Gary L. Ellison

Review of the Gene-Environment Interaction Literature in Cancer: What Do We Know?

Risk of cancer is determined by a complex interplay of genetic and environmental factors. Although the study of gene‐environment interactions (G×E) has been an active area of research, little is reported about the known findings in the literature.

Epigenetic Contributions to the Relationship between Cancer and Dietary Intake of Nutrients, Bioactive Food Components, and Environmental Toxicants.

Epigenetics is the study of heritable changes in gene expression that occur without a change in DNA sequence. Cancer is a multistep process derived from combinational crosstalk between genetic alterations and epigenetic influences through various environmental factors. The observation that epigenetic changes are reversible makes them an attractive target for cancer prevention. Until recently, there have been difficulties studying epigenetic mechanisms in interactions between dietary factors and environmental toxicants. The development of the field of cancer epigenetics during the past decade has been advanced rapidly by genome-wide technologies – which initially employed microarrays but increasingly are using high-throughput sequencing – which helped to improve the quality of the analysis, increase the capacity of sample throughput, and reduce the cost of assays. It is particularly true for applications of cancer epigenetics in epidemiologic studies that examine the relationship among diet, epigenetics, and cancer because of the issues of tissue heterogeneity, the often limiting amount of DNA samples, and the significant cost of the analyses. This review offers an overview of the state of the science in nutrition, environmental toxicants, epigenetics, and cancer to stimulate further exploration of this important and developing area of science. Additional epidemiologic research is needed to clarify the relationship between these complex epigenetic mechanisms and cancer.

Urinary bisphenol A and age at menarche among adolescent girls: Evidence from NHANES 2003–2010

BACKGROUND Bisphenol A (BPA) is an environmental estrogen used in the manufacture of polycarbonate plastics and epoxy resins used to make food and beverage packaging. Increasing evidence suggests that BPA mimics estrogens in the body and may be associated with putative markers of breast cancer risk. OBJECTIVES We analyzed the National Health and Nutrition Examination Survey (NHANES) 2003-2010 data to investigate the association of BPA with age at menarche in adolescent girls. We hypothesized that urinary BPA, as a surrogate biomarker for BPA exposure, is associated with earlier age at menarche, and that body mass index (BMI) may modulate this association. METHODS We conducted cross-sectional analyses of urinary BPA, BMI and age of menarche in a subsample of 987 adolescent girls aged 12-19, using pooled data from the 2003-2010 NHANES. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the association between urinary BPA and early onset of menarche, with adjustment for sampling design. We additionally assessed interaction of BPA with BMI. RESULTS Adolescent girls with moderate BPA levels appeared to be less likely to have early onset of menarche than those with the lowest levels (OR=0.57; 95% CI=0.30, 1.08) after adjusting for age, race/ethnicity, parental education, country of birth, NHANES cycle, BMI and creatinine. BMI appeared to modify the BPA-menarche association. CONCLUSIONS Although a non-significant trend suggests increasing urinary BPA may be associated with delayed menarche in adolescent girls, these results are based on cross-sectional data. Results should be clarified in carefully designed longitudinal cohort studies.

A Randomized Trial Comparing Web-Based Decision Aids on Prostate Cancer Knowledge for African-American Men

OBJECTIVES Few decision aids are tailored for African-American men. We sought to determine if web-based decision aids increased knowledge of prostate cancer screening among African men. METHODS This postintervention, quasiexperimental research measured knowledge of prostate cancer screening among African-American men following receipt of 1 of 2 web-based decision aids: enhanced or usual care. Men ages 40-65 were recruited at the annual convention of the Prince Hall Masons in the summer of 2007, which was attended by 1170 masons. The primary outcome was knowledge of prostate cancer screening. RESULTS There were 87 participants in the sample with a mean age of 52 years (standard deviation = 6.9). Forty-six masons were randomized to the enhanced decision aid, and 41 masons were randomized to the usual care decision aid. Knowledge scores were statistically significantly higher among the men receiving the enhanced decision aid compared to the usual care decision aid after simultaneously adjusting for age, educational level, marital status, family history, previous prostate specific antigen test and digital rectal exam (p = 0.01). CONCLUSION We found evidence that the enhanced web decision aid was significantly more effective than the usual care decision aid in promoting knowledge of the benefits, limitations and risks of prostate cancer screening. Web-based sites may be effective in facilitating discussions about screening between patients and health care providers.

