Distinctive Mutational Spectrum and Karyotype Disruption in Long-term Cisplatin-treated Urothelial Carcinoma Cell Lines

Overview

Journal Sci Rep

Specialty Science

Date 2019 Oct 11

PMID 31597922

Citations 6

Authors

Margaretha A Skowron

Patrick Petzsch

Karin Hardt

Nicholas Wagner

Manfred Beier

Stefanie Stepanow

Matthias Drechsler

Harald Rieder

Karl Kohrer

Gunter Niegisch

Michele J Hoffmann

Wolfgang A Schulz

Affiliations

Soon will be listed here.

Abstract

The DNA-damaging compound cisplatin is broadly employed for cancer chemotherapy. The mutagenic effects of cisplatin on cancer cell genomes are poorly studied and might even contribute to drug resistance. We have therefore analyzed mutations and chromosomal alterations in four cisplatin-resistant bladder cancer cell lines (LTTs) by whole-exome-sequencing and array-CGH. 720-7479 genes in the LTTs contained point mutations, with a characteristic mutational signature. Only 53 genes were mutated in all LTTs, including the presumed cisplatin exporter ATP7B. Chromosomal alterations were characterized by segmented deletions and gains leading to severely altered karyotypes. The few chromosomal changes shared among LTTs included gains involving the anti-apoptotic BCL2L1 gene and losses involving the NRF2 regulator KEAP1. Overall, the extent of genomic changes paralleled cisplatin treatment concentrations. In conclusion, bladder cancer cell lines selected for cisplatin-resistance contain abundant and characteristic drug-induced genomic changes. Cisplatin treatment may therefore generate novel tumor genomes during patient treatment.

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