Copy number variations alter methylation and parallel IGF2 overexpression in adrenal tumors
journal contributionposted on 03.09.2020, 11:01 by Helene Myrtue Nielsen, Alexandre How-Kit, Carole Guerin, Frederic Castinetti, Hans Kristian Moen Vollan, Catherine De Micco, Antoine Daunay, David Taieb, Peter Van Loo, Celine Besse, Vessela N Kristensen, Lise Lotte Hansen, Anne Barlier, Frederic Sebag, Jörg Tost
Overexpression of insulin growth factor 2 (IGF2) is a hallmark of adrenocortical carcinomas and pheochromocytomas. Previous studies investigating the IGF2/H19 locus have mainly focused on a single molecular level such as genomic alterations or altered DNA methylation levels and the causal changes underlying IGF2 overexpression are still not fully established. In the current study, we analyzed 62 tumors of the adrenal gland from patients with Conn's adenoma (CA, n=12), pheochromocytomas (PCC, n=10), adrenocortical benign tumors (ACBT, n=20), and adrenocortical carcinomas (ACC, n=20). Gene expression, somatic copy number variation of chr11p15.5, and DNA methylation status of three differential methylated regions of the IGF2/H19 locus including the H19 imprinting control region were integratively analyzed. IGF2 overexpression was found in 85% of the ACCs and 100% of the PCCs compared to 23% observed in CAs and ACBTs. Copy number aberrations of chr11p15.5 were abundant in both PCCs and ACCs but while PCCs retained a diploid state, ACCs were frequently tetraploid (7/19). Loss of either a single allele or loss of two alleles of the same parental origin in tetraploid samples resulted in a uniparental disomy-like genotype. These copy number changes correlated with hypermethylation of the H19 ICR suggesting that the lost alleles were the unmethylated maternal alleles. Our data provide conclusive evidence that loss of the maternal allele correlates with IGF2 overexpression in adrenal tumors and that hypermethylation of the H19 ICR is a consequence thereof.
DNA methylationH19IGF2adrenocortical tumorscancercopy number analysisimprintingpheochromocytomastetraploidyAdrenal Gland NeoplasmsAdrenocortical AdenomaAdultAgedAllelesCarcinomaChromosomes, Human, Pair 11DNA MethylationFemaleGene DosageGene Expression Regulation, NeoplasticGenomic ImprintingGenotypeHumansInsulin-Like Growth Factor IIMaleMiddle AgedNeoplasm ProteinsPheochromocytomaPloidiesPolymorphism, Single NucleotideUp-RegulationVan Loo11 Medical and Health Sciences06 Biological SciencesOncology & Carcinogenesis