Hypoglycemia from IGF2 overexpression associated with activation of fetal promoters and loss of imprinting in a metastatic hemangiopericytoma.
BACKGROUND
The mechanism of IGF2 overexpression in non-islet-cell tumor hypoglycemia is not understood.


OBJECTIVE
We investigated the imprinting control and promoter usage for IGF2 expression to identify a mechanism for increased IGF-II production in non-islet-cell tumor hypoglycemia.


METHODS
A patient with metastatic hemangiopericytoma was studied. Tissue from the original hemangiopericytoma, metastatic tumor, and uninvolved liver was analyzed for IGF-II immunohistochemistry. IGF2, a paternally imprinted gene, shares a control region with maternally imprinted H19, a putative tumor suppressor. IGF-II and H19 mRNA expression was compared in metastatic tumor and uninvolved liver by quantitative RT-PCR. Imprinting of IGF2/H19 genes and IGF2 promoter usage in metastatic tumor was investigated by RT-PCR and sequence analysis, and the methylation pattern in the IGF2/H19 imprinting control region was analyzed.


RESULTS
IGF-II protein expression was increased in metastatic tumor vs. uninvolved liver and original tumor. In the metastatic tumor, IGF-II mRNA was increased 60-fold, but H19 mRNA was comparable to uninvolved liver; loss of imprinting of IGF2, but not H19, was identified; no major change in methylation of the IGF2/H19 imprinting control regions was observed; and transcripts from four different IGF2 promoters were detected, compared to two in uninvolved liver.


CONCLUSIONS
IGF-2 overexpression, newly acquired in the metastatic tumor, was associated with loss of IGF2 gene imprinting and different promoter usage. The imprinting control mechanism governing the IGF2/H19 locus was intact, as evidenced by normal levels of H19, maintenance of H19 imprinting, and no major change in methylation of the imprinting control regions.
Lawson
Elizabeth A
EA
Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Zhang
Xun
X
Crocker
Jonathan T
JT
Wang
Wei-Lien
WL
Klibanski
Anne
A
D005333:Fetus / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D018392:Genomic Imprinting; D006393:Hemangiopericytoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007003:Hypoglycemia / Q000235:genetics*; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D015854:Up-Regulation
C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D007335:Insulin-Like Growth Factor II