Whole-genome sequencing in bladder cancer

Ian's photo
Professor Ian Tomlinson

For the first time a team at the WTCHG, working with colleagues at Oxford’s CRUK Cancer Centre and elsewhere, has used high-depth, whole-genome sequencing to search for genetic variants in tumours of the bladder. The molecular markers they have uncovered could potentially offer clinicians a new way to classify early-stage tumours and make more accurate assessments of their patients’ prospects.

The study, reported in Nature Communications on 29 April, is part of WGS500, a collaboration between WTCHG, the Oxford BRC Genomic Medicine Theme and the technology company Illumina. Using whole-genome sequencing in 500 selected patients with a variety of hard-to-treat diseases, the collaboration is identifying new genes of interest that could potentially be drug targets or markers for improved diagnosis and prognosis.

Ian Tomlinson and his colleagues compared whole-genome sequences derived from bladder cancers removed from 14 patients, and compared them with whole-genome sequences of the same patients’ blood. This enabled them to distinguish variants patients had acquired as part of their genetic inheritance from somatic mutations that had arisen during the replication of cells in body tissues.

The WGS study detected the mutations that were already known to be drivers of bladder cancer. It also revealed damaging mutations in two further genes, subsequently confirmed in a larger sample of tumours. One of these genes, p21 (CDKN1A), showed up as a causal factor even when p53 or MDM2, which lie upstream in the same tumour suppression pathway, was also mutated.

The study also found that late-stage tumours were more likely to contain two or more populations of cells, or clones, with different genetic profiles, as well as containing more mutations overall and a higher number of chromosomal additions or deletions. ‘In principle, the identification of sub-clones with greater diversity or a higher burden of mutation within early-stage or low-grade tumours could identify lesions with a high risk of invasive progression’, says Tomlinson. ‘What we still don’t know is why CDKN1A  mutations drive the growth of bladder cancer, but almost no other tumours, and why they have an added effect even when p53 is mutated.’

J-B Cazier, SR Rao, CM McLean, AL Walker, BJ Wright, EEM Jaeger, C Kartsonaki, L Marsden, C Yau, C Camps, P Kaisaki, The Oxford-Illumina WGS500 Consortium, J Taylor, JW Catto, IPM Tomlinson, AE Kiltie, FC Hamdy. Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden, Nature Communications, 5, Article number: 3756, doi:10.1038/ncomms4756, 29 April 2014.