Genome-wide amplification and allelotyping of sporadic pituitary adenomas identify novel regions of genetic loss.
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.
Simpson
D J
DJ
Centre for Cell and Molecular Medicine, School of Postgraduate Medicine, Keele University, North Staffordshire Hospital, Stoke-on-Trent, United Kingdom.
Bicknell
E J
EJ
Buch
H N
HN
Cutty
S J
SJ
Clayton
R N
RN
Farrell
W E
WE
D000236:Adenoma / Q000235:genetics*; D000483:Alleles; D014408:Biomarkers, Tumor / Q000235:genetics; D002869:Chromosome Aberrations; D002874:Chromosome Mapping / Q000379:methods; D015331:Cohort Studies; D017353:Gene Deletion; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D021141:Nucleic Acid Amplification Techniques / Q000379:methods*; D010911:Pituitary Neoplasms / Q000235:genetics*
D014408:Biomarkers, Tumor