Hamartomatous polyps - a clinical and molecular genetic study

Area of Science:

• Gastroenterology
• Clinical Genetics
• Oncology

Background:

• Hamartomatous polyps (HPs) are rare in adults but common in children, presenting with symptoms like rectal bleeding and abdominal pain.
• HPs are classified as juvenile polyps or Peutz-Jeghers polyps, with some individuals having hereditary hamartomatous polyposis syndromes (HPS) that increase cancer risk.
• Early diagnosis and surveillance are crucial for HPS patients, including juvenile polyposis syndrome, Peutz-Jeghers syndrome, and PTEN hamartoma tumor syndrome.

Purpose of the Study:

• To expand knowledge on the clinical course and molecular genetics of HPs and HPS.
• To investigate the attitudes of research participants towards receiving results from extensive genetic testing.
• To assess the clinical and genetic characteristics of HPs and associated syndromes.

Main Methods:

• Analysis of Danish national pathology data for juvenile polyp occurrence and demographics.
• Comprehensive literature review of hereditary hamartomatous polyposis syndromes.
• Next-generation sequencing of 26 HPS-associated genes in patients with single juvenile polyps.
• Semi-structured interviews to explore participant preferences regarding incidental genetic findings.
• Registry-based investigation of Peutz-Jeghers syndrome phenotype and genotype in Denmark.
• Genotype-phenotype description of juvenile polyposis syndrome patients with SMAD4 mutations.

Main Results:

• Juvenile polyps were found in 1772 patients in Denmark (1995-2014), with most patients being adults and only 1% meeting criteria for juvenile polyposis syndrome.
• Genetic screening of patients with one or few juvenile polyps did not identify definitively pathogenic variants, suggesting genetic screening is not indicated in these cases.
• A significant majority of research participants (61%) desired information on all incidental genetic findings.
• The prevalence of Peutz-Jeghers syndrome in Denmark is approximately 1 in 195,000, with a median age of diagnosis at 29 years and a high incidence of cancer.
• Patients with juvenile polyposis syndrome and SMAD4 mutations often exhibit symptoms of both juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia, necessitating multidisciplinary follow-up.

Conclusions:

• Genetic screening for HPS is not recommended for patients with isolated juvenile polyps.
• Hereditary hamartomatous polyposis syndromes require careful diagnosis and lifelong surveillance due to significant cancer predisposition.
• Research participants generally prefer comprehensive disclosure of genetic findings, including incidental results.
• Peutz-Jeghers syndrome and SMAD4-associated juvenile polyposis syndrome have diverse clinical presentations and require tailored management strategies.