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Analysis of genetic and phenotypic heterogeneity in juvenile polyposis
K Woodford-Richens1, S Bevan, M Churchman
1Molecular and Population Genetics Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, UK.
Insights
Genetic mutations in PTEN and PTCH are unlikely to cause juvenile polyposis syndrome (JPS). However, DPC4 (SMAD4) gene mutations are found in a proportion of JPS patients, indicating further genetic factors are involved.
Area of Science:
- Genetics
- Gastroenterology
- Oncology
Background:
- Juvenile polyposis syndrome (JPS) is a condition of gastrointestinal hamartomatous polyps with increased cancer risk.
- JPS diagnosis is challenging due to overlapping features with Cowden (CS), Bannayan-Ruvalcaba-Riley (BRRS), and Gorlin (GS) syndromes.
- Germline mutations in PTCH, PTEN, and DPC4 (SMAD4) genes are associated with GS, CS/BRRS, and JPS, respectively.
Purpose of the Study:
- To investigate the role of mutations in PTCH, PTEN, and DPC4 (SMAD4) genes in patients diagnosed with JPS.
- To differentiate JPS from other related genetic syndromes based on genetic markers.
Main Methods:
- Screening of 47 individuals from 15 families and 9 sporadic cases with JPS for germline mutations.
- Analysis focused on the PTCH, PTEN, and DPC4 (SMAD4) genes.
Main Results:
- No mutations were identified in the PTEN or PTCH genes among the JPS patients.
- Five distinct germline mutations in the DPC4 (SMAD4) gene were detected in a subset of JPS patients.
- No specific clinical features distinguished patients with DPC4 (SMAD4) mutations.
Conclusions:
- Mutations in PTEN and PTCH are improbable causes of JPS without features of CS, BRRS, or GS.
- Approximately 21% of JPS patients in this cohort carried DPC4 (SMAD4) mutations.
- The findings suggest significant genetic heterogeneity in JPS, with unidentified genetic factors contributing to the syndrome.
Background:
Juvenile polyposis syndrome (JPS) is characterised by gastrointestinal (GI) hamartomatous polyposis and an increased risk of GI malignancy. Juvenile polyps also occur in the Cowden (CS), Bannayan-Ruvalcaba-Riley (BRRS) and Gorlin (GS) syndromes. Diagnosing JPS can be problematic because it relies on exclusion of CS, BRRS, and GS. Germline mutations in the PTCH, PTEN and DPC4 (SMAD4) genes can cause GS, CS/BRRS, and JPS, respectively.
Aims:
To examine the contribution of mutations in PTCH, PTEN, and DPC4 (SMAD4) to JPS.
Methods:
Forty seven individuals from 15 families and nine apparently sporadic cases with JPS were screened for germline mutations in DPC4, PTEN, and PTCH.
Results:
No patient had a mutation in PTEN or PTCH. Five different germline mutations were detected in DPC4; three of these were deletions, one a single base substitution creating a stop codon, and one a missense change. None of these patients had distinguishing clinical features.
Conclusions:
Mutations in PTEN and PTCH are unlikely to cause juvenile polyposis in the absence of clinical features indicative of CS, BRRS, or GS. A proportion of JPS patients harbour DPC4 mutations (21% in this study) but there remains uncharacterized genetic heterogeneity in JPS.
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