Abstract 661: Identification of epigenomic markers on chromosome 11 that distinguish between choroid plexus carcinoma (CPC) and papilloma (CPP).
Authors: Pienkowska Malgorzata , Choufani Sanaa , Lach Boleslaw , Merino Diana M. , Novokmet Ana , Tabori Uri , Gilbertson Richard , Malkin David 
Published: August 2014

Choroid plexus tumors are rare epithelial brain tumors occurring predominantly in early childhood.

Understanding molecular events leading to development and progression of these tumors is critical in determining patient treatment and increased survival.

Loss of heterozygosity (LOH) is a common alteration observed during carcinogenesis. To investigate somatic genetic abnormalities in different subtypes of choroid plexus cancers and identify LOH hotspots, we utilized SNP 6.0 arrays (Affymetrix). Allele specific copy number analysis of 25 CPCs and 31 CPPs using Chromosome Analysis Suite (Affymetrix) revealed much higher frequency of LOH events throughout the genome in CPCs (8.4/case) compared with CPPs (1.2/case). One LOH hotspot, neutral copy loss of heterozygosity on chromosome 11, was identified in most CPCs but in no CPPs. Chromosome 11 is known to harbor an imprinted cluster that has been associated with growth dysregulation and pediatric cancer. Both maternal (KvDMR1) and paternal (H19DMR) differentially methylated regions overlap this imprinting cluster. Therefore, we investigated whether the observed LOH is related to uniparental disomy (UPD). Bisulfite pyrosequencing on a subset of CPP and CPC were studied for DNA methylation at both H19DMR and KvDMR1. Our data showed a reverse correlation in the degree of DNA methylation between the 2 DMRs in CPCs and CPPs. These data correlate well with the concept of UPD identified through our SNP arrays. Next, we investigated whether the observed higher expression of insulin like growth factor (IGF2) in CPP compared to CPC is associated with DNA methylation aberrations at the imprinted control region (H19 DMR) on 11p15.5. We identified higher DNA methylation at the H19DMR in CPC compared to CPP. Increased activity of the IGF2 gene has been associated with many types of cancer. To investigate the mechanism of CPC distinct IGF2 expression we examined the expression levels of microRNAs (miRNAs). MicroRNAs are often found to be misregulated in human cancer, and they can act posttranscriptionally as either potent oncogenes or tumor suppressor genes. We studied expression of miR-675-3p, miR-483-3p as well as miR-125-a-3p associated with IGF2/H19 imprinted locus. By quantitative RT-PCR, both miR-675 and miR-125 were found to be more significantly upregulated in CPCs than in CPPs whereas miR-483 was expressed at very low levels in CPCs and in higher levels in CPPs compared with normal control tissues . Misregulation of miR-483 was positively correlated with IGF2 levels in both groups. Our data suggest that dysregulation of epigenetic mechanisms contribute to the molecular events leading to tumor development and progression in CPC and may eventually facilitate identification of new diagnostic markers for CPC, as well as new therapeutic targets for this aggressive, lethal tumor.

Citation Format: Malgorzata Pienkowska, Sanaa Choufani, Boleslaw Lach, Diana M. Merino, Ana Novokmet, Uri Tabori, Richard Gilbertson, David Malkin. Identification of epigenomic markers on chromosome 11 that distinguish between choroid plexus carcinoma (CPC) and papilloma (CPP). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 661. doi:10.1158/1538-7445.AM2013-661