Related Experiment Videos
Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome
S B Gruber1, M M Entius, G M Petersen
1Division of Molecular Medicine and Genetics, University of Michigan, Ann Arbor 48109, USA. sgruber@umich.edu
Insights
Peutz-Jeghers syndrome (PJS) is linked to mutations in the STK11 gene, which acts as a tumor suppressor. Hamartomas in PJS patients may be precursors to adenocarcinoma, with additional genetic events driving cancer progression.
Area of Science:
- Genetics
- Oncology
- Gastroenterology
Background:
- Peutz-Jeghers syndrome (PJS) is an inherited disorder characterized by polyps and increased cancer risk.
- Understanding the genetic basis of PJS is crucial for diagnosing and managing affected families.
Purpose of the Study:
- To identify the molecular basis of Peutz-Jeghers syndrome.
- To characterize the pathogenesis of gastrointestinal hamartomas and adenocarcinomas in PJS patients.
Main Methods:
- Linkage analysis and germ-line mutation screening of the STK11 gene.
- Loss of heterozygosity (LOH) analysis in PJS tumors (hamartomas and adenocarcinomas).
- Immunohistochemistry for p53 and analysis of microsatellite instability and K-ras mutations.
Main Results:
- Germ-line mutations in the STK11 gene were identified in all studied PJS families.
- Loss of heterozygosity (LOH) of 19p markers near STK11 occurred in 70% of PJS tumors, confirming STK11 as a tumor suppressor gene.
- LOH of 17p and 18q, and altered p53, were observed in adenocarcinomas but not hamartomas, suggesting late-stage events in cancer development.
Conclusions:
- STK11 is a tumor suppressor gene acting as an early gatekeeper in PJS, regulating hamartoma development.
- PJS hamartomas may be precursors to adenocarcinoma, with additional somatic mutations driving malignant progression.
- The molecular events in PJS-associated cancers share similarities with sporadic colorectal carcinomas.
Abstract:
Peutz-Jeghers syndrome (PJS) is an autosomal dominant condition characterized by intestinal hamartomatous polyps, mucocutaneous melanin deposition, and increased risk of cancer. Families with PJS from the Johns Hopkins Polyposis Registry were studied to identify the molecular basis of this syndrome and to characterize the pathogenesis of gastrointestinal hamartomas and adenocarcinomas in PJS patients. Linkage analysis in the family originally described by Jeghers in 1949 and five other families confirmed linkage to 19p13.3 near a recently identified gene responsible for PJS. Germ-line mutations in this gene, STK11, were identified in all six families by sequencing genomic DNA. Analysis of hamartomas and adenocarcinomas from patients with PJS identified loss of heterozygosity (LOH) of 19p markers near STK11 in 70% of tumors. Haplotype analysis indicated that the retained allele carried a germ-line mutation, confirming that STK11 is a tumor suppressor gene. LOH of 17p and 18q was identified in an adenocarcinoma but not in hamartomas, implying that allelic loss of these two regions corresponds to late molecular events in the pathogenesis of cancer in PJS. The adenocarcinomas showing 17p LOH also demonstrated altered p53 by immunohistochemistry. None of the 18 PJS tumors showed microsatellite instability, LOH on 5q near APC, or mutations in codons 12 or 13 of the K-ras proto-oncogene. These data provide evidence that STK11 is a tumor suppressor gene that acts as an early gatekeeper regulating the development of hamartomas in PJS and suggest that hamartomas may be pathogenetic precursors of adenocarcinoma. Additional somatic mutational events underlie the progression of hamartomas to adenocarcinomas, and some of these somatic mutations are common to the later stages of tumor progression seen in the majority of colorectal carcinomas.