Abstract 5334: Genome-wide copy number analysis reveals two novel loci for susceptibility to sporadic osteosarcoma
Authors: Porat Rinnat M. , Pasic Ivan , Shlien Adam , Golgoz Nalan , Andrulis Irene , Wunder Jay S. , Malkin David 
Published: June 2012

Abstract
Copy-number variants (CNVs) frequently overlap genomic regions that contain genes associated with cancer. In addition, copy number alterations (CNAs) often coincide with sites of CNVs and may arise through progression of CNVs. Osteosarcoma (OS), the most common human bone malignancy, can arise in familial or sporadic forms. While germline mutations of tumor suppressor genes have been implicated in some hereditary forms of OS, little is known about genetic changes that contribute to the etiology of sporadic OS. Using high-resolutation SNP/CNV arrays, we have observed a high global CNV frequency in patients with sporadic osteosarcoma. We hypothesized that these genomic alterations are linked to susceptibility to OS. Here we investigate whether CNAs in OS tumor DNA reflect extensive constitutional CNVs in OS patients and whether OS tumor CNAs arise by progression of constitutional CNVs in these patients.
Paired samples from blood and pre-therapy tumor biopsies of 44 OS patients were hybridized to Affymetrix GW 6.0 arrays and analyzed using Partek Genomics Suite and Nexus Copy Number™ software. Analysis focused on CNVs which fulfilled the following criteria: 1) absent from normal controls, 2) recurrent, 3) previously unreported, 4) mapped within or nearby known genes and 5) overlapped with paired tumour CNA. Regions identified in this analysis were validated as candidate regions by quantitative PCR.
Two candidate CNVs have been identified: a copy-number loss at 1q43 and a copy-number gain at 2p11.2. The copy number loss at 1q43 was present in DNA of 43% of the blood and 40% of tumor samples. 38% of the 1q43 deletions in the tumors were de novo events. This CNV is upstream of the centrosomal protein 170kDa gene (CEP170) which has been shown to maintain microtubule organization and cell morphology. As microtubule function is critical for proper chromosome segregation during cell division, copy-number change-driven dysregulation of CEP170 might be related to the characteristic genomic instability in OS. We are currently exploring this possibility via expression profiling. The copy-number gain at 2p11.2 was identified in 45% of the OS blood derived DNA and in 65% of those, the gain was also seen in matched tumor DNA. This CNV is in proximity to FLJ40330, a non-coding RNA, and to ribose 5-phosphate isomerase (RPI). A custom CGH array platform is currently being used to further characterize these loci on paired blood and tumor DNA samples from an additional cohort of OS patients.
These findings support the premise that excessive constitutional CNV is a hallmark of sporadic OS and may open new avenues for the discovery of novel specific CNVs and genes implicated in susceptibility to OS which may be of diagnostic and/or prognostic relevance.
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 5334. doi:10.1158/1538-7445.AM2011-5334