Our results indicate that both the total intake of vitamin A and retinol could reduce breast cancer risk. However, associations between other vitamins and breast cancer seem to be limited.

PurposeThe known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.MethodsWe sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.ResultsThe ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive.ConclusionsWe have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

Inflammatory bowel disease (IBD) and colorectal cancer (CRC) are common health problems worldwide. Tumor necrosis factor (TNF) is a type of cytokine that induces inflammation and inhibits tumorigenesis. Several studies have assessed the relationship between the polymorphism of TNF-a-308 G4A and the susceptibility to IBD and CRC; however, the results have been controversial. In addition, the hypothesis whether the increased risk of CRC in IBD patients could be partly ascribed to the polymorphism of TNF-a-308 G4A was unclear. Therefore, we conducted this meta-analysis to confirm these associations. Pooled odd ratios (ORs) and 95% confidence intervals (95% CIs) were calculated on the basis of data from 14, 18, and 7 studies from a total of 27 studies for the associations between the polymorphism of TNF-a-308 G4A and ulcerative colitis, Crohn's disease (CD) and CRC. In Europeans, the AA genotype increased the risk of ulcerative colitis (UC) (OR, 2.041; 95% CI, 1.261-3.301) and CD (OR, 1.730; 95% CI, 1.168-2.564) significantly, without obvious heterogeneity and publication bias. Meanwhile, the GA genotype increased the risk of UC in Asians (OR, 2.360; 95% CI, 1.269-4.390) significantly. However, no significant association was observed for CRC in any ethnic population. The results of this meta-analysis suggested that the polymorphism of TNF-a-308 G4A participates in modifying the susceptibility to UC and CD in Europeans and Asians. The increased risk of CRC in IBD patients should be clarified as the combined effects of polymorphisms in TNF-a and other cytokines, and the interaction with environmental factors, in future studies.

Cyclooxygenase-2 (COX-2), 12-lipoxygenase (12-LOX) and phospholipaseA2 (PLA2) played important roles in the modulation of apoptosis, angiogenesis, carcinogenesis and invasion of colorectal cancer (CRC). The polymorphisms in COX-2, 12-LOX and PLA2 may affect their roles. Therefore, we investigated if COX-2 -1195G > A, 12-LOX 261Arg > Gln and PLA2 c.349 + 191A > G polymorphisms were associated with risk and prognosis of CRC as well as possible interactions with the environmental factors on the risk of CRC in Northeast of China. A case-control study with 451 cases and 631 controls were carried out, a cohort with 386 patients were followed up. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Compared with the 261Arg/Arg genotype, 12-LOX 261Arg/Gln genotype and 261Arg/Gln + Gln/Gln genotypes reduced the risk of rectal cancer by 33% (adjusted OR = 0.67, 95% CI 0.47-0.97, p = 0.03) and 32% (adjusted OR = 0.68, 95% CI 0.49-0.96, p = 0.03), respectively. The adjusted HR for the association between 12-LOX 261Gln/Gln genotype and overall survival in patients with CRC was 1.68 (95% CI 1.06-2.68, p = 0.03). There was also evidence of an interaction between the PLA2 c.349 + 191 A > G genotypes and the overnight food consumption (adjusted ORi = 1.92, 95% CI 1.14-3.25, P(interaction) = 0.01). These observations indicate that 12-LOX 261Arg > Gln polymorphism may affect risk of rectal cancer, and it may be a potential predictive marker for prognosis of CRC.

The relationship between gene-specific DNA methylation in peripheral blood leukocytes and colorectal cancer (CRC) susceptibility is unclear. In this case-control study, the methylation status of a panel of 10 CRC-related genes in 428 CRC cases and 428 cancer-free controls were detected with methylation-sensitive high-resolution melting analysis. We calculated a weighted methylation risk score (MRS) that comprehensively combined the methylation status of the panel of 10 genes and found that the MRS_10 was significantly associated with CRC risk. Compared with MRS-Low group, MRS-High group and MRS-Medium group exhibited a 6.51-fold (95% CI, 3.77-11.27) and 3.85-fold (95% CI, 2.72-5.45) increased risk of CRC, respectively. Moreover, the CRC risk increased with increasing MRS_10 (Ptrend < 0.0001). Stratified analyses demonstrated that the significant association retained in both men and women, younger and older, and normal weight or underweight and overweight or obese subjects. The area under the receiver operating characteristic curves for the MRS_10 model was 69.04% (95% CI, 65.57-72.66%) and the combined EF and MRS_10 model yielded an AUC of 79.12% (95% CI, 76.22-82.15%). Together, the panel of 10 gene-specific DNA methylation in leukocytes was strongly associated with the risk of CRC and might be a useful marker of susceptibility for CRC.