Chronic inflammation, which is suspected to play a role in the development of colorectal cancer (CRC), has rarely been studied in colorectal adenoma. We investigated the inter-relationships of serum levels of the inflammatory proteins CRP and in IL-6, single nucleotide polymorphisms (SNPs) in the CRP (rs1205, rs1130864, rs1800947) and IL6 (rs1800795) genes, and lifestyle factors with colorectal adenoma in a sigmoidoscopy-based case-control study of 271 adenoma cases and 539 age-, sex-, and race/ethnicity-matched controls in Hawaii. We found no association of serum CRP or IL-6 levels with the risk of adenoma. A multiple regression with stepwise selection identified elevated BMI, Caucasian and Native Hawaiian versus Japanese race/ethnicity, and current smoking as being associated with significantly higher serum CRP and IL-6 levels. Female versus male gender was also associated with higher CRP levels and older age with higher IL-6 levels. The C allele of rs1205 and the A allele of rs1130864 were significantly associated with higher serum CRP levels (p (trend): 0.0002 and 0.01, respectively), as well as with a decreased adenoma risk [rs1205: OR for CT and CC vs. TT = 0.69 (95% CI: 0.48-0.98) and 0.53 (0.34-0.83), respectively, p (trend) = 0.008; rs1130864: OR for GA and AA versus GG = 0.65 (0.45-0.93) and 0.74 (0.31-1.76), respectively, p (trend) = 0.04]. The findings of lower serum CRP and IL-6 levels in Japanese (a group with a high CRC risk) and of a decreased adenoma risk observed for alleles associated with higher circulating CRP levels suggest a protective effect for CRP in early colorectal neoplasia that warrants further study.

The basis for associations between lung cancer and major histocompatibility complex genes is not completely understood. Here the authors further consider genetic variation within the MHC region in lung cancer patients and identify independent associations within HLA genes that explain MHC lung cancer associations in Europeans and Asian populations.

Background Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. Objective We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. Design, setting, and participants Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. Outcome measurements and statistical analysis Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. Results and limitations Longer genetically inferred telomere length was associated with an increased risk of RCC (OR = 2.07 per predicted kilobase increase, 95% confidence interval [CI]: = 1.70–2.53, p < 0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2 > 0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR = 1.73, 95% CI = 1.36–2.21, p < 0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N = 5573, OR = 1.93, 95% CI = 1.50–2.49, p < 0.0001), papillary (N = 573, OR = 1.96, 95% CI = 1.01–3.81, p = 0.046), and chromophobe RCC (N = 203, OR = 2.37, 95% CI = 0.78–7.17, p = 0.13). Conclusions Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk. Patient summary Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.

Background Germline genetic variation contributes to lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated susceptibility loci involved in smoking propensity and DNA repair genes, but further work is required to identify susceptibility variants. Methods To identify LC susceptibility loci, a family history-based genome-wide association (GWAx) study of LC (48,843 European “proxy” LC cases, 195,387 controls) was combined with previously LC GWAS (29,266 cases, 56,450 controls) by meta-analysis. Colocalisation was used to explore candidate genes and overlap with existing traits at discovered susceptibility loci. Polygenic Risk Scores (PRS) were tested within an independent validation cohort (1,666 LC cases vs 6,664 controls) using variants selected from the LC susceptibility loci and a novel selection approach using published GWAS summary statistics. Finally, the effects of the LC PRS on somatic mutational burden were explored in patients whose tumour resections have been profiled by exome (n = 685) and genome sequencing (n = 61). Statistical tests were 2-sided. Results The GWAx-GWAS meta-analysis identified 8 novel LC loci. Colocalization implicated DNA repair genes (CHEK1), metabolic genes (CYP1A1) and smoking propensity (CHRNA4 and CHRNB2). PRS analysis demonstrated that these variants, as well as sub-genome wide significant variants related to eQTLs and/or smoking propensity, assisted in LC genetic risk prediction (OR = 1.37, 95% CI 1.29–1.45, P = 1.44 x10-25). Patients with higher genetic PRS loads of smoking-related variants tended to have higher mutation burdens in their lung tumours. Conclusions This study has expanded the number of LC susceptibility loci and provided insights into the molecular mechanisms by which these susceptibility variants contribute to LC development.

Large international efforts are describing how germline variants influence susceptibility to lung cancer. We have undertaken a genome-wide association by proxy (GWAx) study of lung cancer in 48,843 proxy “cases” with a parent/sibling with lung cancer to 195,387 proxy controls without a family history of any cancer from the UK Biobank and meta-analysed the results with previously described GWA study results. 21 loci achieved genome-wide statistical significance, including 8 novel loci including expression quantitative trait loci (eQTLs) in DNA repair genes (CHEK1, MDM4) and metabolic genes (CYP1A1). This study also discovered loci associated with propensity to smoke, such as both subunits of a key element in nicotine response, the neuronal α4β2 nicotinic acetylcholine receptor. Polygenic risk scores (PRS) analysis of variants below genome-wide significant threshold in an independent lung cancer population demonstrated that variants related to eQTLs and/or smoking propensity are enriched for susceptibility variants. PRS of lung cancer variants related to propensity to smoke were associated with somatic mutation burden in matched tumours from the same patients, with individuals with higher polygenic genetic risk having increased mutation burden in two case cohorts. This study has expanded the number of susceptibility loci linked with lung cancer and provided insights into how the molecular mechanisms by which these susceptibility variants contribute to the development of lung cancer.TagsLung Cancer, GWAx, GWAS, Smoking, Cancer, CHRNA4, CHRNB2, Mutational Burden, CHEK1, MDM4, CYP1A1, α4β2 nicotinic acetylcholine receptor, Mutational Signatures, RP11-10O17.1