Genome‐wide amplification and allelotyping of sporadic pituitary adenomas identify novel regions of genetic loss

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Abstract
Through the use of a candidate gene approach, several previous studies have identified loss of heterozygosity (LOH) at putative tumor‐suppressor gene (TSG) loci in sporadic pituitary tumors. This study reports a genome‐wide allelotyping by use of 122 microsatellite markers in a large cohort of tumors, consisting of somatotrophinomas and non‐functioning adenomas. Samples were first subject to prior whole genome amplification by primer extension pre‐amplification (PEP) to circumvent limitations imposed by insufficient DNA for whole‐genome analysis with this number of microsatellite markers. The overall mean frequency of loss in invasive tumors was significantly higher than that in their non‐invasive counterparts (7 vs. 3% somatotrophinomas; 6 vs. 3% non‐functioning adenomas, respectively). Analysis of the mean frequency of LOH, across all markers to individual chromosomal arms, identified 13 chromosomal arms in somatotrophinomas and 10 in non‐functioning tumors, with LOH greater than the 99% upper confidence interval calculated for the rate of overall random allelic loss. In the majority of cases, these losses were more frequent in invasive tumors than in their non‐invasive counterparts, suggesting these to be markers of tumor progression. Other regions showed similar frequencies of LOH in both invasive and non‐invasive tumors, implying these to be early changes in pituitary tumorigenesis. This genome‐wide study also revealed chromosomal regions where losses were frequently associated with an individual marker, for example, chromosome arm 1q (LOH > 30%). In some cases, these losses were subtype‐specific and were found at a higher frequency in invasive tumors than in their non‐invasive counterparts. Identification of these regions of loss provides the first preliminary evidence for the location of novel putative TSGs involved in pituitary tumorigenesis that are, in some cases, subtype‐specific. This investigation provides an unbiased estimate of global aberrations in sporadic pituitary tumors as assessed by LOH analysis. 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.