Pancreatic insulinomas in multiple endocrine neoplasia, type I knockout mice can develop in the absence of chromosome instability or microsatellite instability

Peter C. Scacheri, Alyssa L. Kennedy, Koei Chin, Meghan T. Miller, J. Graeme Hodgson, Joe W. Gray, Stephen J. Marx, Allen M. Spiegel, Francis S. Collins

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Multiple endocrine neoplasia, type I (MEN1) is an inherited cancer syndrome characterized by tumors arising primarily in endocrine tissues. The responsible gene acts as a tumor suppressor, and tumors in affected heterozygous individuals occur after inactivation of the wild-type allele. Previous studies have shown that Men1 knockout mice develop multiple pancreatic insulinomas, but this occurs many months after loss of both copies of the Men 1 gene. These studies imply that loss of Men 1 is not alone sufficient for tumor formation and that additional somatic genetic changes are most likely essential for tumorigenesis. The usual expectation is that such mutations would arise either by a chromosomal instability or microsatellite instability mechanism. In a study of more then a dozen such tumors, using the techniques of array-based comparative genomic hybridization, fluorescent in situ hybridization, loss of heterozygosity analysis using multiple microsatellite markers across the genome, and real time PCR to assess DNA copy number, it appears that many of these full-blown clonal adenomas remain remarkably euploid. Furthermore, the loss of the wild-type Men1 allele in heterozygous Men1 mice occurs by loss and reduplication of the entire mutant-bearing chromosome. Thus, the somatic genetic changes that are postulated to lead to tumorigenesis in a mouse model of MEN1 must be unusually subtle, occurring at either the nucleotide level or through epigenetic mechanisms.

Original languageEnglish (US)
Pages (from-to)7039-7044
Number of pages6
JournalCancer Research
Volume64
Issue number19
DOIs
StatePublished - Oct 1 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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