Abstract 3937: Comparative genomic hybridization reveals complex genomic changes in plasmacytoid urothelial carcinoma
Authors: Wach Sven , Ellmann Christina , Stoehr Robert , Weigelt Katrin , Goebell Peter J. , Kunath Frank , Taubert Helge , Hartmann Arndt , Wullich Bernd , Keck Bastian 
Published: August 2015

Introduction The WHO classification of 2004 defined several histologic subtypes of urothelial carcinoma (UC) such as plasmacytoid UC (PUC). Since this definition, molecular characterization of these different tumor types has gained increasing attention. For the majority of histologic variants, it seems that they are associated with an even worse clinical outcome than conventional UC. However, PUC in particular is reported to be associated with an aggressive clinical course and advanced disease at the time of diagnosis. Nevertheless, genomic characterization of PUC, which examined genomic imbalances and chromosomal aberrations, is still missing.

Material and Methods We analyzed formalin-fixed archival tissue of 25 PUCs using metaphase comparative genomic hybridization (CGH) for detecting genomic imbalances. Aberrant chromosomal regions were defined as characteristic when they were found in at least 20% of the tumors analyzed. Representative genes in aberrant chromosomal regions were additionally analyzed for copy number variations (CNV) using quantitative PCR to explore their possible roles in PUC carcinogenesis.

Results Chromosomal aberrations were detected in every PUC analyzed and the average number of aberrations was 10.24 (ranging from 1-15). Characteristic aberrations were gains on 1q (48%), 3p (20%), 6p (32%), 11q (72%), 15q (36%), 16q (44%), 17p (76%), 17q (88%), and 20q (88%) and losses on 2q (24%) 4p (36%), 4q (84%), 5q (44%), 6q (68%), 13q (20%), and Xq (52%). PCR based analysis of CNV for CCND1 (11q13) showed a deletion in 73% of the cases. CDH1 (16q22) was deleted in 72% and amplified in 5%. ERBB2 (17q12) displayed remarkably few copy number alterations, with only 14% showing an amplification. SNAI1 (20q13) showed reduced gene copy numbers in 59.1% of the cases, while no copy number gains were detected. FOXO3 (6q21) exhibited the lowest number of copy number alterations, with 9% of all cases showing an amplification.

Conclusions In PUCs, the frequency of aneuploidy and the complexity of genomic changes per tumor are greater than those described in conventional UC. The aberrations described in PUC involve the same regions that are associated with aggressive biological behavior in conventional UC. Gains on 11q, 17q, 17p and 20q and losses on 4q and 6q affect the majority of PUCs and seem to harbor important chromosomal regions for PUC carcinogenesis. Large-scale deletions on chromosome 9 were not detected. CNV analysis indicates heterozygous deletion of CDH1 as one underlying mechanism of loss of membranous E-cadherin in PUC. Loss of CCND1 and SNAI1 are common molecular features and could contribute to the aggressive biological behavior of PUC.

Acknowledgements This study was supported by a grant from the ELAN Funds of the University Hospital Erlangen to BK and RS.

Citation Format: Sven Wach, Christina Ellmann, Robert Stoehr, Katrin Weigelt, Peter J. Goebell, Frank Kunath, Helge Taubert, Arndt Hartmann, Bernd Wullich, Bastian Keck. Comparative genomic hybridization reveals complex genomic changes in plasmacytoid urothelial carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3937. doi:10.1158/1538-7445.AM2015-3937