Copy number variations alter methylation and parallel IGF2 overexpression in adrenal tumors

    1. Jörg Tost15
    1. 1Laboratory for Functional Genomics, Fondation Jean Dausset – Centre d'Etude du Polymorphisme Humain (CEPH), Paris, France
      2Institute of Biomedicine, Aarhus University, Aarhus, Denmark
      3Endocrine and Metabolic Surgery Department, AP-HM La Conception, Marseille, France
      4Department of Endocrinology, AP-HM La Timone, Marseille, France
      5Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
      6Division of Surgery, Transplantation and Cancer Medicine, Department of Oncology, Oslo University Hospital, Oslo, Norway
      7The K G Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
      8Pathology Department, AP-HM La Timone, Marseille, France
      9Nuclear Endocrine Imaging and Treatment Department, AP-HM La Timone, Marseille, France
      10Cancer Research UK, London Research Institute, London, UK
      11Department of Human Genetics, University of Leuven, Leuven, Belgium
      12Genotyping Facilities, Centre National de Génotypage, CEA-Institut de Génomique, Evry, France
      13Department of Clinical Molecular Biology (EpiGen), University of Oslo, Ahus, Lokerod, Norway
      14Laboratory of Molecular Biology, AP-HM La Conception and CRN2M, Aix-Marseille University, Marseille, France
      15Laboratory for Epigenetics and Environment, Centre National de Génotypage, CEA-Institut de Génomique, Evry, France
    1. Correspondence should be addressed to J Tost; Email: tost{at}


    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.

    • Revision received 18 September 2015
    • Accepted 22 September 2015
    • Made available online as an Accepted Preprint 23 September 2015
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