TY - JOUR
T1 - Histologic and molecular profile of pediatric insulinomas
T2 - Evidence of a paternal parent-of-origin effect
AU - Bhatti, Tricia R.
AU - Ganapathy, Karthik
AU - Huppmann, Alison R.
AU - Conlin, Laura
AU - Boodhansingh, Kara E.
AU - MacMullen, Courtney
AU - Becker, Susan
AU - Ernst, Linda M.
AU - Scott Adzick, N.
AU - Ruchelli, Eduardo D.
AU - Ganguly, Arupa
AU - Stanley, Charles A.
N1 - Publisher Copyright:
© 2016 by the Endocrine Society.
PY - 2016/3
Y1 - 2016/3
N2 - Context: Acquired insulinomas are rare causes of hyperinsulinemic hypoglycemia in children and are much less common than focal lesions of congenital hyperinsulinism. The latter are known to be associated with isodisomy for paternally transmitted ATP-sensitive potassium channel mutations on 11p15; however, the molecular basis for pediatric insulinomas is not well characterized. Objective: The purpose of this study was to characterize the histopathological and molecular defects in a large group of 12 pediatric insulinomas seen at The Children's Hospital of Philadelphia. Results: Twelve children with insulinomas were seen between 1971 and 2013, compared to 201 cases with focal congenital hyperinsulinism seen between 1997 and 2014. The age of insulinoma patients ranged from 4-16 years at the time of surgery. Features of MEN1 syndrome were present in five of the 12, including four cases with heterozygous mutations of MEN1 on 11q. Immunohistochemical analysis revealed nuclear loss of p57 staining consistent with loss of the maternal 11p15 allele in 11 of the 12 insulinomas, including all five MEN1-associated tumors. Imbalance of the paternal 11p allele was confirmed by single nucleotide polymorphism genotyping and methylation assays of the 11p imprinting control loci in four of five MEN1-associated tumors and six of seven sporadic insulinomas. In addition, single nucleotide polymorphism genotyping revealed extensive tumor aneuploidy beyond chromosome 11. Conclusions: These data indicate thatMEN1mutations aremorecommonin insulinomas in children than in adults. Aneuploidy of chromosome 11 and other chromosomes is common in both MEN1 andnon-MEN1insulinomas.Thenovel observation of a paternal parent-of-origin effect in allMEN1 and most non-MEN1 tumors suggests a critical role for imprinted growth-regulatory genes in the 11p region in the genesis of β-cell endocrine tumors in children.
AB - Context: Acquired insulinomas are rare causes of hyperinsulinemic hypoglycemia in children and are much less common than focal lesions of congenital hyperinsulinism. The latter are known to be associated with isodisomy for paternally transmitted ATP-sensitive potassium channel mutations on 11p15; however, the molecular basis for pediatric insulinomas is not well characterized. Objective: The purpose of this study was to characterize the histopathological and molecular defects in a large group of 12 pediatric insulinomas seen at The Children's Hospital of Philadelphia. Results: Twelve children with insulinomas were seen between 1971 and 2013, compared to 201 cases with focal congenital hyperinsulinism seen between 1997 and 2014. The age of insulinoma patients ranged from 4-16 years at the time of surgery. Features of MEN1 syndrome were present in five of the 12, including four cases with heterozygous mutations of MEN1 on 11q. Immunohistochemical analysis revealed nuclear loss of p57 staining consistent with loss of the maternal 11p15 allele in 11 of the 12 insulinomas, including all five MEN1-associated tumors. Imbalance of the paternal 11p allele was confirmed by single nucleotide polymorphism genotyping and methylation assays of the 11p imprinting control loci in four of five MEN1-associated tumors and six of seven sporadic insulinomas. In addition, single nucleotide polymorphism genotyping revealed extensive tumor aneuploidy beyond chromosome 11. Conclusions: These data indicate thatMEN1mutations aremorecommonin insulinomas in children than in adults. Aneuploidy of chromosome 11 and other chromosomes is common in both MEN1 andnon-MEN1insulinomas.Thenovel observation of a paternal parent-of-origin effect in allMEN1 and most non-MEN1 tumors suggests a critical role for imprinted growth-regulatory genes in the 11p region in the genesis of β-cell endocrine tumors in children.
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U2 - 10.1210/jc.2015-2914
DO - 10.1210/jc.2015-2914
M3 - Article
C2 - 26756113
AN - SCOPUS:84960908135
SN - 0021-972X
VL - 101
SP - 914
EP - 922
JO - Journal of clinical endocrinology and metabolism
JF - Journal of clinical endocrinology and metabolism
IS - 3
ER -