Christine Q. Chang

A systematic review of cancer GWAS and candidate gene meta-analyses reveals limited overlap but similar effect sizes.

Candidate gene and genome-wide association studies (GWAS) represent two complementary approaches to uncovering genetic contributions to common diseases. We systematically reviewed the contributions of these approaches to our knowledge of genetic associations with cancer risk by analyzing the data in the Cancer Genome-wide Association and Meta Analyses database (Cancer GAMAdb). The database catalogs studies published since January 1, 2000, by study and cancer type. In all, we found that meta-analyses and pooled analyses of candidate genes reported 349 statistically significant associations and GWAS reported 269, for a total of 577 unique associations. Only 41 (7.1%) associations were reported in both candidate gene meta-analyses and GWAS, usually with similar effect sizes. When considering only noteworthy associations (defined as those with false-positive report probabilities ≤0.2) and accounting for indirect overlap, we found 202 associations, with 27 of those appearing in both meta-analyses and GWAS. Our findings suggest that meta-analyses of well-conducted candidate gene studies may continue to add to our understanding of the genetic associations in the post-GWAS era.

The Geometric Increase in Meta-Analyses from China in the Genomic Era

Meta-analyses are increasingly popular. It is unknown whether this popularity is driven by specific countries and specific meta-analyses types. PubMed was used to identify meta-analyses since 1995 (last update 9/1/2012) and catalogue their types and country of origin. We focused more on meta-analyses from China (the current top producer of meta-analyses) versus the USA (top producer until recently). The annual number of meta-analyses from China increased 40-fold between 2003 and 2011 versus 2.4-fold for the USA. The growth of Chinese meta-analyses was driven by genetics (110-fold increase in 2011 versus 2003). The HuGE Navigator identified 612 meta-analyses of genetic association studies published in 2012 from China versus only 109 from the USA. We compared in-depth 50 genetic association meta-analyses from China versus 50 from USA in 2012. Meta-analyses from China almost always used only literature-based data (92%), and focused on one or two genes (94%) and variants (78%) identified with candidate gene approaches (88%), while many USA meta-analyses used genome-wide approaches and raw data. Both groups usually concluded favorably for the presence of genetic associations (80% versus 74%), but nominal significance (P<0.05) typically sufficed in the China group. Meta-analyses from China typically neglected genome-wide data, and often included candidate gene studies published in Chinese-language journals. Overall, there is an impressive rise of meta-analyses from China, particularly on genetic associations. Since most claimed candidate gene associations are likely false-positives, there is an urgent global need to incorporate genome-wide data and state-of-the art statistical inferences to avoid a flood of false-positive genetic meta-analyses.

Potential increased risk of cancer from commonly used medications: an umbrella review of meta-analyses

Several commonly used medications have been associated with increased cancer risk in the literature. Here, we evaluated the strength and consistency of these claims in published meta-analyses. We carried out an umbrella review of 74 meta-analysis articles addressing the association of commonly used medications (antidiabetics, antihyperlipidemics, antihypertensives, antirheumatics, drugs for osteoporosis, and others) with cancer risk where at least one meta-analysis in the medication class included some data from randomized trials. Overall, 51 articles found no statistically significant differences, 13 found some decreased cancer risk, and 11 found some increased risk (one reported both increased and decreased risks). The 11 meta-analyses that found some increased risks reported 16 increased risk estimates, of which 5 pertained to overall cancer and 11 to site-specific cancer. Six of the 16 estimates were derived from randomized trials and 10 from observational data. Estimates of increased risk were strongly inversely correlated with the amount of evidence (number of cancer cases) (Spearmans correlation coefficient = -0.77, P < 0.001). In 4 of the 16 topics, another meta-analysis existed that was larger (n = 2) or included better controlled data (n = 2) and in all 4 cases there was no statistically significantly increased risk of malignancy. No medication or class had substantial and consistent evidence for increased risk of malignancy. However, for most medications we cannot exclude small risks or risks in population subsets. Such risks are unlikely to be possible to document robustly unless very large, collaborative studies with standardized analyses and no selective reporting are carried out.

