Sir John Burn Delivers Seminar on Prediction and Prevention of Colorectal Cancer in Patients with Lynch Syndrome
In July, Sir John Burn, M.D., Professor of Clinical Genetics at the Institute of Genetic Medicine in Newcastle University, United Kingdom, spent two days with DCEG staff and fellows as a Visiting Scholar.
His seminar, “Getting Ahead of Cancer: Prediction and Prevention,” was the cornerstone of his visit, hosted by Chief and senior investigator of the Laboratory of Translational Genomics, Ludmila Prokunina-Olsson, Ph.D. Sir John's animated lecture covered a wide spectrum of issues related to cancer genetics, both past and future. He presented new insights into the mechanisms and natural history of colorectal cancer associated with Lynch Syndrome and the longitudinal trials on protective effects of aspirin. He also presented efforts to build robust, international, annotated genetic databases and reflected on his important contributions to the International Society for Gastrointestinal Hereditary Tumours (InSiGHT), which he helped develop for inherited colorectal cancer; the Human Variome Project, a large scale effort to one day annotate all genes; and the BRCA Exchange, a demonstration project for the Global Alliance for Genomics and Health, designed to catalog and annotate BRCA1/BRCA2 genetic variants.
Sir John began his talk by explaining the role of mismatch repair (MMR) deficiency, which is characteristic of Lynch Syndrome, and how genome instability can have profound effects on cancer risk profiles—colorectal cancer, specifically. In healthy cells, the MMR system cleans up mutations that occur frequently with cell division. Cells that are MMR deficient, such as in Lynch Syndrome, create thousands of mutations and each of them can inactivate proteins by introducing frameshifts and stop codons, eventually inactivating tumor suppressor genes. Although MMR deficiency can be strongly associated with cancer risk, as in colorectal cancer, MMR-deficient cancers represent suitable targets for immunotherapy because these mutations create neoepitopes recognized by the immune system.
He noted that scientists have traditionally thought that MMR deficiency first manifests in polyps (adenoma), which then leads to cancer, but new research suggests that MMR deficiency precedes adenoma. Furthermore, a few studies have demonstrated that the immune system in some patients with MMR-deficient cancers may control carcinogenesis naturally by destroying cells generating nonsense peptides. “Removing adenomas, which is the current standard practice,” Sir John explained, “will not actually prevent cancer. On top of that, colonoscopies may be merely finding lesions that could potentially go away on their own.” Because the colonoscopy procedure poses risk, current clinical practice for these patients may need revision.
Sir John went on to discuss his research into the protective effect of aspirin on colorectal cancer risk among patients with Lynch Syndrome. In the Cancer Prevention Program 2 (CaPP2), he and his colleagues found that participants who took 600 mg of aspirin per day for two years experienced an over fifty percent reduced risk of cancer at 5 years. They also found that aspirin intake essentially negated the elevated cancer risk associated with obesity. Sir John hypothesized, “the inflammatory drive of obesity may increase cancer risk in people with Lynch syndrome but maybe aspirin is pulling it back.” Additional studies reported a delayed effect associated with aspirin use: greater risk reduction a decade or more after initiation. Sir John suggested that in these cases, aspirin may not merely reduce inflammation, but also encourage pro-apoptotic behavior in premalignant lesions, which could explain why the effect is not seen until much later. Sir John and his colleagues are now conducting a subsequent study, CAPP3, to better determine the ideal dose for risk reduction.
To facilitate collaboration among genetic researchers in colorectal cancer, Sir John and others initiated the creation of InSiGHT, an aggregated genetic database of variants in hereditary colorectal cancers. At an early meeting of the GA4GH, Sir John discussed with Dr. Harold Varmus, then NCI Director, an idea to first develop an international program for the iconic BRCA1 and BRCA2 genes, as a demonstration project that could be extended to others.
In addition to his lecture, Sir John visited with many investigators, genetic counselors, and fellows to discuss various topics including the future of whole-genome sequencing and genetic counseling, low and medium penetrance variants with actionable treatments, and much more. The division participated in two roundtable discussions entitled, “Classification of disease susceptibility variants” and “Cancer prevention – expectations and reality.” Fellows enjoyed a brown bag lunch with him, organized by Lauren Hurwitz, Ph.D., and Rouf Banday, Ph.D. “He was extremely personable,” Dr. Hurwitz said, “and his research was also very topical to my own on aspirin use for cancer prevention. Sir John pointed out that while it’s true that using aspirin may come with risks, there are also risks with other, well-accepted interventions like colonoscopy. This helped me reframe my thinking around cancer prevention.”
Overall, it was a successful visit, filled with lively, engaging scientific discussion.