Journal of the National Cancer Institute Advance Access originally published online on December 30, 2008
JNCI Journal of the National Cancer Institute 2009 101(1):4-5; doi:10.1093/jnci/djn452
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© The Author 2008. Published by Oxford University Press.
EDITORIALS |
Building a Knowledge Base on Genetic Variation and Cancer Risk Through Field Synopses
Affiliation of authors: National Office of Public Health Genomics, Coordinating Center for Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA
Correspondence to: Ajay Yesupriya, MPH, National Office of Public Health Genomics, Centers for Disease Control and Prevention, 4770 Buford Highway Mailstop K-89, Atlanta, GA 30341 (e-mail address: ayesupriya{at}cdc.gov).
The number of assessed genetic associations has grown tremendously in the past few years (1), especially with the recent advent of genome-wide association studies (GWAS) (2). However, the nonreplication of findings across multiple studies remains a documented issue for human genome epidemiology, even in the GWAS era (3, 4). It has been recommended that systematic reviews including meta-analyses be conducted to assess or adjust for factors that may contribute to the nonreplication of research findings (5). However, meta-analyses still represent a small minority of the published articles on genetic associations and thus many frequently studied genetic associations have not been examined in meta-analyses (6). Indeed, Janssens et al. (7) recently found that only about half of genes included in genomic profiles sold by several companies to provide consumers with their risk of developing common diseases had undergone formal meta-analyses. This is a matter of concern given that the majority of the genetic associations in these meta-analyses had synthetic odds ratios that were not different from unity (7).
The Human Genome Epidemiology Network (HuGENet), a global collaboration of researchers working in the field of genetic epidemiology, has advocated a concerted approach to conducting systematic reviews of genetic associations (5). Originally, this effort focused on HuGE Reviews, which were designed to provide systematic reviews of specific candidate genetic associations including gene–gene and gene–environment interactions (8). To date, 72 HuGE reviews have been published and additional topics have been registered at the HuGENet Web site (http://www.cdc.gov/genomics/hugenet/). However, these reviews are part of a larger effort to conduct systematic reviews on genetic associations, and more than 800 meta-analyses are currently included in the HuGE Navigator database (9).
Recently, HuGENet collaborators recognized that integrating the evidence from GWAS and candidate gene studies depends on combined efforts in data collection, online publication, database development, and continuously updated data synthesis (5). In outlining a road map for reliable genetic epidemiology, HuGENet suggested that investigators organized into networks around common research interests should develop field synopses (5), that is, reports that would summarize the results of all genetic association studies for a particular genetic pathway, disease, or group of closely related phenotypes. Cumulative evidence for each genetic association would be summarized by meta-analysis, and its credibility would be graded according to interim guidelines (Venice guidelines) developed to assess the amount of evidence, the extent of replication, and protection from bias (10). The complete set of field synopses would be maintained online in continuously updated repositories providing a resource to the broader research and practice communities.
Twenty-seven networks have registered with HuGENet, thus creating a network of investigator networks (11) (http://www.dhe.med.uoi.gr/networklist.php), and field synopses have been developed for several diseases, for example, schizophrenia (12). Several methodological and practical challenges in developing field synopses have become apparent and were discussed in a recent HuGENet workshop (http://www.cdc.gov/genomics/hugenet/hugewkshp_jan08.htm).
In this issue of the Journal, Vineis et al. present the findings of the first HuGE field synopsis on cancer susceptibility, one developed by a network of investigators concerned with DNA repair genes and cancer (13). They examined 1123 associations of low-penetrant variants in DNA repair genes with cancer and classified at most three as having strong credibility. The data are maintained and updated in an online database at http://www.episat.org, which provides a ready resource for future meta-analyses and assessments of the cumulative evidence as additional studies are conducted. Although studies on cancer susceptibility constitute a sizable proportion of genetic epidemiological research, the disappointing fraction of reported associations that were deemed to have strong credibility in this study are consistent with a systematic review of 161 previously published meta-analyses and pooled analyses that found that only 13 of 344 gene-variant cancer associations (or fewer, depending on prior assumptions) were statistically significant (P < .05) and had a false-positive report probability less than 0.2 (14).
The identification of reliable genetic associations is fundamental to the translation of genomic research findings to clinical and public health applications (15). By synthesizing research findings and assessing cumulative evidence, field synopses can recognize the most credible genetic associations. Because of their scale, a sustainable approach to conducting these projects requires collaboration among researchers. Fourteen networks currently registered with HuGENet are concerned with genetic susceptibility to cancer. Researchers who would like to collaborate with these networks can find their contact information online at http://www.dhe.med.uoi.gr/networklist.php. Other networks interested in developing field synopses are invited to join HuGENet in this endeavor.
NOTES
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
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