The high-mobility group A2 (HMGA2) gene has a critical role in benign
tumors where it is frequently rearranged, and in malignant
tumors, where it is overexpressed in the absence of structural modification of the HMGA2 locus. By previous fluorescence in situ hybridization (FISH) and
reverse transcriptase PCR analyses on human
prolactin-secreting pituitary adenomas we detected rearrangement of the HMGA2 gene and amplification of its native region associated with activated expression. These data indicated a role for the HMGA2 gene in the development of human pituitary
prolactinomas, since they are consistent with the appearance of
prolactin/
growth hormone adenomas in transgenic mice overexpressing the HMGA2 gene. To assess a more general role for HMGA2 in pituitary
oncogenesis, we investigated HMGA2 amplification and expression in a panel of non-functioning
pituitary adenomas (NFPAs) which account for 25% of all
pituitary adenomas. We provide evidence that out of 18 NFPA
tumors tested, 12 expressed HMGA2, but, different from
prolactinomas, only in two cases the upregulation of the gene could be associated with amplification and/or rearrangement of the HMGA2 locus. Increased dosage of chromosome 12 was found in the expressing and non-expressing NFPAs, confirming that this sole event is insufficient to drive up activation of the HMGA2 gene. A role for chromosome 12 polysomy to promote structural instability of HMGA2 is confirmed, but the mechanism via
trisomy is less prevalent in the frequently diploid NFPAs than in the usually hyperdiploid
prolactinomas. Micro-rearrangements of HMGA2 gene not detectable by FISH analysis and/or sequence alterations could contribute to upregulation of HMGA2 gene in
pituitary adenomas of the NFPA subtype. However, it cannot be excluded that the HMGA2 overexpression may be due, in some NFPA patients, to the same, still mainly unknown, mechanisms responsible for HMGA2 overexpression in malignant
neoplasias.