Evidence synthesis and guideline development in genomic medicine: current status and future prospects

Purpose:With the accelerated implementation of genomic medicine, health-care providers will depend heavily on professional guidelines and recommendations. Because genomics affects many diseases across the life span, no single professional group covers the entirety of this rapidly developing field.Methods:To pursue a discussion of the minimal elements needed to develop evidence-based guidelines in genomics, the Centers for Disease Control and Prevention and the National Cancer Institute jointly held a workshop to engage representatives from 35 organizations with interest in genomics (13 of which make recommendations). The workshop explored methods used in evidence synthesis and guideline development and initiated a dialogue to compare these methods and to assess whether they are consistent with the Institute of Medicine report “Clinical Practice Guidelines We Can Trust.” Results:The participating organizations that develop guidelines or recommendations all had policies to manage guideline development and group membership, and processes to address conflicts of interests. However, there was wide variation in the reliance on external reviews, regular updating of recommendations, and use of systematic reviews to assess the strength of scientific evidence.Conclusion:Ongoing efforts are required to establish criteria for guideline development in genomic medicine as proposed by the Institute of Medicine.Genet Med advance online publication 19 June 2014

Paramutation-Like Interaction of T-DNA Loci in Arabidopsis

In paramutation, epigenetic information is transferred from one allele to another to create a gene expression state which is stably inherited over generations. Typically, paramutation describes a phenomenon where one allele of a gene down-regulates the expression of another allele. Paramutation has been described in several eukaryotes and is best understood in plants. Here we describe an unexpected paramutation-like trans SALK T-DNA interaction in Arabidopsis. Unlike most of the previously described paramutations, which led to gene silencing, the trans SALK T-DNA interaction caused an increase in the transcript levels of the endogenous gene (COBRA) where the T-DNA was inserted. This increased COBRA expression state was stably inherited for several generations and led to the partial suppression of the cobra phenotype. DNA methylation was implicated in this trans SALK T-DNA interaction since mutation of the DNA methyltransferase 1 in the suppressed cobra caused a reversal of the suppression. In addition, null mutants of the DNA demethylase ROS1 caused a similar COBRA transcript increase in the cobra SALK T-DNA mutant as the trans T-DNA interaction. Our results provide a new example of a paramutation-like trans T-DNA interaction in Arabidopsis, and establish a convenient hypocotyl elongation assay to study this phenomenon. The results also alert to the possibility of unexpected endogenous transcript increase when two T-DNAs are combined in the same genetic background.

Prevalence and Correlates of Receiving and Sharing High-Penetrance Cancer Genetic Test Results: Findings from the Health Information National Trends Survey

Background/Aims: The aim of this study was to explore the prevalence and correlates of receiving and sharing high-penetrance cancer genetic test results. Methods: Participants completed the population-based, cross-sectional 2013 Health Information National Trends Survey. We examined sociodemographic characteristics of participants reporting having had BRCA1/2 or Lynch syndrome genetic testing, and sociodemographic and psychosocial correlates of sharing test results with health professionals and family members. Results: Participants who underwent BRCA1/2 or Lynch syndrome genetic testing (n = 77; 2.42% of respondents) were more likely to be female and to have a family or personal history of cancer than those not undergoing testing. Approximately three-quarters of participants shared results with health professionals and three-quarters with their family; only 4% did not share results with anyone. Participants who shared results with health professionals reported greater optimism, self-efficacy for health management, and trust in information from their doctors. Participants who shared results with their family were more likely to be female and to have a personal history of cancer, and had greater self-efficacy for health management, perceived less ambiguity in cancer prevention recommendations, and lower cancer prevention fatalism. Conclusions: We identified several novel psychosocial correlates of sharing genetic information. Health professionals may use this information to identify patients less likely to share information with at-risk family members.

