A New Study Links XRCC2 Mutations to Cisplatin Resistance in Testicular Cancer
Whole-exome sequencing of testicular germ cell tumours
A major research study has uncovered several new genetic mutations that could drive testicular cancer and also identified a gene which may contribute to tumours becoming resistant to platinum chemotherapy. The study is the first to use whole-exome sequencing technology to explore in detail testicular germ cell tumours, which make up the vast majority of testicular cancers and are the most common cancers in young men.
The study was led by scientists at The Institute of Cancer Research, London, UK and funded by the Movember Foundation. The findings are published in the Nature Communications on 22 January 2015. The study examined tumour samples from 42 patients with testicular cancer treated at the Royal Marsden NHS Foundation Trust.
The researchers uncovered that the mutation rate is uniformly low in all of the tumours as compared with common cancers, consistent with the embryological origin of testicular germ cell tumours. In addition to expected copy number gain of chromosome 12p and mutation of KIT, they identified recurrent mutations in the tumour suppressor gene CDC27 (11.9%).
Copy number analysis revealed recurring amplification of the spermatocyte development gene FSIP2 (15.3%) and a 0.4 Mb region at Xq28 (15.3%). Two treatment-refractory patients are shown to harbour XRCC2 mutations, a gene strongly implicated in defining cisplatin resistance.
Although generally testicular cancer responds well to treatment, resistance to platinum-based chemotherapy is associated with a poor long-term survival rate. The research provides a clue to why around 3% of patients develop resistance to platinum chemotherapy, as well as new insights into testicular germ cell tumours generally.
Dr Clare Turnbull, Team Leader in Predisposition and Translational Genetics at The Institute of Cancer Research, London, and Honorary Consultant in Clinical Genetics at The Royal Marsden NHS Foundation Trust, said: "We now need additional studies with a larger number of patients, focusing in particular on platinum-resistant tumours, to help our discoveries lead to new options for those unlucky men whose cancer progresses in spite of the best available treatments."
Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said: "This study has used the latest DNA sequencing technologies to provide a window into the development of testicular cancer, and reveals some potentially important clues as to how the disease could be treated more effectively. Knowing which are the key genes driving a cancer's development or helping it dodge the effects of chemotherapy is crucial to help us use existing drugs more effectively and to design the next generation of drugs for personalized medicine."