Prevalence of Gene Mutations in Polyposis Varies by Adenoma Count.

Mutations in the APC gene but not the MUTYH gene increased with adenoma count.

Patients with classic familial adenomatous polyposis (FAP) — traditionally defined as 100 adenomas in the colorectum but sometimes including cases with <100 — usually have germline mutations in the adenomatous polyposis coli (APC) gene. However, biallelic mutations in the mutY homolog (MUTYH) gene can produce a nearly identical phenotype of multiple colorectal adenomas. To understand the relative contributions of these gene mutations to the adenomatous polyposis phenotypes, investigators examined the prevalence of each mutation and whether it varied by adenoma count and other clinical characteristics in 8676 patients who had undergone genetic testing.

For individuals with 1000 adenomas, 80% had a pathogenic APC mutation and 2% had a biallelic MUTYH mutation. The prevalence of APC mutation increased in patients with 1000 adenomas who were diagnosed at a younger age (e.g., 97% for patients aged 20 at diagnosis). For individuals with 100 to 999 adenomas, the prevalence of APC mutation declined to 56%, but remained about the same for biallelic MUTYH mutation (7%). For patients with 20 to 99 polyps, 10% had a pathogenic APC mutation and 7% had a biallelic MUTYH mutation. Patients with 20 to 99 adenomas who had a history of colorectal cancer in a first-degree relative had a higher prevalence of APC or MUTYH mutations than those without such a history (15% vs. 8%), but this association did not exist for patients with 1000 adenomas. For those with 10 to 19 adenomas, APC mutations were found in 5% and MUTYH mutations in 4%, and most mutation carriers did not have a family history of colorectal cancer.

Comment: An important finding to emphasize for endoscopists and genetics counselors is that 18% of patients with 1000 adenomas and one third of those with 100 to 999 adenomas did not have a mutation identified in either the APC or MUTYH genes by current genetic testing methods. This suggests either the need for better testing methods or the presence of mutations in undiscovered genes. Clinically, it means that any patient with >100 adenomas and negative genetic testing should be treated like a patient with FAP, and their first-degree relatives should be screened by endoscopy with a presumption of dominant inheritance.

Whether the authors’ proposed model to predict the probability of mutations can be applied to colonoscopic findings in routine practice is uncertain and should be tested further. The results are likely subject to referral bias and were not adjusted for gender (which affects adenoma prevalence) or smoking status. In my own practice, where there are numerous high-level adenoma detectors doing colonoscopy, we often see older male smokers with 10 adenomas. Do such patients need genetic testing? The answers to this and similar questions await the results of prospective studies.

Source: Journal Watch Gastroenterology



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