Abstract 3460: Genome-wide copy number analysis reveals novel somatic mutations associated with choroid plexus tumorigenesis

Abstract

Abstract Choroid plexus carcinomas (CPCs) are aggressive pediatric neoplasms accounting for less than 1% of brain tumors, but representing more than 10% of brain tumors in children under 1 year of age. CPCs are frequently observed in the context of the Li-Fraumeni Syndrome (LFS), yet this association has not been fully elucidated. The genetic mechanisms leading to this disease are poorly understood; however, we have recently demonstrated that TP53 status and total structural variation are correlated with tumor subtype and clinical outcome in choroid plexus tumor (CPT) patients, distinguishing between individuals with CPC and choroid plexus papilloma (CPP), a benign tumor with a more favorable prognosis. We set out to characterize genomic regions in which copy number variation and gene expression changes are uniquely associated with CPC tumors in order to identify genes that may serve as markers in tumor diagnosis and prognosis. DNA and RNA from 59 choroid plexus tumors (CPC, n=29 and CPP, n=30) and two samples of normal choroid plexus tissue were obtained from a multi-institutional tissue and clinical database. We conducted high-resolution copy number alteration (CNA) and gene expression analysis for each tumor sample using highly dense microarrays (Affymetrix SNP 6.0 and Exon 1.0 ST array, respectively). DNA microarray data was segmented using a Hidden Markov Model (HMM) approach. Statistical analysis was carried out using Partek Genomics Suite in which CNAs and gene expression changes between CPC, CPP, and normal choroid plexus samples were contrasted. We identified 14 CPC-unique loci harboring CNAs with corresponding gene expression changes (p>0.05). We observed that CNAs were found at loci where cancer genes with well-characterized oncogenic functions have been previously identified (1p13.2, 1p13.3, 1p21.3, 1p22.1 and 5q13.3). Furthermore, more than 90% of tumors with copy number alterations and expression changes at these five loci also harbored mutant TP53. These observations suggest involvement of several genes in the malignant progression of CPCs, which may help elucidate the aggressiveness and poor clinical outcome of this tumor subtype compared to the more favorable CPP. Further analysis of CNAs and expression at these loci in the context of TP53 mutations, will provide a more refined genetic profile that will facilitate diagnosis of CPTs and aid in predicting patient outcome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3460. doi:10.1158/1538-7445.AM2011-3460