Abstract 3894: Copy number alterations in urothelial carcinomas: Their clinicopathological significance and correlation with DNA methylation alterations

Abstract

Abstract Purpose: The aim of this study was to clarify the genetic backgrounds underlying the clinicopathological characteristics of urothelial carcinomas (UCs). Experimental Design: We analyzed copy number alterations by array comparative genomic hybridization analysis using a high-resolution (244K) oligonucleotide array, DNA methylation alterations on a genome-wide scale using bacterial artificial chromosome array-based methylated CpG island amplification, and DNA methylation status on C-type CpG islands using bisulfite modification in 49 samples of UCs of the urinary bladder, ureter and renal pelvis. The clinicopathological significance of copy number alterations and the correlations between alterations of copy number and those of DNA methylation were examined. Results: Losses of 2q33.3-q37.3, 4p15.1-q26 and 5q13.3-q35.2 and gains of 7p11.2-q11.23 and 20q13.11-q13.31 were correlated with higher histological grade, and gain of 7p21.2-p21.1 was correlated with deeper invasion. Losses of 6q14.1-q27 and 17p13-q11.1 and gains of 19q13.11-q13.12 and 20q13.12-q13.33 were correlated with lymph vessel involvement. Loss of 16p12.2-p12.1 and gains of 3q26.31-q29 and 20q13.2-q13.33 were correlated with vascular involvement. Losses of 5q14.1-q23.2, 6q14.1-q27, 8p22-p21.3, 11q13.5-q14.1 and 15q11.2-q22.2 and gains of 3q27.3-q29, 7p11.2-q11.22, 10p13-p12.33, 12q24.31 and 19q13.11-q13.2 were correlated with the development of aggressive non-papillary UCs. Losses of 1p33-p31.1, 2q22.1-q23.1, 10q11.23-q21.1 and 15q21.3 were correlated with tumor recurrence. Unsupervised hierarchical clustering analysis based on copy number alterations clustered UCs into three subclasses, clusters A, B1 and B2: copy number alterations associated with genome-wide DNA hypomethylation, regional DNA hypermethylation on C-type CpG islands associated with chromosomal losses, and genome-wide DNA hypo- and hypermethylation, were accumulated in clusters A, B1 and B2, respectively. Conclusions: There is a need to explore tumor-related genes that may encode potential therapeutic targets at chromosomal loci where copy number alterations are correlated with clinicopathological parameters reflecting the malignant potential of UCs. Chromosomal loci where copy number alterations are correlated with UC recurrence may be potential indicators of prognosis. Both genetic and epigenetic events appear to accumulate during urothelial carcinogenesis, reflecting the clinicopathological diversity and histological heterogeneity of UCs. 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 3894. doi:10.1158/1538-7445.AM2011-3894