Copy Number Variations among Renal Cell Neoplasms Exhibit Heterogenity Across Subtypes, Homogeneity within Subtypes and Correlated Changes in Transcriptional Profiles.
J Michael Krill-Burger, Maureen A Lyons, Christin M Sciulli, Lori A Kelly, Sheldon I Bastacky, Rajiv Dhir, Anil V Parwani, William A LaFramboise. University of Pittsburgh, PA
Background: DNA changes in a few gene loci have been identified in renal cell carcinomas (RCC), but the extent of familial and somatic DNA rearrangements underlying RCC is unknown. High density SNP arrays allow genome-wide interrogation of tumors at 1-2kb resolution to characterize copy number variations (CNV) and loss of heterozygosity (LOH). Application of molecular techniques to renal neoplasms may reveal DNA changes correlated with morphological differences and clinical behavior as well as provide new discriminants for tumors difficult to classify by current methods.
Design: High-density SNP analysis (Affymetrix 6.0) and whole genome expression assays (Affymetrix exon arrays) were performed on DNA and RNA obtained from frozen renal tumors (n=18) plus “adjacent normal” renal tissue (n=5) and an in house reference library of normal tissue (n=17). Samples included papillary, oncocytoma, chromophobe and conventional specimens classified independently by 3 pathologists.
Results: Individual RCC tumors contained as few as 8 (papillary RCC) and as many as 4917 (chromophobe RCC) CNV segments. Adjacent normal renal tissue exhibited 10 to 97 CNV changes compared to donor normal specimens. No significant differences in global CNV numbers and segment lengths were detected among tumor classes (mean+/-S.E.: 945+/-358) although they were consistently higher than adjacent normal tissue (39+/-16 CNV segments). No CNV region was common to all RCCs with highest overlap comprising a 26kb segment at 15q11.2 found in 39% of RCC samples. However, common CNV segments were identified in individual RCC subtypes ranging from 2 amplifications present in all 4 oncocytomas to 212 amplifications found in 4 of 5 papillary RCCs. Whole genome expression studies demonstrated that significant changes in levels of mRNA and microRNA transcripts located within CNV segments correlated with copy number changes. Significant changes occurred in critical gene families associated with tumorigenesis including DNA repair (BRCA1, ATAD5, XRCC2), cell cycling (GRB2, ANLN, BOD1) and transcription regulation (FOXI1, RNF213).
Conclusions: These data reveal extensive global heterogeneity of CNV rearrangements in RCC including copy number variations in adjacent normal renal tissue. However, there was consistent, correlated overlap of CNV changes and encoded mRNA transcripts within individual RCC subtypes suggesting the presence of common diagnostic molecular signatures and distinct pathways that may serve as novel therapeutic targets for future studies.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer
Monday, February 28, 2011 1:00 PM
Poster Session II # 233, Monday Afternoon