Journal Article

Genomic landscape of platinum resistant and sensitive testicular cancers

Litchfield, Kevin, Levy, Max, de Castro, David Gonzalez, Shipley, Janet, Chowdhury, Simon, Proszek, Paula Z., Turnbull, Clare, Grist, Emily, Dudakia, Darshna, Huddart, Robert, Loveday, Chey, Cornish, Alex J., Houlston, Richard S., Bakir, Maise Al, Swanton, Charles, Holryod, Amy, Powles, Tom, O’Connor, Simon, Benton, Barbara, Santo, Flavia, Reid, Alison, Macintyre, Geoff, Broderick, Peter, Hiley, Crispin, Brenton, James D.

2020

Overview

While most testicular germ cell tumours (TGCTs) exhibit exquisite sensitivity to platinum chemotherapy, ~10% are platinum resistant. To gain insight into the underlying mechanisms, we undertake whole exome sequencing and copy number analysis in 40 tumours from 26 cases with platinum-resistant TGCT, and combine this with published genomic data on an additional 624 TGCTs. We integrate analyses for driver mutations, mutational burden, global, arm-level and focal copy number (CN) events, and SNV and CN signatures. Albeit preliminary and observational in nature, these analyses provide support for a possible mechanistic link between early driver mutations in RAS and KIT and the widespread copy number events by which TGCT is characterised. Most testicular germ-cell tumours are exquisitely sensitive to platinum-based chemotherapies, but little is known about why 10% are resistant. Here, the authors explore the potential underlying mechanisms by probing the genomic landscape of platinum-resistant disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45 / 45/23 / 49/61 / 631/67/1836 / 631/67/68 / Chemotherapy / Copy number / DNA Copy Number Variations / Drug Resistance, Neoplasm - drug effects / Exome Sequencing - methods / Genetic Predisposition to Disease - genetics / Genomics / Genomics - methods / Humanities and Social Sciences / Humans / Male / multidisciplinary / Mutation / Neoplasms, Germ Cell and Embryonal - drug therapy / Neoplasms, Germ Cell and Embryonal - genetics / Neoplasms, Germ Cell and Embryonal - metabolism / Organoplatinum Compounds - therapeutic use / Platinum / Platinum - therapeutic use / Proto-Oncogene Proteins c-kit - genetics / Proto-Oncogene Proteins c-kit - metabolism / ras Proteins - genetics / ras Proteins - metabolism / Science / Science (multidisciplinary) / Sequences / Signal Transduction - genetics / Testes / Testicular cancer / Testicular Neoplasms - drug therapy / Testicular Neoplasms - genetics / Testicular Neoplasms - metabolism / Tumors