[Show abstract][Hide abstract]ABSTRACT: Most tumor suppressor genes show a widespread pattern of expression, yet individuals with germline, heterozygous loss of function of such genes develop tumors in a restricted set of tissues. This paradox has generated a multitude of speculative hypotheses. The gene for multiple endocrine neoplasia type I (MEN1) encodes a ubiquitously expressed tumor suppressor of unknown function called menin. Humans and mice with germline, heterozygous loss-of-function mutations in the MEN1 gene almost always develop at least one endocrine tumor by late adulthood, and examination of those tumors invariably reveals loss of the wild-type allele. To investigate the paradox of tissue-specific tumor phenotype in MEN1, mice homozygous for an Men1 gene with exons 3-8 flanked by loxP sites were bred to transgenic mice expressing cre from the albumin promoter. This strategy allowed us to generate mice with homozygous deletion of the Men1 gene in liver, a tissue not normally predisposed to developing tumors in humans or mice with heterozygous MEN1 loss-of-function mutations. Livers that were completely null for menin expression appeared entirely normal and remained tumor free until late adulthood. These results argue against certain hypotheses previously proposed for the tissue specificity of tumor suppressor genes and provide insights to the mechanism of tissue specificity in MEN1.
Full-text available · Article · Dec 2004 · Mammalian Genome
[Show abstract][Hide abstract]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 Men1 gene. These studies imply that loss of Men1 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.
Full-text available · Article · Nov 2004 · Cancer Research