BackgroundGenome-wide association studies have identified hundreds of genetic variants associated with specific cancers. A few of these risk regions have been associated with more than one cancer site; however, a systematic evaluation of the associations between risk variants for other cancers and lung cancer risk has yet to be performed.MethodsWe included 18023 patients with lung cancer and 60543 control subjects from two consortia, Population Architecture using Genomics and Epidemiology (PAGE) and Transdisciplinary Research in Cancer of the Lung (TRICL). We examined 165 single-nucleotide polymorphisms (SNPs) that were previously associated with at least one of 16 non–lung cancer sites. Study-specific logistic regression results underwent meta-analysis, and associations were also examined by race/ethnicity, histological cell type, sex, and smoking status. A Bonferroni-corrected P value of 2.5×10–5 was used to assign statistical significance.ResultsThe breast cancer SNP LSP1 rs3817198 was associated with an increased risk of lung cancer (odds ratio [OR] = 1.10; 95% confidence interval [CI] = 1.05 to 1.14; P = 2.8×10–6). This association was strongest for women with adenocarcinoma (P = 1.2×10–4) and not statistically significant in men (P = .14) with this cell type (P het by sex = .10). Two glioma risk variants, TERT rs2853676 and CDKN2BAS1 rs4977756, which are located in regions previously associated with lung cancer, were associated with increased risk of adenocarcinoma (OR = 1.16; 95% CI = 1.10 to 1.22; P = 1.1×10–8) and squamous cell carcinoma (OR = 1.13; CI = 1.07 to 1.19; P = 2.5×10–5), respectively.ConclusionsOur findings demonstrate a novel pleiotropic association between the breast cancer LSP1 risk region marked by variant rs3817198 and lung cancer risk.
BackgroundSeveral regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk.MethodsWe evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE-BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex-stratified analyses were performed across studies.ResultsWe observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8x10-4), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0x10-4). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e-4).ConclusionsWe provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near TPCN2, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes.
Background Multiple primary cancers account for ~16% of all incident cancers in the U.S.. While genome-wide association studies (GWAS) have identified many common genetic variants associated with various cancer sites, no study has examined the association of these genetic variants with risk of multiple primary cancers (MPC). Methods As part of the NHGRI Population Architecture using Genomics and Epidemiology (PAGE) study, we used data from the Multiethnic Cohort and Women’s Health Initiative. Incident MPC (IMPC) cases (n=1,385) were defined as participants diagnosed with >1 incident cancers after cohort entry. Participants diagnosed with only one incident cancer after cohort entry with follow-up equal to or longer than IMPC cases served as controls (single-index cancer controls; n= 9,626). Fixed-effects meta-analyses of unconditional logistic regression analyses were used to evaluate the association between cancer risk variants and IMPC risk. To account for multiple comparisons, we used the false positive report probability (FPRP) to determine statistical significance. Results A nicotine dependence-associated and lung cancer variant, CHRNA3 rs578776 (OR=1.16, 95% CI=1.05–1.26; p=0.004) and two breast cancer variants, EMBP1 rs11249433 and TOX3 rs3803662 (OR=1.16, 95% CI=1.04–1.28; p=0.005 and OR=1.13, 95% CI=1.03–1.23; p=0.006) were significantly associated with risk of IMPC. The associations for rs578776 and rs11249433 remained (p<0.05) after removing subjects who had lung or breast cancers, respectively (p-values≤0.046). These associations did not show significant heterogeneity by smoking status (p-heterogeneity≥0.53). Conclusions Our study has identified rs578776 and rs11249433 as risk variants for IMPC. Impact These findings may help to identify genetic regions associated with IMPC risk.
Genome-wide association studies (GWAS) have identified a large number of cancer-associated single nucleotide polymorphisms (SNPs), several of which have been associated with multiple cancer sites suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesized that SNPs associated with other cancers may be additionally associated with endometrial cancer. We examined 213 SNPs previously associated with 14 other cancers for their associations with endometrial cancer in 3758 endometrial cancer cases and 5966 controls of European ancestry from two consortia: Population Architecture Using Genomics and Epidemiology and the Epidemiology of Endometrial Cancer Consortium. Study-specific logistic regression estimates adjusted for age, body mass index and the most significant principal components of genetic ancestry were combined using fixed-effect meta-analysis to evaluate the association between each SNP and endometrial cancer risk. A Bonferroni-corrected P value of 2.35×10(-4) was used to determine statistical significance of the associations. SNP rs7679673, ~6.3kb upstream of TET2 and previously reported to be associated with prostate cancer risk, was associated with endometrial cancer risk in the direction opposite to that for prostate cancer [meta-analysis odds ratio = 0.87 (per copy of the C allele), 95% confidence interval = 0.81, 0.93; P = 7.37×10(-5)] with no evidence of heterogeneity across studies (P heterogeneity = 0.66). This pleiotropic analysis is the first to suggest TET2 as a susceptibility locus for endometrial cancer.
Overall survival (OS) as the primary endpoint (49 reports): no information on post-trial treatment in 27 reports.Quality of life (QoL) was the primary endpoint only in 6 trials, and was not reported as secondary endpoint in 79.2 % of all trials.Toxicity: 58.4 % of reports provided very fragmented information and offered no data on the proportion of patients with any grade 3 or greater toxicity. Conclusion:The quality of research protocols and of reporting the experience from trials on advanced lung cancer are often sub-optimal. Better design of trial protocols, timely precise reporting and meticulous review of papers submitted for publication are strongly encouraged, so as to offer adequate information for clinical practice and for further research. Considering the importance of QoL for any patient with incurable disease, lack of data on QoL is most embarrassing. Information on QoL should be a part of every report; this goal is achievable only with simple, easy-to-use instruments such as EQ-5D-5L self-administered questionnaire.
Background: Tobacco smoke is the primary cause of chronic obstructive pulmonary disease (COPD) and lung cancer, and among smokers, COPD is associated with increased lung cancer risk. However, fewer than 30% of smokers are diagnosed with either disease, suggesting that genetic factors also influence the pathogenesis of both diseases. Despite the plausibility for shared genetic predisposition, knowledge about pleiotropy between COPD and lung cancer is limited. Methods: Using the Genetic Epidemiology Research on Adult Health and Aging cohort established at Kaiser Permanente Northern California (KPNC), an integrated healthcare system, we examined non-Hispanic white smokers aged 40 years diagnosed with lung cancer (n¼489), including those with COPD (n¼243) or without COPD (n¼174), and neither disease (n¼26,553) through January 31, 2014. Those with lung cancer were identified from KPNC Cancer Registry data. Those with COPD were identified from electronic health record data, requiring at least one hospitalization with a principal discharge diagnosis or two outpatient visits with a diagnosis of chronic bronchitis, emphysema, or COPD (ICD-9 codes: 491.*, 492.*, 496.*). We examined 16 single nucleotide polymorphisms (SNPs) in 10 risk loci identified previously for COPD or airflow obstruction by genome-wide association studies (1q41, 4q22.1, 4q31.21, 5q32, 6p21.32, 11q22, 14q32, 15q25.1, 16p11.2, 19q13) for their associations with lung cancer risk, overall and stratified by COPD. SNPs were examined individually and also jointly as an unweighted 16-SNP risk score. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression, adjusted for age, sex, pack-years of smoking, and principal components of genetic ancestry. Results: Only two SNPs at 15q25.1, a risk locus also known for lung cancer and nicotine dependence, were associated with overall lung cancer risk: rs8034191 (per-allele OR¼1.22, 95%
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