Identification of molecular alterations in gastrointestinal carcinomas and dysplastic hamartomas in Peutz-Jeghers syndrome

Carcinogenesis. 2013 Jul;34(7):1611-9. doi: 10.1093/carcin/bgt068. Epub 2013 Feb 20.

Abstract

Peutz-Jeghers syndrome (PJS) is caused by mutations in the LKB1 gene. It is characterized by gastrointestinal polyposis and an increased cancer risk, mainly in the gastrointestinal tract. Mechanisms of PJS-associated carcinogenesis are unclear. We investigated the involvement of candidate genes and molecular pathways in PJS-associated gastrointestinal cancers and dysplastic hamartomas. Cases were selected from the Dutch PJS cohort. Available tissue was immunostained for phospho-S6, β-catenin, P53 and SMAD4. DNA was isolated from carcinoma tissue and dysplastic and non-dysplastic areas of hamartomas specifically. Mutation analyses were done for BRAF, KRAS and P53, and loss of heterozygosity (LOH) analyses for LKB1 and P53. Twenty-four of 144 patients (17%) developed 26 gastrointestinal malignancies at a median age of 49 years (interquartile range: 35-60). Eleven of 792 hamartomas (1.4%) of 9 patients were classified as dysplastic. LOH of LKB1 was detected in three of six (50%) carcinomas and in the dysplastic part of three of five (60%) hamartomas. Aberrant P53 expression was observed in 8 of 15 (53%) carcinomas. Six carcinomas with P53 overexpression harboured a P53 mutation, with loss of the remaining wild-type allele in four. Two hamartomas showing P53 overexpression in high-grade dysplastic foci harboured a P53 mutation with LOH. Loss of nuclear SMAD4 was observed in high-grade dysplastic foci of two of four (50%) hamartomas, in contrast to low-grade dysplastic foci (0/4) and non-dysplastic epithelium. Our findings suggest a role for mutant P53 in PJS-associated gastrointestinal carcinogenesis. Inactivation of transforming growth factor-β/bone morphogenetic protein signalling and complete loss of LKB1 might be involved in dysplastic transformation of gastrointestinal hamartomas specifically.

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • Adult
  • Alleles
  • Cohort Studies
  • DNA Mutational Analysis
  • Female
  • Gastrointestinal Neoplasms / genetics*
  • Gastrointestinal Neoplasms / pathology
  • Gene Expression Regulation, Neoplastic*
  • Germ-Line Mutation
  • Hamartoma / genetics*
  • Hamartoma / pathology
  • Humans
  • Immunohistochemistry
  • Loss of Heterozygosity
  • Male
  • Middle Aged
  • Netherlands
  • Pedigree
  • Peutz-Jeghers Syndrome / genetics*
  • Peutz-Jeghers Syndrome / pathology
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism
  • Transforming Growth Factor beta / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • SMAD4 protein, human
  • Smad4 Protein
  • TP53 protein, human
  • Transforming Growth Factor beta
  • Tumor Suppressor Protein p53
  • Protein Serine-Threonine Kinases
  • STK11 protein, human
  • AMP-Activated Protein Kinase Kinases