A Common Polymorphism within the IGF2 Imprinting Control Region Is Associated with Parent of Origin Specific Effects in Infantile Hemangiomas.
Infantile hemangioma (IH) is the most common tumor of the pediatric age group, affecting up to 4% of newborns ranging from inconsequential blemishes, to highly aggressive tumors. Following well defined growth phases (proliferative, plateau involutional) IH usually regress into a fibro-fatty residuum. Despite the high prevalence of IH, little is known regarding the pathogenesis of disease. A reported six fold decrease in IGF2 expression (correlating with transformation of proliferative to involuted lesions) prompted us to study the IGF-2 axis further. We demonstrate that IGF2 expression in IH is strongly related to the expression of a cancer testes and suspected oncogene BORIS (paralog of CTCF), placing IH in the unique category of being the first known benign BORIS positive tumor. IGF2 expression was strongly and positively related to BORIS transcript expression. Furthermore, a stronger association was made when comparing BORIS levels against the expression of CTCF via either a percentage or difference between the two. A common C/T polymorphism at CTCF BS6 appeared to modify the correlation between CTCF/BORIS and IGF2 expression in a parent of origin specific manner. Moreover, these effects may have phenotypic consequences as tumor growth also correlates with the genotype at CTCF BS6. This may provide a framework for explaining the clinical variability seen in IH and suggests new insights regarding CTCF and BORIS related functionality in both normal and malignant states.
University of Washington, Division of Plastic Surgery, Seattle, WA, United States of America.
Brent
B
Schultz
Yale Center for Analytic Sciences at YSPH, New Haven, CT, United States of America.
Xiaopan
X
Yao
Yale Center for Analytic Sciences at YSPH, New Haven, CT, United States of America.
Yanhong
Y
Deng
Vascular Birthmark Institute, New York, NY, United States of America.
Milton
M
Waner
University of Miami Hospital, Miami, FL, United States of America.
Christopher
C
Spock
Division of Plastic Surgery, University of Washington, Seattle, WA, United States of America.
Laura
L
Tom
Yale Plastic and Reconstructive Surgery, New Haven, United States of America.
John
J
Persing
Yale Plastic and Reconstructive Surgery, New Haven, United States of America.
Deepak
D
Narayan
D000483:Alleles; D000076246:CCCTC-Binding Factor; D016022:Case-Control Studies; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D056426:Genetic Loci; D018392:Genomic Imprinting; D005838:Genotype; D006391:Hemangioma / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D016017:Odds Ratio; D010290:Parents; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic; D016896:Treatment Outcome; D014456:Ulcer / Q000235:genetics
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C456540:CTCFL protein, human; D004268:DNA-Binding Proteins; C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D012097:Repressor Proteins; D007335:Insulin-Like Growth Factor II