Gastroenterologists should be skilled in recognition of patients with inherited risk of colorectal neoplasia.Fay Kastrinos, MD, presented a 49-year-old female who had more than 10 cumulative adenomas and a cecal adenocarcinoma on two colonoscopies, the first of which was performed for evaluation of rectal bleeding. Carol Burke, MD, reviewed the differential diagnosis of adenomatous polyposis (defined as >10 cumulative adenomas).
Germline syndromes include familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), and a number of rare germline syndromes. Lynch syndrome should be considered especially for carriers of pathogenic variants in MSH6 who can present with a polyposis phenotype, as well as in children with constitutional mismatch repair deficiency syndrome. Finally, polyposis can be due to smoking, familial clustering, or previous abdominal radiation called therapy-associated polyposis. Polyposis without a known cause is referred to as colonic polyposis of unknown etiology (CPUE).
Dr. Kastrinos reviewed the patient’s three-generation family history of a brother and mother with “polyps” and second-degree relatives with endometrial and colon cancer. Niloy Jewel Samadder, MD, presented on the role of taking a comprehensive family history, tumor tests for Lynch syndrome, selection of genetic test type, and risks, benefits, and alternatives of genetic testing. Dr. Samadder reviewed indications for germline genetic testing for colorectal neoplasia of which the patient met two criteria, namely colorectal cancer under age 50 and 10 or more cumulative adenomas.
The final section was presented by this author on multigene panel testing, in which multiple genes are sequenced simultaneously. This patient’s panel showed two pathogenic variants in the MUTYH gene consistent with MAP, a recessive polyposis syndrome typically with 10s-100 cumulative adenomas. The test also showed a variant of uncertain significance (VUS) which is not clinically actionable. Providers counseling patients on multigene panel testing should discuss the possibility of VUS results (especially in individuals of non-European descent), moderate penetrant genes for which management recommendations are uncertain, or unexpected findings in genes not associated with colonic neoplasia. Studies have shown that the prevalence of finding an inherited syndrome is increased at younger ages of disease onset.
Dr. Kastrinos summarized key points from the session, including hereditary colorectal cancer syndromes are not rare, red flags for inherited syndromes, include early onset colorectal neoplasia and/or numerous relatives with colorectal and other extra-colonic cancer, extended family history assessment is recommended, and genetic risk assessment and genetic testing with multigene panels is a process and should be personalized. The question and answer session was lively with discussion of cost as well as direct-to-consumer genetic testing.
Sonia Kupfer, MD, AGAF, is an associate professor in the section of gastroenterology, hepatology, and nutrition at the University of Chicago. She has no financial conflicts of interest. These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2021.