by ecancer reporter Clare Sansom

NCRI Conference: Wednesday 7 November

The 2012 NCRI cancer conference ended with two plenary lectures with similar themes: the potential of high throughput genome sequencing to revolutionise both basic cancer biology and clinical oncology.

First to speak was Robert Bristow from Ontario Cancer Institute, Toronto, Canada.

Bristow explained that on presentation, prostate cancers can be divided into three broad categories: indolent, which require no treatment; intermediate; and metastatic, with a poor prognosis.

Sixty to eighty percent of the intermediate tumours are curable with surgery and/or radiotherapy; the difficulty is in identifying which these are.

Bristow is using whole genome sequencing and DNA arrays to investigate the genetic aberrations involved in prostate cancer recurrence.

Prostate biopsies were taken from 250 men whose cancers were graded “intermediate” with similar clinical characteristics, and who had been treated with radical prostatectomy and/or radiotherapy.

The level of genetic instability (mutations and copy number changes) in the cancer genomes varied by as much as 100x between samples.

Bristow described the very clear correlation he discovered between high genetic instability and poor prognosis by saying that “for every 1% increase in genetic instability there was a 1% increase in tumour failure”, and added that this was the most important prognostic factor.

Tumour tissue was also tested for hypoxia, which was also found to be a predictor of poor prognosis. Patients with hypoxic tumours that were also genetically unstable were least likely to respond to surgery or radiotherapy alone.

Prolonged hypoxia leads to a decrease in DNA repair by homologous recombination, and defects in DNA repair genes were also found in many of the tumours with high levels of genetic instability.

This suggested both that hypoxia and genetic instability were linked, and that PARP inhibitors might be a useful treatment for tumours with defects in DNA repair.

Bristow and his co-workers have now set up the MATADOR trial in which only patients with “intermediate grade” prostate cancer whose tumours are discovered after biopsy to be either hypoxic or genetically unstable are treated with PARP inhibitors alongside surgery or radiotherapy.

The final plenary of the conference was given by William Hahn of the Dana-Farber Cancer Institute in Boston, Massachusetts.

Hahn described how we are now at a “watershed moment” in science with most of the molecular major pathways in carcinogenesis close to being elucidated; the challenge will be to mine and interpret this wealth of data.

It will be particularly challenging to determine which of the many mutations observed in a cancer cell line are important driver mutations, and which are simply “passengers”.

Genes are most likely to be “cancer drivers” if they are mutated in many cases of the same cancer type and also occur in pathways that have been linked to that cancer.

Bristow has set up “Project Achilles” to screen cancer genomes for essential genes using shRNA.

This led to the discovery of the gene ID4 as being amplified in about 30% of ovarian cancer cell lines tested, and to the identification of this gene, which encodes a DNA binding protein, as an oncogene in this cancer.

Similarly, beta catenin was discovered to play an important role in the development of colon cancer, through forming complexes with DNA-binding proteins.

Dasatinib, which inhibits the protein YES1 in one of these complexes, was discovered to inhibit beta-catenin driven cell proliferation in vivo.

So far, these screens have only examined one aspect of the tumour cell phenotype: proliferation and survival. Bristow’s group plans to study other phenotypes, including invasion and metastasis, in a similar way.