Martha L. Slattery

Are dietary factors involved in DNA methylation associated with colon cancer

Disturbances in DNA methylation have been hypothesized as being involved in carcinogenesis. It has been proposed that dietary factors such as folate, alcohol, and methionine may be associated with colon cancer because of their involvement in DNA methylation processes. Data from a large retrospective population-based case-control study of incident colon cancer were used to evaluate whether intake of alcohol and other dietary factors involved in DNA methylation are associated with colon cancer. Dietary data were obtained using a detailed diet history questionnaire. We did not observe strong independent associations between folate, vitamin B6, vitamin B12, methionine, or alcohol and risk of colon cancer after adjusting for body size, physical activity, cigarette smoking patterns, energy intake, and dietary intake of fiber and calcium. However, when assessing the associations between colon cancer and a composite dietary profile based on alcohol intake, methionine, folate, vitamin B12, and vitamin B6, we observed a trend of increasing risk as one moved from a low- to a high-risk group. This trend was modest and most marked in those diagnosed at a younger age [odds ratio (OR) for men = 1.3, 95% confidence interval (CI) = 0.9-1.9; OR for women = 1.6, 95% CI = 1.0-2.6]. We observed that associations with this high-risk dietary profile were greater among those who took aspirin or nonsteroidal anti-inflammatory drugs on a regular basis and were younger at the time of diagnosis (men OR = 1.7, 95% CI = 1.0-3.2; women OR = 2.2, 95% CI = 1.0-4.8) and for distal tumors (men OR = 1.4, 95% CI = 0.9-2.3; women OR = 2.0, 95% CI = 1.0-3.8). Findings from this study provide only limited support for previously reported associations between dietary factors involved in DNA methylation and risk of colon cancer.

Drugs and colon cancer

In a case–control study of colon cancer conducted in three geographic regions of the United States, 1993 case subjects and 2410 control subjects were interviewed. In addition to queries regarding other known or suspected risk factors, subjects were asked about their use of eight drugs or drug groups. Two of these, aspirin and other nonsteroidal anti‐inflammatory drugs (NSAIDs), have been inversely associated with risk in other studies. Three others—asthma medications, digitalis preparations, and phenmetrazine—were positively associated and the last three—diazepam, penicillin, and phenformin—were negatively associated with risk of colon cancer in an earlier study that screened pharmaceuticals for possible carcinogenic effects. Reported use of aspirin and NSAIDs were both inversely related to risk with essentially the same odds ratios (0·7, 95% confidence interval 0·6–0·8) for both drugs in both univariate and multivariate analyses controlling for use of each other and for other colon cancer risk factors. Subdivision by age at starting the drug, duration of use, latency interval, sex, race, family history of colon cancer, or proximal versus distal cancer revealed no substantial differences among subgroups for either aspirin or NSAIDs, but reduced risk was associated primarily with recent aspirin use. Phenformin showed a strong positive association but the data concerning this drug appeared to be inaccurate. The other drugs and drug groups showed essentially no association with colon cancer risk.

Estimating the heritability of colorectal cancer

A sizable fraction of colorectal cancer (CRC) is expected to be explained by heritable factors, with heritability estimates ranging from 12 to 35% twin and family studies. Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) associated with CRC risk. Although it has been shown that these CRC susceptibility SNPs only explain a small proportion of the genetic risk, it is not clear how much of the heritability these SNPs explain and how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we estimated the heritability of CRC under different scenarios using Genome-Wide Complex Trait Analysis in the Genetics and Epidemiology of Colorectal Cancer Consortium including 8025 cases and 10 814 controls. We estimated that the heritability explained by known common CRC SNPs identified in GWAS was 0.65% (95% CI:0.3-1%; P = 1.11 × 10-16), whereas the heritability explained by all common SNPs was at least 7.42% (95% CI: 4.71-10.12%; P = 8.13 × 10(-8)), suggesting that many common variants associated with CRC risk remain to be detected. Comparing the heritability explained by the common variants with that from twin and family studies, a fraction of the heritability may be explained by other genetic variants, such as rare variants. In addition, our analysis showed that the gene × smoking interaction explained a significant proportion of the CRC variance (P = 1.26 × 10(-2)). In summary, our results suggest that known CRC SNPs only explain a small proportion of the heritability and more common SNPs have yet to be identified.

Risk of colon cancer associated with a family history of cancer or colorectal polyps: The Diet, Activity, and Reproduction in Colon Cancer Study

The Diet, Activity, and Reproduction in Colon Cancer (DARCC) study is a large, multi‐center case‐control study of colon cancer. We examined family histories of cancer among first‐degree relatives obtained by computer‐assisted in‐person interviews from the DARCC to study the impact of family histories of several cancers and colorectal polyps on colon cancer risk. We examined familial cancer risks both by treating a family history of polyps or cancer as a covariate in a logistic regression model, and by comparing cancer or polyp incidence among relatives of cases to incidence among relatives of controls in a proportional hazards model. There were few differences between the odds ratios (OR) or confidence intervals (CI) generated from logistic regression models and the hazard rate ratios (HRR) generated from the proportional hazards models. Overall, the OR of colon cancer among subjects with a family history of colorectal cancer was 1.77. There were only minor differences in risk by sex, age and subsite. A family history of colorectal polyps also increased risk by about the same amount as a family history of colorectal cancer. The increased risk associated with a family history of polyps did not appear to decrease with age. Int. J. Cancer 78:157–160, 1998.© 1998 Wiley‐Liss, Inc.

Cross cancer genomic investigation of inflammation pathway for five common cancers: Lung, ovary, prostate, breast, and colorectal cancer

BACKGROUNDnInflammation has been hypothesized to increase the risk of cancer development as an initiator or promoter, yet no large-scale study of inherited variation across cancer sites has been conducted.nnnMETHODSnWe conducted a cross-cancer genomic analysis for the inflammation pathway based on 48 genome-wide association studies within the National Cancer Institute GAME-ON Network across five common cancer sites, with a total of 64 591 cancer patients and 74 467 control patients. Subset-based meta-analysis was used to account for possible disease heterogeneity, and hierarchical modeling was employed to estimate the effect of the subcomponents within the inflammation pathway. The network was visualized by enrichment map. All statistical tests were two-sided.nnnRESULTSnWe identified three pleiotropic loci within the inflammation pathway, including one novel locus in Ch12q24 encoding SH2B3 (rs3184504), which reached GWAS significance with a P value of 1.78 x 10(-8), and it showed an association with lung cancer (P = 2.01 x 10(-6)), colorectal cancer (GECCO P = 6.72x10(-6); CORECT P = 3.32x10(-5)), and breast cancer (P = .009). We also identified five key subpathway components with genetic variants that are relevant for the risk of these five cancer sites: inflammatory response for colorectal cancer (P = .006), inflammation related cell cycle gene for lung cancer (P = 1.35x10(-6)), and activation of immune response for ovarian cancer (P = .009). In addition, sequence variations in immune system development played a role in breast cancer etiology (P = .001) and innate immune response was involved in the risk of both colorectal (P = .022) and ovarian cancer (P = .003).nnnCONCLUSIONSnGenetic variations in inflammation and its related subpathway components are keys to the development of lung, colorectal, ovary, and breast cancer, including SH2B3, which is associated with lung, colorectal, and breast cancer.