An overview of recommendations and translational milestones for genomic tests in cancer

Purpose:To understand the translational trajectory of genomic tests in cancer screening, diagnosis, prognosis, and treatment, we reviewed tests that have been assessed by recommendation and guideline developers. Methods:For each test, we marked translational milestones by determining when the genomic association with cancer was first discovered and studied in patients, and when a health application for a specified clinical use was successfully demonstrated and approved or cleared by the US Food and Drug Administration. To identify recommendations and guidelines, we reviewed the websites of cancer, genomic, and general guideline developers and professional organizations. We searched the in vitro diagnostics database of the US Food and Drug Administration for information, and we searched PubMed for translational milestones. Milestones were examined against type of recommendation, Food and Drug Administration approval or clearance, disease rarity, and test purpose. Results:Of the 45 tests we identified, 9 received strong recommendations for their usage in clinical settings, 14 received positive but moderate recommendations, and 22 were not currently recommended. For 18 tests, two or more different sources had issued recommendations, with 67% concordance. Only five tests had Food and Drug Administration approval, and an additional five had clearance. The median time from discovery to recommendation statement was 14.7 years. Conclusion:In general, there were no associations found between translational trajectory and recommendation category.Genet Med 17 6, 431–440.

The Cancer Genomics and Epidemiology Navigator: An NCI Online Tool to Enhance Cancer Epidemiology Research

The Epidemiology and Genomics Research Program (EGRP) at the National Cancer Institute (NCI) has undergone strategic planning in an effort to transform the practice of cancer epidemiology in the 21st century ([1][1]). Through these efforts, the program has focused on the need for knowledge

Abstract 254: How can epidemiology become more effective in reducing the burden of cancer in the 21st century? An analysis of NCI-funded grants and the scientific literature

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Concurrent with an NCI sponsored 2012 workshop on the future of cancer epidemiology, a set of “drivers” were identified to accelerate the field of cancer epidemiology across the translational research continuum in the 21st century: (i) emerging technologies; (ii) multi-level analyses and interventions; (iii) knowledge integration from basic, clinical and population sciences; and (iv) collaboration and team science. Objective: To map the evolution of identified “drivers” and key translational phases (T0-T4) in the past decade. Methods: We analyzed grants funded by the NCIs Epidemiology and Genomics Research Program and published literature for 2000, 2005, and 2010. For each year, we evaluated the aims of all new and competing grants and randomly selected 100 cancer epidemiology articles from PubMed. We used two-sample t-tests to compare differences between “drivers” and multivariate logistic regression to investigate the relationship between multi-institutional collaboration and the remaining “drivers”. Results: Our results show a significant shift from single-institution studies that focused on traditional questionnaire-based epidemiology studies to technology-driven, multi-disciplinary consortia-driven studies for both NCI grants and published literature. Compared to grants that were single-institution-based, consortia grants were significantly more likely to incorporate key contemporary technologies (OR= 3.53; 95% CI=1.44-8.61; p-value = 0.005) and engaged in multi-level analyses (OR =2.27; 95% CI=1.06-4.86, p-value=0.035). The vast majority of grants (82%) and publications (86%) analyzed were discovery (T0) or characterization (T1) research suggesting a critical need for more T2-T4 translational studies. Our evaluation also indicates a dearth of research in two areas: 1) multi-level analyses that takes into account the combination of molecular, individual, social and environmental determinants and 2) knowledge integration that evaluates the robustness and interpretation of scientific evidence derived from basic, clinical and population sciences. Summary: Cancer epidemiology is at the cusp of a paradigm shift–propelled by a need to accelerate the pace of translating scientific discoveries to impart population health benefits. While multi-institutional and technology-drive collaboration is happening, our evaluation of funded grants and published literature in the first decade of the 21st century provide concrete evidence that concerted efforts to incorporate other key elements that influence the future of cancer epidemiology are warranted for the discipline to meet the challenges of this changing landscape. Citation Format: Tram K. Lam, Christine Q. Chang, Scott D. Rogers, Muin J. Khoury, Sheri D. Schully. How can epidemiology become more effective in reducing the burden of cancer in the 21st century? An analysis of NCI-funded grants and the scientific literature. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 254. doi:10.1158/1538-7445.AM2014-254