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A Common Polymorphism Within the IGF2 Imprinting Control Region is Associated With Parent of Origin Specific Effects in Infantile Hemangiomas
brent schultz, MD1, Xiaopan Yao, PhD2, Yanhong Deng, MPH2, Milton Waner, MD3, Christopher Spock, MD4, Laura Tom, MD1, John Persing, MD2, Deepak Narayan, MD2.
1University of Washington, seattle, WA, USA, 2Yale University, New Haven, CT, USA, 3Vascular Birthmark Institute, New York, NY, USA, 4University of Miami, Miami, FL, USA.
Infantile hemangioma (IH) is the most common pediatric tumor. They begin as aggressive vascular masses but then spontaneously regress. This study identified potential predictors of growth and possible mechanisms of involution. These findings may be relevant to both the management of IH and potentially generalizable to oncologic processes.
29 tissue samples were obtained at the time of IH excision and subjected to protein/transcript quantitation as well as SNP analysis. Clinical correlations were made retrospectively between lesion size at the time of excision and SNP analysis. This was performed under an established IRB protocol at Yale Medical School.
Previous studies have demonstrated a six-fold decrease in the expression of Insulin Like Growth factor 2 (IGF2,) a known mitogen, from proliferative to regressing hemangiomas. This study extends that research by quantifying the expression of two known regulators of IGF2. The first is CTCF (Known as the Regulator of Imprinted Sites) that binds to a key regulatory region of IGF2 and blocks its expression. The second factor BORIS (Brother of the Regulator of Imprinted Sites) binds to the same region and likely upregulates IGF2 transcription. All samples tested regardless of clinical stage expressed BORIS--a known cancer testes gene. This places IH in the unique category of being the first non-malignant BORIS positive tumor. The relative level of CTCF to BORIS was predictive of clinical stage, particularly at the protein level. Furthermore, the difference between CTCF and BORIS mRNA strongly correlated with IGF2 transcript levels. This relationship was modified by the presence of a common C/T polymorphism within the key regulatory binding site for CTCF and BORIS in a parent of origin specific manor. Specifically, the paternal C bearing samples demonstrated an approximate 6-fold increase in slope compared to their paternal T bearing counterparts p = .05. The allele status of this binding site may affect more than IGF2 transcription alone. In a retrospective study of 29 patients, those bearing the T/T genotype grew at a significantly faster rate compared to all non T/T groups p = .0025.
Within the gamut of human tumors, IH is unique. Studying the pathogenesis of IH is an opportunity to compare dynamic molecular processes against an equally dynamic but predictable disease course. Central to these findings is that IH can now be classified as the first non-malignant BORIS positive tumor. A natural “dose response” curve of CTCF to BORIS can be used to explore the potential effects of these regulators across a gamut of molecular and clinical phenomena. This analysis revealed possible parent of origin specific effects of a common polymorphism at both the cellular and clinical levels. This genotype to phenotype analysis offers the first testable model that may explain much of the clinical variation of IH. If validated with prospective work, identifying high-risk genotypes, would obviate the need to wait for lesions to become aggressive and decrease the complications of delay. Furthermore, these findings may suggest new insights regarding CTCF and BORIS related functionality in both normal and malignant states.
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