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03-10-2011 | Genetics | Article

'Hypermutated', treatment-resistant prostate cancer subtypes identified


Free abstract

MedWire News: Findings of a genome-wide analysis undertaken in mice reveal the existence of a "hypermutated" prostate cancer subtype that is resistant to treatment and comes from lethal human forms of the disease.

The results could lead to targeted cancer therapies for men with the most lethal forms of prostate cancer.

The researchers sequenced the DNA of 23 prostate cancers, 16 of which came from lethal metastatic tumors, and found three genomes that exhibited 2-4000 novel coding variants per genome, a substantially higher frequency of mutations than any other subtype.

"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 Peter Nelson from the Fred Hutchinson Cancer Research Center in Seattle, Washington, USA.

Nelson and colleagues also compared treatment-resistant and non-resistant forms of the disease and found that mutations in the Wnt pathway could potentially contribute to development of castration resistance (resistance to hormone therapy).

"Although recent studies have detailed the landscape of genomic alterations in localized prostate cancers... the genetic composition of lethal and advanced disease is poorly defined," writes the team in PNAS.

Analysis revealed 131 genes with novel nonsynonymous single-nucleotide variants (nov-nsSNVs) in two or more tumors.

However, the genomes of three of these prostate cancer tumors (LuCaP 58, LuCaP 73, and LuCaP 147, grafted onto immunodeficient mice), representing 15% of the total analyzed, had a significant 10-fold higher number of nov-nsSNVs than other tumors.

A comparison with a nonxenografted tumor confirmed that the hypermutator phenotype arose before the tumor's passage into mice, notes the team.

Nelson and co-workers suggest that a possible explanation for the large numbers of mutations seen in the three prostate cancer subtypes could lie in the acquisition of a mutator phenotype, in which alterations in DNA polymerase or DNA repair genes result in an accelerated rate of mutations.

One of the tumor types, LuCaP 58, had three such candidate genes in MSH6 - a gene known to promote mismatch repair and microsatellite stability.

Analysis of castration-sensitive and castration-resistant tumors showed that no genes recurrently mutated in castration-resistant tumors alone, however, the investigators found "significant enrichment" for genes participating in the Wnt pathway, including FZD6 (in LuCaP 23.1AI), GSK3B (in LuCaP 96AI), and WNT6 (in LuCaP 35V).

Co-author Jay Shendure (Unversity of Washington, Seattle, USA) concluded that: "Although further work is certainly necessary, our hope is that identifying the genes in which these mutations occur will facilitate biological insights and the development of new therapeutic strategies."

By Sarah Guy

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