Molecular Evidence For A Parent Of Origin Effect In Pediatric Insulinomas

Insulinomas are well-differentiated pancreatic endocrine tumors that cause abnormal beta cell proliferation and hyperinsulinimic hypoglycemia. With an incidence of 2-4 cases per million per year, insulinomas are rare in adults and even less common in children. Since congenital focal hyperinsulinism, another developmental lesion, is associated with paternal isodisomy for the imprinted 11p15 locus, we sought to characterize the role of this region and of mutations in MEN1 on 11q13 in pediatric insulinoma cases. We identified 13 pediatric insulinoma cases, which is the largest pediatric series reported, and performed immunohistochemical analysis for the maternally expressed tumor suppressor marker p57 located in 11p15. Using blood and tumor DNA, we tested 9 candidate genes associated with congenital hyperinsulinism including ABCC8, KCNJ11 and the MEN1 tumor suppressor. We performed methylation analysis of imprint control regions (ICR) that included the paternally expressed IGF2 (ICR1) and maternally expressed CDKN1C (ICR2) located on 11p15 and genome-wide SNP array analysis with tumor DNA. MEN1 mutations were found in 4 cases and suspected in one (MEN1 group); all 5 tumors stained negative for p57 and were hypermethylated at ICR1 and hypomethylated at ICR2 indicating loss of the maternal allele. SNP arrays confirmed loss of heterozygosity (LOH) of entire chromosome 11 in 4 cases. Four out of the 6 remaining non-MEN1 cases also stained negative for p57; in confirmation, 2 of the 4 cases carried mosaic copy number abnormality of chromosome 11. SNP array data demonstrated extensive genome-wide aneuploidy in MEN1 and non-MEN1 cases; however interstitial changes were not present in any of the cases. Notably, MEN1 cases carried only entire chromosome changes, while non-MEN1 cases carried whole arm changes in addition whole chromosome changes. In conclusion, MEN1 mutations are more common in pediatric insulinomas than in adult insulinoma cases (40% in this study vs. 8% in adults). Compared to adult cases, our pediatric insulinoma cases had smaller sized tumors and a shorter median duration of symptoms, suggesting that these tumors are rapidly growing and that the most common chromosome gains and losses very likely represent early events in insulinoma development. Mechanistically, our data suggest that loss of p57 expression, in conjunction with loss of either MEN1 and/or additional imprinted genes on 11p, play a role in the pathogenesis of most insulinomas. In cases with a germ-line MEN1 mutation, we identified a previously unreported paternal parent-of-origin effect that is unique to pediatric insulinomas but not to other MEN1 endocrine tumors (e.g., prolactinoma, parathyroid adenoma). Since a congenital focal hyperinsulinism has a similar parent of origin effect this suggests a broader role for the imprinted locus, 11p15, in not just the pathogenesis of pediatric insulinomas but also in beta-cell replication. Citation Format: Arupa Ganguly, Tricia Bhatti, Karthik Ganapathy, Laura Conlin, Courtney MacMullen, Susan Becker, Eduardo Ruchelli, Charles Stanley. Molecular evidence for a parent of origin effect in pediatric insulinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3293. doi:10.1158/1538-7445.AM2015-3293