In the July 2010 issue of GI & Hepatology News, Dr. Howard Levy reviewed a number of strategies for recognizing of hereditary colon cancer, specifically Lynch syndrome. At that time, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) working group had recommended universal molecular tumor testing.
The EGAPP recommendation was the first of several ensuing endorsements of universal tumor testing using immunohistochemistry (IHC) or microsatellite instability (MSI) analysis. For example, the AGA Guideline on Diagnosis and Management of Lynch Syndrome (Gastroenterology. 2015;149[3]:777-82) issued a strong recommendation for tumor testing. We have learned about reflexive BRAF or promoter hypermethylation testing and, in some cases, tumor sequencing for double somatic mutations to identify sporadic MSI-high cases. While tumor testing is widely endorsed and is cost effective, implementation and quality control still remain challenges in clinical practice.
In addition to widespread endorsement of tumor testing, there have been a number of important developments in our understanding of Lynch syndrome. A recent publication estimated the prevalence of mismatch-repair gene mutations associated with Lynch syndrome at 1 in 279. Cancer risks in Lynch syndrome are significantly elevated over the general population, and it has become clear that there are distinct risk estimates depending on the gene that is mutated. New risk prediction models, such as PREMM1,2,6, have improved test characteristics over Amsterdam and Bethesda criteria for identification of mutation carriers. The Colorectal Adenoma/Carcinoma Prevention Programme (CAPP) trials have shown that aspirin is chemopreventive in Lynch syndrome. Survival in Lynch syndrome patients who develop colorectal cancer is over 90% based on results from a prospective database. Immune checkpoint inhibitor therapy has been shown to be effective in treatment of metastatic MSI-high colorectal cancer including from Lynch syndrome patients. Immunotherapy has also shown to be effective in patients with biallelic mismatch repair deficiency (BMMRD), a childhood cancer syndrome characterized by brain and gastrointestinal tumors, among others.
Dr. Sonia S. Kupfer
Sonia S. Kupfer, MD, is assistant professor of gastroenterology, director of the Gastrointestinal Cancer Risk and Prevention Clinic at the University of Chicago, and an Associate Editor of GI & Hepatology News.
