Comprehensive Genomic Analysis of Unilateral Retinoblastoma Tumors: Old Disease, New Clues. A. Ganguly¹, C. MacMullen¹, L. Swanson¹, S. Diskin², G. Grant², E. Rappaport³, G. Bunin⁴, C. Shields⁵, A. Meadows⁴, K. Nichols⁴. 1) Department of Genetics, University of Pennsylvania, Philadelphia, PA; 2) Department of Bioinformatics university of Pennsylvania; 3) Department of Pediatric Oncology Childrens Hospital of Philadelphia; 4) NAPCORE, CHOP; 5) Wills Eye Hospital, Philadelphia.
   Background Retinoblastoma (RB) is a childhood onset ocular tumor associated with compromised vision and death in many cases. Inactivation of both copies of the RB1 gene in a retinal cell is followed by additional genetic changes leading to tumor formation. It is known that inactivations of p53, p107/p130 in addition to pRb proteins are required to initiate RB formation in mice. However, in human RB tumors, TP53 mutations have not been observed. Methods Whole genome SNP based assays were performed on DNA isolated from a set of 25 sporadic, unilateral RB tumors and matched blood samples using Affymetrix 10K SNP-Chips. Gene expression analysis was performed using Affymetrix U133 V2.0 chips on a subset of 18 RB tumors to detect correlations with genomic amplification/loss. Results and Discussion The results confirmed previous observations and identified 2q33-37, 3p21, 3q25, 11q14, 11q23, 14q22-23, 15q26.3 and 20q13.12, as novel regions of amplification. In addition,1q21.1, 1q32.2 and 1q44, were identified as minimal regions of gain. RB tumor clusters were defined by presence/absence of loss of heterozygosity (LOH) of chromosome 13. The LOH in most cases was due to copy neutral events caused by mitotic recombination or non-disjunction. No correlation to age, gender or mutation at RB1 was observed. However, the gene expression profiles of tumors were variable. In particular, expression of genes present on 1q32 resulted in two clusters of RB tumors defined by ages of onset. Higher expression of MDM4(1q32) was observed among other genes. This observation is significant as MDM4 in conjunction with MDM2 have unique roles in modulating the level of p53. We will discuss the implications of this finding for novel therapeutic options targeting the MDM4/MDM2 molecules.