MEN1 gene mutation analysis of sporadic adrenocortical lesions

Int J Cancer. 1999 Jan 29;80(3):373-9. doi: 10.1002/(sici)1097-0215(19990129)80:3<373::aid-ijc7>3.0.co;2-b.

Abstract

To clarify the role of the MEN1 gene in the tumorigenesis of sporadic adrenocortical tumors, we performed a molecular study on 35 adrenocortical lesions including 6 hyperplasias, 19 adenomas and 10 carcinomas. Loss of heterozygosity (LOH) of the MEN1 gene was assessed by PCR using an intragenic (D11S4946) and 2 flanking microsatellite markers (D11S4936, PYGM) and/or fluorescence in situ hybridization (FISH) with a 40-kb cosmid probe containing the MEN1 gene. The complete coding sequence of the MEN1 gene was screened for mutations using non-radioactive, PCR-based single-strand conformation polymorphism (SSCP) analysis and MDE heteroduplex gel electrophoresis. PCR-LOH and FISH analyses performed in 29 tumors (PCR-LOH in 4, FISH in 17 and both in 8 tumors) revealed allelic deletion of the MEN1 locus in 8 (27.5%) and at 11q13 in 9 (31%) tumors. Furthermore, the frequency of LOH at 11q13 was significantly higher in adrenocortical carcinomas (60%) than in benign lesions (11%). Mutation analysis of tumor samples revealed 9 polymorphisms in 7 tumors (S145S, R171Q, R171Q together with L432L) but no mutations, with the exception of one adrenocortical adenoma. The latter tumor contained a somatic E109X stop codon mutation in exon 2 and a 5178-9G-->A splice mutation in intron 4, which was also detectable in various nontumorous tissues and blood indicative of a germ-line mutation. The patient, who had no clinical signs or family history of MEN1, later also developed a neuroendocrine carcinoma (atypical carcinoid) of the lung. Our findings indicate that inactivating mutations of the MEN1 tumor-suppressor gene appear not to play a prominent role in the development of sporadic hyperplastic or neoplastic lesions of the adrenal cortex and that the newly reported 5178-9G-->A splice mutation in intron 4 might cause a variant of the MEN1 phenotype.

MeSH terms

  • Adrenal Cortex / pathology
  • Adrenal Cortex Neoplasms / genetics*
  • Adrenocortical Adenoma / genetics
  • Adrenocortical Carcinoma / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Female
  • Humans
  • Hyperplasia / genetics
  • Loss of Heterozygosity*
  • Male
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Polymerase Chain Reaction
  • Polymorphism, Single-Stranded Conformational
  • Proto-Oncogene Proteins*

Substances

  • MEN1 protein, human
  • Neoplasm Proteins
  • Proto-Oncogene Proteins