Updated American College of Gastroenterology guidance strongly recommends germline multigene panel testing (MGPT) for patients with at least 20 lifetime colorectal adenomas and suggests it for those with 10 to 19. The guideline was published in the American Journal of Gastroenterology.
“This is a timely guideline given the increasing use of MGPT in patients with or at risk for hereditary cancer,” corresponding author Carol A. Burke, MD, MACG, of the Department of Gastroenterology, Hepatology, and Nutrition at Cleveland Clinic, and the Director of Hereditary Polyposis in the Weiss Center in the Department of Colorectal Surgery at the clinic, told GI & Hepatology News. It addresses who should undergo testing and how to manage affected patients and families, she said.
The eight-member writing group — five gastroenterologists with hereditary polyposis expertise, two methodologists, and a medical librarian — searched the literature through January 2025 and issued [12] graded recommendations, three of them strong, along with 31 key concept statements that were not graded.
According to Dr. Burke and her fellow guideline panel members, large studies found a disease-causing gene variant in 12.3% to 20.5% of patients with 20 to 99 lifetime adenomas and 5.3% to 11.3% of those with 10 to 19 adenomas.
For patients with 10 to 19 adenomas, testing is favored in those younger than 60 or with a personal or first-degree family history of colorectal cancer, and “may reasonably be deferred” in older patients without such history, the panel wrote. The evidence is insufficient to support an age-specific cutoff, according to the guideline.
The panel debated adding an age cutoff for testing at 10 to 19 adenomas but did not, Dr. Burke said. She cited a large U.S. commercial lab study that found a detection rate at or above 5% at any age and adenoma number. “We did not impose the restriction and acknowledge the limitations to the currently available evidence,” she said.
The guideline advises that panels include at least 17 genes linked to polyposis and inherited cancer syndromes. It advises further evaluation for patients whose earlier negative testing did not include those genes, whose personal or family cancer history has changed, or who were tested before 2013, with referral to a hereditary cancer specialist. Patients with 20 or more adenomas and uninformative results should be considered for referral to weigh adenomatous polyposis coli (APC) mosaicism testing case by case, according to the guideline.
The panel also strongly recommends APC gene testing for patients with signs linked to familial adenomatous polyposis (FAP). These include desmoid tumors, a rare type of thyroid cancer called cribriform-morular thyroid carcinoma, specific retinal abnormalities in both eyes or in multiple areas, and hepatoblastoma.
For patients with a harmful APC gene variant, or who may have classic FAP but have not been tested, the guideline advises a first colonoscopy between ages 10 and 15, followed by another every one to three years. For attenuated FAP and MUTYH-associated polyposis (MAP), it advises starting colonoscopy between ages 18 and 20 and continuing every one to three years, depending on the number, size, and histology of polyps found. For rarer syndromes, the guideline advises referral to an expert center, citing their rarity, evolving cancer risks, and need for multispecialty care. These include polymerase proofreading-associated polyposis and NTHL1-, AXIN2-, MSH3-, MLH3-, and MBD4-associated syndromes.
The guideline calls colectomy the cornerstone of colorectal cancer risk reduction in FAP. For patients with FAP who need surgery and have more than 20 rectal adenomas, the panel suggests total proctocolectomy with ileal pouch-anal anastomosis over total colectomy with ileorectal anastomosis. That suggestion applies to those who prioritize a marginal reduction in the risk of secondary proctectomy and rectal cancer over functional outcomes. For patients with 20 or fewer rectal adenomas, it suggests colectomy with ileorectal anastomosis to improve quality of life after surgery.
The panel emphasized that the rectal adenoma cutoff is “not immutable” and that the decision must be individualized. According to the guideline, surgical decisions should also consider cancer risk, rectal involvement, symptoms, desmoid risk, complications, bowel function, and psychosocial well-being. After either procedure, the guideline advises annual lower endoscopy, or more frequent exams with a high or advanced adenoma burden.
The panel strongly recommends against using medicines to prevent polyps in place of colectomy when surgery is needed. It suggests sulindac (150 mg twice daily) or celecoxib (400 mg twice daily) as an adjunct to endoscopic surveillance and polypectomy. The panel noted that the drugs can reduce colorectal polyps but that whether they lower cancer risk or delay surgery is unclear.
