Hypoglycemia from IGF2 Overexpression Associated with Activation of Fetal Promoters and Loss of Imprinting in a Metastatic Hemangiopericytoma

• Published in: The journal of clinical endocrinology and metabolism 2009-07, Vol.94 (7), p.2226-2231
• Main Authors: Lawson, Elizabeth A., Zhang, Xun, Crocker, Jonathan T., Wang, Wei-Lien, Klibanski, Anne
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; DNA methylation; Endocrinopathies; Feeding. Feeding behavior; Fetus - metabolism; Fetuses; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation, Neoplastic; Genomic Imprinting; Hemangiopericytoma - genetics; Hemangiopericytoma - pathology; Humans; Hypoglycemia; Hypoglycemia - genetics; Immunohistochemistry; Insulin-like growth factor II; Insulin-Like Growth Factor II - genetics; Liver; Male; Medical sciences; Metastases; Metastasis; Middle Aged; Neoplasm Metastasis; Polymerase chain reaction; Promoter Regions, Genetic; Promoters; Protein folding; RNA, Long Noncoding; RNA, Untranslated - genetics; RNA, Untranslated - metabolism; Sequence analysis; Skin Neoplasms - genetics; Skin Neoplasms - pathology; Tumor suppressor genes; Tumors; Up-Regulation; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2009-0153

Context: 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. Patient and 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. IGF-2 overexpression associated with activation of fetal promoters and loss of imprinting in a case of non-islet-cell tumor hypoglycemia due to metastatic hemangiopericytoma.