Coding variants in NOD-like receptors: An association study on risk and survival of colorectal cancer.

Nod-like receptors (NLRs) are important innate pattern recognition receptors and regulators of inflammation or play a role during development. We systematically analysed 41 non-synonymous single nucleotide polymorphisms (SNPs) in 21 NLR genes in a Czech discovery cohort of sporadic colorectal cancer (CRC) (1237 cases, 787 controls) for their association with CRC risk and survival. Five SNPs were found to be associated with CRC risk and eight with survival at 5% significance level. In a replication analysis using data of two large genome-wide association studies (GWASs) from Germany (DACHS: 1798 cases and 1810 controls) and Scotland (2210 cases and 9350 controls) the associations found in the Czech discovery set were not confirmed. However, expression analysis in human gut-related tissues and immune cells revealed that the NLRs associated with CRC risk or survival in the discovery set were expressed in primary human colon or rectum cells, CRC tissue and/or cell lines, providing preliminary evidence for a potential involvement of NLRs in general in CRC development and/or progression. Most interesting was the finding that the enigmatic development-related NLRP5 (also known as MATER) was not expressed in normal colon tissue but in colon cancer tissue and cell lines. Future studies may show whether regulatory variants instead of coding variants might affect the expression of NLRs and contribute to CRC risk and survival.

Short article: Influence of regulatory NLRC5 variants on colorectal cancer survival and 5-fluorouracil-based chemotherapy.

BACKGROUND: NLRC5 is an interferon γ-inducible protein, which plays a role in immune surveillance with a potential influence on cancer survival. OBJECTIVE: We aimed to evaluate the effect of potential regulatory variants in NLRC5 on overall survival and survival after 5-fluorouracil (5-FU)-based therapy of colorectal cancer (CRC) patients. PATIENTS AND METHODS: We carried out a case-only study in a Czech population of 589 cases; 232 received 5-FU-based therapy. Eleven variants within NLRC5 were selected using in-silico tools. Associations between polymorphisms and survival were assessed by Cox regression analysis adjusting for age at diagnosis, sex, and TNM stage. Survival curves were derived using the Kaplan-Meier method. RESULTS: Two variants showed a significant association with survival. All patients and metastasis-free patients at the time of diagnosis (pM0) who were homozygous carriers of the minor allele of rs27194 had a decreased overall survival (OSall and OSpM0) and event-free survival (EFSpM0) under a recessive model (OSall P=0.003, OSpM0 P=0.005, EFSpM0 P=0.01, respectively). OS was also decreased for all patients and for pM0 patients who carried at least one minor allele of rs289747 (OSall P=0.03 and OSpM0 P=0.003, respectively). Among CRC patients, who underwent a 5-FU-based adjuvant regimen, rs12445252 was associated with OSall, OSpM0 and EFSpM0, according to the dosage of the minor allele T (OSall P=0.0004, OSpM0 P=0.0001, EFSpM0 P=0.008, respectively). CONCLUSION: Our results showed that polymorphisms in NLRC5 may be used as prognostic markers of survival of CRC patients, as well as for survival in response to 5-FU treatment.

GWAS-identified common variants for obesity are not associated with the risk of developing colorectal cancer.

BACKGROUND: Observational studies have consistently associated obesity with colorectal cancer risk. Because both traits are genetically determined and share some metabolic biomarkers, we hypothesized that obesity-related polymorphisms could also influence the risk of developing colorectal cancer. METHODS: We conducted a comprehensive population-based case-control study in 1,792 German colorectal cancer cases and 1,805 controls to explore associations between 28 obesogenic variants identified through genome-wide association studies (GWAS) and colorectal cancer risk. We also evaluated interactions between polymorphisms and body mass index (BMI), type II diabetes (T2D), and gender. RESULTS: No evidence of association between obesogenic variants and colorectal cancer risk was observed after correction for multiple testing. There was only a remarkable interaction between the LTArs1041981 polymorphism and gender, which modified the risk of colorectal cancer [Pinteraction = 0.002; males: odds ratio (OR), 1.14; 95% confidence intervals (CI), 1.00-1.30 vs. females: OR, 0.83; 95% CI, 0.71-0.97]. CONCLUSIONS: Our findings showed that obesogenic variants are not a major pathogenetic risk factor for colorectal cancer. IMPACT: This comprehensive population-based case-control study does not provide evidence of a shared genetic component between obesity and colorectal cancer.

Familial risks for childhood acute lymphocytic leukaemia in Sweden and Finland: far exceeding the effects of known germline variants.

Despite recent successes in the identification of genetic susceptibility loci, no familial risk has been demonstrated for childhood acute lymphoblastic leukaemia (ALL). We identified 3994 childhood ALL cases from two cancer registries; family members were obtained from population registers. The standardized incidence ratio for familial risk in singleton siblings and twins was 3·2 (95% confidence interval 1·5-5·9) and 162·6 (70·2-320·4), respectively. The present data constitute the first demonstration of familial risk for singleton siblings; the high risk for twins is believed to result from shared prenatal blood circulation. The data suggest that currently unidentified genetic loci underlie these observed familial effects.