The guideline advises starting upper endoscopic surveillance at ages 20 to 25 in FAP and attenuated FAP and 30 to 35 in MAP, or earlier based on family history. The panel suggests surveillance that includes visualization of the duodenal papilla. It ties duodenal intervals to Spigelman stage, from every three to five years at stage 0 to every three to six months at stage IV.
For duodenal adenomas larger than 10 mm or with any high-grade dysplasia, the panel suggests treatment over surveillance alone. It says the choice between endoscopic and surgical resection should be individualized to duodenal and ampullary disease burden, patient preference, and access to an experienced therapeutic endoscopy team.
Gastric cancer, reported in 1.3% to 5% of Western patients with FAP or attenuated FAP, is becoming a leading cause of FAP-related cancer death among patients who have undergone colectomy, according to the guideline. The guideline lists the high-risk gastric features as carpeting of proximal polyposis, polypoid mounds, solitary polyps 10 mm or larger, and white mucosal patches. The panel suggests removing all antral polyps, gastric adenomas, polyps 10 mm or larger, proximal polypoid mounds, and white mucosal patches.
Only one of the 12 recommendations — against using chemoprevention in place of colectomy — rests on moderate-certainty evidence, the panel noted. The other 11 are based on low- or very low-certainty evidence, drawn largely from retrospective studies at high-risk centers. Evidence was especially limited for rare syndromes, surveillance intervals, long-term chemoprevention, and whether endoscopic treatment prevents cancer, according to the guideline.
Even so, “this is an important comprehensive resource that all digestive disease providers should review,” Dr. Burke said.
The guideline received no outside funding. Dr. Burke reported research support from Emtora/Biodexa and consulting fees from Lumabridge. Three coauthors also reported research support from Emtora/Biodexa, and one reported research support from Exact Sciences. Two reported consulting fees from Phathom Pharmaceuticals that they described as unrelated to the guideline.
Expert Insight
Dr. Burke spoke with GI & Hepatology News about the guideline.
In your opinion, what are the top concepts from this document?
Dr. Burke: The key concepts in the guideline include 1. how to identify individuals who should undergo germline genetic testing to uncover a hereditary adenomatous colorectal polyposis syndrome; and 2. the management strategies for individuals and families found to harbor a germline pathogenic variant for a hereditary adenomatous polyposis syndrome and approach to patients with colonic polyposis of unknown etiology (CPUE).
As you and your coauthors put together this guideline, was there a topic, or perhaps more than one, that caused more deliberation than usual?
Dr. Burke: There is disparity between countries regarding the use of germline MGPT in CPUE/multiple colorectal adenomas (MCRA)/idiopathic adenomatous polyposis (IAP). Many European countries restrict MGPT to specific populations based on number of adenomas and age or other clinical risk factors. However, the use of germline MGPT is relatively common in the U.S., covered by insurance when patients meet specific clinical criteria (or usually, for less than a few hundred dollars if not covered by insurance) and considered by most U.S. guidelines to be indicated for patient[s] with 10 or more cumulative lifetime adenomas regardless of age.
The evidence shows the yield of MGPT in patients with 10 to 19 cumulative adenomas is significantly less than individuals with 20 to 99 adenomas particularly when the individual is diagnosed with the syndrome over age 60. We deliberated over whether there is enough data to add an age cutoff for MGPT in CPUE. In the end, we did not add an age cutoff. Since the impact of finding a germline pathogenic variant (GPV) has substantial impact for the patient and family and the detection rate of a GPV for a hereditary colorectal polyposis or cancer syndrome in a large study from a commercial lab in the U.S. was at or above 5% at any age and adenoma number, we did not impose the restriction and acknowledge the limitations to the currently available evidence.
Did any aspect of your clinical practice change because of helping to form this guideline?
Dr. Burke: Yes. More patients in my practice that were clinically managed as FAP but without a detectable APC GPV are undergoing a discussion of the approach to mosaicism as a cause and appropriate patients are encouraged to consider mosaicism testing.
What additional research may be needed/what questions remain unanswered on this topic?
Dr. Burke: We need prospective studies on the clinical outcomes and evidence-based management [of] patients with CPUE/MCRA/IAP. Likewise, the cost effectiveness of MGPT in individual[s] with 10 to 19 versus 20 to 99 cumulative lifetime adenomas. We need trials which randomize FAP patients to different colonoscopy surveillance intervals. Prospective, multicenter, international studies which can inform providers on the noncancerous features in the duodenum, stomach, or colon which warrant surgical intervention.