Renal Cell Tumors Share Common Type-Specific Copy Number Variations Identified Via SNP Arrays and Whole Genome Sequencing
William A LaFramboise, Sheldon I Bastacky, Anil V Parwani, Rajiv Dhir. University of Pittsburgh, Pittsburgh, PA
Background: Annual renal cell carcinoma (RCC) cases have increased steadily in the United States for 3 decades with diagnosis complicated by overlapping RCC tumor subclassifications. Differential diagnosis relies largely on morphological and immunohistochemical analysis of tissue specimens.
Design: Copy number variant (CNV) analysis was performed on 5 to 7 prototypical renal cell carcinoma (RCC) specimens per tumor classification (chromophobe, clear cell, oncocytoma, papillary 1, papillary 2) using high resolution SNP arrays (1.85 million probes) for comparison to a SNP database of 31 normal tissues created in our laboratory. Two additional papillary 2 specimens (blood and tumor) were subjected to post-hoc array analysis and whole genome sequencing using massively parallel next generation sequencing (Life Technologies: SOLiD4 platform).
Results: RCC samples exhibited diverse genomic changes within and across tumor types ranging from 106 CNV segments in a clear cell specimen to 2238 CNV segments in a papillary type 2 specimen. Despite the genomic heterogeneity, distinct CNV segments were common within each of 4 tumor classifications: chromophobe (7 segments), clear cell (3 segments), oncocytoma (9 segments), and papillary type 2 (2 segments). Shared segments ranged from a 6.1 Kb deletion among oncocytomas to a 208.3 Kb deletion common to chromophobes. Among common tumor type-specific variations, chromophobe, clear cell and oncocytomas comprised exclusively non-coding DNA. No CNV regions were common to papillary 1 specimens although there were 12 amplifications and 12 deletions in 5 of 6 samples. Three microRNAs and 12 mRNA genes had ≥ 98% of their coding region contained within CNV regions including multiple gene families (chromophobe: amylase 1A, 1B, 1C; oncocytoma: general transcription factor 2H2, 2B, 2C, 2D). Gene deletions involved in histone modification and chromatin remodeling affected individual subtypes (clear cell: SFMBT, SETD2; papillary 2: BAZ1A) as well as the collective RCC group (KDM4C). Fine mapping of chromosomes 9 and 14 using whole genome sequencing identified deletions in two regions (9p24.1, 14q13.2) concordant with changes identified in all papillary 2 specimens using SNP arrays.
Conclusions: The finding that 4 of 5 subclassifications of renal neoplasms shared common copy number variants was unexpected given the prevailing theory that cancers arise from disparate genomic changes that induce tumorigenesis. The genomic amplifications/deletions identified in each renal tumor type represent potential diagnostic and/or prognostic biomarkers.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 268, Tuesday Morning