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.
Kenneth Offit, MD, MPH
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 the
BRCA1 and BRCA2 genes just
a decade ago, many felt it premature
to introduce these predictive
molecular markers into clinical practice.
At the time, there were concerns
regarding perceived limitations of
cancer genetic tests, including the limited
accuracy of risk estimates associated
with mutations of BRCA (and
other susceptibility genes), the complex
technology needed for sequence
analysis of large genes, the unproven
options for cancer prevention and early
detection for mutation carriers, the
limited number of cancer genetic specialists,
and the potential for adverse
sequelae following cancer genetic testing.
The review by Peshkin and Isaacs
provides an excellent summary of the
progress over the past decade in addressing
these concerns. Nonetheless,
as will be summarized here, important
challenges remain in each of these