Kenneth Offit, MD, MPH

In this article, we use a case-based approach to focus on the hereditary aspects of the most common GI cancers, including pancreatic, gastric, and colon cancer.

Genome-wide association studies (GWAS) have emerged as a new approach for investigating the genetic basis of complex diseases. In oncology, genome-wide studies of nearly all common malignancies have been performed and more than 100 genetic variants associated with increased risks have been identified. GWAS approaches are powerful research tools that are revealing novel pathways important in carcinogenesis and promise to further enhance our understanding of the basis of inherited cancer susceptibility. However, “personal genomic tests” based on cancer GWAS results that are currently being offered by for-profit commercial companies for cancer risk prediction have unproven clinical utility and may risk false conveyance of reassurance or alarm.

Approximately 6% of colorectal cancers can be attributed to recognizable heritable germline mutations. Familial adenomatous polyposis is an autosomal dominant syndrome classically presenting with hundreds to thousands of adenomatous colorectal polyps that are caused by mutations in the APC gene.

Following the discovery of theBRCA1 and BRCA2 genes justa decade ago, many felt it prematureto introduce these predictivemolecular markers into clinical practice.At the time, there were concernsregarding perceived limitations ofcancer genetic tests, including the limitedaccuracy of risk estimates associatedwith mutations of BRCA (andother susceptibility genes), the complextechnology needed for sequenceanalysis of large genes, the unprovenoptions for cancer prevention and earlydetection for mutation carriers, thelimited number of cancer genetic specialists,and the potential for adversesequelae following cancer genetic testing.The review by Peshkin and Isaacsprovides an excellent summary of theprogress over the past decade in addressingthese concerns. Nonetheless,as will be summarized here, importantchallenges remain in each of theseareas.

Rubinstein and colleagues provide an excellent review of mathematical models for estimating breast cancer risk, including the risk of carrying inherited mutations of BRCA1 and BRCA2. Since we and others reviewed early models to predict the likelihood of inherited susceptibility to breast cancer,[1] newer quantitative tools, most notably by Parmigiani and colleagues,[2] have been developed. These models have been made available on CD-ROM, over the Internet, and in other electronic versions that are accessible to most clinicians and researchers. These quantitative resources constitute useful and important aids in genetic counseling.

At the beginning of the 1997 International Union AgainstCancer (UICC) conference in Kobe, Japan, the speakers invoked Buddhist imagery to inspire the audience to embrace cancer genetics in the “battle” against “the enemy.” Asura, a figure with