important genetic component in etiology or shared environmental exposures within the family. Incidence rates of kidney cancer are particularly high in Central Europe, although no data were available on the familial aggregation or genetic background of kidney cancer in this region. We have, therefore, investigated the role of family history in first-degree relatives in a large multicenter case-control study in Central Europe. A total number of 1,097 cases of kidney cancer and 1,555 controls were recruited from 2000 to 2003 from seven centers in Czech Republic, Poland, Romania, and Russia. The risk of kidney cancer increased with the increasing number of relatives with history of any cancer [odds ratio (OR), 1.15; 95% confidence interval (95% CI), 1.00-1.31 per affected relative], and this association seemed to be more prominent among subjects with young onset (OR, 1.55; 95% CI, 1.09-2.20 per affected relative). Overall, the OR was 1.40 (95% CI, 0.71- 2.76) for the subjects who had at least one first-degree relative with kidney cancer after adjusting for tobacco smoking, body mass index, and medical history of hypertension, and this association was most apparent among subjects with affected siblings (OR, 4.09; 95% CI, 1.09-15.4). Based on the relative risk to siblings in our study population, we estimated that 80% of the kidney cancer cases are likely to occur in 20% of the population with the highest genetic risk, which indicate the importance of further investigation of genetic factors in cancer prevention for kidney cancer.