Endocrine Abstracts (2002) 3 P121

High resolution allelotyping of adenomas identifies novel regions of genetic loss

DJ Simpson, HN Buch, EJ Bicknell, SJ Cutty, RN Clayton & WE Farrell

School of Post-graduate Medicine, University of Keele, North Staffordshire Hospital, Stoke-on-Trent, UK.

Candidate gene approaches have identified loss of heterozygosity (LOH) at putative tumour suppressor gene (TSG) loci in sporadic pituitary tumours. This study reports a high-resolution genome wide allelotyping in a large cohort of somatotrophinomas and non-functioning pituitary adenomas (NFA). Samples were first subjected to whole genome amplification by primer extension amplification (PEP) to circumvent limitation imposed by insufficient DNA for the whole genome analysis with 122 microsatellite markers. The overall frequency of LOH in invasive tumours was significantly higher than their non-invasive counterparts (7 vs 3% somatotrophinomas; 6 vs 3% NFA respectively). Analysis of the mean frequency of LOH, across all the markers to individual chromosomal arms, identified 13 chromosomal arms in somatotrophinomas and 10 in NFA, with LOH > the upper 99% confidence interval calculated for the rate of random allelic loss. In the majority of cases these losses were more frequent in invasive tumours suggesting these to be markers of tumour progression. Other regions showed similar frequencies of LOH in both invasive and non-invasive tumours implying these to be early changes in pituitary tumourigenesis. The genome wide studies also revealed losses frequently associated with an individual marker which in some cases were found at a higher frequency in invasive tumours. Identification of these regions of loss provides the first preliminary evidence for the location of novel TSG involved in pituitary tumourigenesis that are in some cases sub-type specific.

This investigation provides an unbiased estimate of global genetic aberrations in sporadic pituitary tumours as assessed by LOH analysis, and the identification of multiple 'hotspots' throughout the genome may be a reflection of an unstable chromatin structure that is susceptible to a deletion or epigenetic mediated gene silencing events.

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