Genetic screens detect 'hypermutated' prostate cancers

Sequencing tissue samples from patients with deadly forms of prostate cancer has revealed previously undefined, drug-resistant tumour types that are ten times more mutated than other varieties, report researchers. The findings could help scientists develop screening methods and treatments specific to these 'hypermutated' forms of the disease.

'We don't know the cause of these hypermutated tumours, but the frequency of the mutations suggests these tumours might evolve very rapidly to develop resistance to therapies', said Dr Peter Nelson from the Fred Hutchinson Cancer Research Center in Seattle, USA.

For the study, published in the journal Proceedings of the National Academy of Sciences, the researchers sequenced the exomes (the parts of the DNA that code for proteins) of 23 prostate cancers grown in immunodeficient mice, of which 16 had originated as lethal metastatic cancers, and three as high-grade forms of the disease in humans.

The team found unexpected results; three of the prostate cancer genomes displayed much higher mutation frequencies than tumours derived from other tumour samples — in the region of 2,000 to 4,000 novel coding variants per exome. 'That was very surprising and unusual', said Dr Nelson.

After comparison of treatment-resistant and non-resistant versions of these tumours, the researchers saw that the mutations were in the Wnt pathway. This is a network of proteins known for their role in cancer development and progress, which could help future research into why some prostate cancers are resistant to drugs.

Co-author Dr Jay Shendure said: 'The mutations underlying the progression of prostate cancer to an advanced state have been understudied to date. Although further work is necessary, our hope is that identifying the genes in which these mutations occur will facilitate biological insights and the development of new therapeutic strategies'.