A recent cross-sectional study (PP Stanich et al. Clin Gastroenterol Hepatol 2019; 17: 2008-15, editorial 1942-44) identified a high frequency of genetic mutations among adults with at least 10 colonic polyps (cumulative burden of either adenomatous or hamartomatous).

This study had 3789 subjects who underwent multigene panel testing (MGPT) from 2012-16.

• All subjects had at least 14 CRC-associated genes tested: APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, TP53
• A subset had 3 more newly recognized polyposis genes: GREM1, POLD1, and POLE

Key findings:

• A mutation in at least 1 gene was found in 13.7%
• In those with fewer than 20 cumulative adenomas, 7.6% had a disease-associated genetic mutation with the majority (5.3%) being nonpolyposis CRC genes
• Younger patients, 18-29, were more likely to have mutations in any gene.  For example, among patients with 10-19 polyps, these younger patients had a mutation in one of these genes in 27.8%; this is more than double the rate in any other age group.
• Hamartomatous polyps, regardless of number, had a very high yield with genetic testing: 40% with 10-19 polyps and 72% with 20-99 polyps.

Limitations:

• There is a referral bias in that the population was derived from a testing laboratory (Ambry)
• In clinical practice, genetic testing frequently results in variants of unknown significance

My take: This study shows that genetic mutations are fairly frequent in patients with cumulative polyp burden of 10 or more, especially in younger age groups.  The surprising finding is the high frequency of nonpolyposis CRC genes.  Thus, in patients with adenomatous polyposis, testing beyond APC and MUTYH may be needed.

Related blog posts:

• Review: Polyposis in Pediatrics
• What I Like About ESPGHAN Familial Adenomatous Polyposis Guidelines These recommendations, however, suggest starting screening at 12-14 years.
• ESPGHAN Juvenile Polyposis Syndrome Recommendations  These recommendations are different in that they do not recommend EGD in the pediatric age group: “Surveillance of the upper GI tract in affected or at-risk JPS patients is not required in childhood or teenage years, unless there is unexplained anaemia or upper GI symptoms.”
• ESPGHAN Peutz-Jeghers syndrome Guidelines
• Are You Familiar with CMMR-D? The term CMMR-D refers to constitutional mismatch repair deficiency.  This occurs when an individual inherits two MMR gene defects (rather than one gene defect in Lynch syndrome); with CMMR-D screening recommendations include yearly endoscopic evaluation beginning at age 3 years or at diagnosis.
• Updated Guidelines on Genetic Testing/management for Hereditary GI Cancer Syndromes
• Update for Peutz-Jegher Syndrome
• Screenshots: Peutz-Jeghers Syndrome, Alcohol #1 for Liver Transplantation, Case report Fanconi Syndrome due to Tenofovir Alafenamid

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