Isocyanates and human health: multistakeholder information needs and research priorities.

Objectives: To outline the knowledge gaps and research priorities identified by a broad base of stakeholders involved in the planning and participation of an international conference and research agenda workshop on isocyanates and human health held in Potomac, Maryland, in April 2013. Methods: A multimodal iterative approach was used for data collection including preconference surveys, review of a 2001 consensus conference on isocyanates, oral and poster presentations, focused break-out sessions, panel discussions, and postconference research agenda workshop. Results: Participants included representatives of consumer and worker health, health professionals, regulatory agencies, academic and industry scientists, labor, and trade associations. Conclusions: Recommendations were summarized regarding knowledge gaps and research priorities in the following areas: worker and consumer exposures; toxicology, animal models, and biomarkers; human cancer risk; environmental exposure and monitoring; and respiratory epidemiology and disease, and occupational health surveillance.

A Review of NCI's Extramural Grant Portfolio: Identifying Opportunities for Future Research in Genes and Environment in Cancer

Background: Genetic and environmental factors jointly influence cancer risk. The NIH has made the study of gene–environment (GxE) interactions a research priority since the year 2000. Methods: To assess the current status of GxE research in cancer, we analyzed the extramural grant portfolio of the National Cancer Institute (NCI) from Fiscal Years 2007 to 2009. Publications attributed to selected grants were also evaluated. Results: From the 1,106 research grants identified in our portfolio analysis, a random sample of 450 grants (40%) was selected for data abstraction; of these, 147 (33%) were considered relevant. The most common cancer type was breast (20%, n = 29), followed by lymphoproliferative (10%, n = 14), colorectal (9%, n = 13), melanoma/other skin (9%, n = 13), and lung/upper aerodigestive tract (8%, n = 12) cancers. The majority of grants were studies of candidate genes (68%, n = 100) compared with genome-wide association studies (GWAS) (8%, n = 12). Approximately one-third studied environmental exposures categorized as energy balance (37%, n = 54) or drugs/treatment (29%, n = 43). From the 147 relevant grants, 108 publications classified as GxE or pharmacogenomic were identified. These publications were linked to 37 of the 147 grant applications (25%). Conclusion: The findings from our portfolio analysis suggest that GxE studies are concentrated in specific areas. There is room for investments in other aspects of GxE research, including, but not limited to developing alternative approaches to exposure assessment, broadening the spectrum of cancer types investigated, and conducting GxE within GWAS. Impact: This portfolio analysis provides a cross-sectional review of NCI support for GxE research in cancer. Cancer Epidemiol Biomarkers Prev; 22(4); 501–7. ©2013 AACR.

Gene-environment interactions in cancer epidemiology

Cancer risk is determined by a complex interplay of genetic and environmental factors. Genome‐wide association studies (GWAS) have identified hundreds of common (minor allele frequency [MAF] > 0.05) and less common (0.01 < MAF < 0.05) genetic variants associated with cancer. The marginal effects of most of these variants have been small (odds ratios: 1.1–1.4). There remain unanswered questions on how best to incorporate the joint effects of genes and environment, including gene‐environment (G × E) interactions, into epidemiologic studies of cancer. To help address these questions, and to better inform research priorities and allocation of resources, the National Cancer Institute sponsored a “Gene‐Environment Think Tank” on January 10–11, 2012. The objective of the Think Tank was to facilitate discussions on (1) the state of the science, (2) the goals of G × E interaction studies in cancer epidemiology, and (3) opportunities for developing novel study designs and analysis tools. This report summarizes the Think Tank discussion, with a focus on contemporary approaches to the analysis of G × E interactions. Selecting the appropriate methods requires first identifying the relevant scientific question and rationale, with an important distinction made between analyses aiming to characterize the joint effects of putative or established genetic and environmental factors and analyses aiming to discover novel risk factors or novel interaction effects. Other discussion items include measurement error, statistical power, significance, and replication. Additional designs, exposure assessments, and analytical approaches need to be considered as we move from the current small number of success stories to a fuller understanding of the interplay of genetic and environmental factors.