New cancer-causing gene identified

Cambridge-led research team links a new gene to tumour development in over one per cent of all cancers.

A Cambridge-based team of scientists has discovered that when a transcription factor gene, called CUX1, is faulty and becomes deactivated, a biological pathway is triggered that increases the growth of tumour cells.

The research team found that mutation of the CUX1 gene accounted for around one per cent of cancers in their analysis of genetic data from over 7,600 cancer patients.

Although this genetic defect is rare, the research on 28 different tumour types revealed that the mutation occurs in many different types of cancer. This means that work can begin on developing new targeted therapies that could be used to treat many patients with a range of different cancers.

Around 300,000 people in the UK are diagnosed with cancer each year, so for more than 3,000 of these patients a defect in the CUX1 gene could be a significant cause of their disease. And if these figures are scaled up to reflect the global incidence of cancer, the newly-identified genetic mutation could be an underlying cause of many cancers.

‘Our research is a prime example of how understanding the genetic code of cancers can drive the search for targeted cancer therapies that work more effectively and efficiently,’ says Dr David Adams, lead author from the Wellcome Trust Sanger Institute. ‘This could improve the lives of thousands of people suffering from cancer.’ 

‘Our work harnesses the power of combining large-scale cancer genomics with experimental genetics,’ says Dr Chi Wong, first author from the Wellcome Trust Sanger Institute and practising Haematologist at Addenbrooke’s Hospital. ‘CUX1 defects are particularly common in myeloid blood cancers, either through mutation or acquired loss of chromosome 7q. As these patients have a dismal prognosis currently, novel targeted therapies are urgently needed.’

Dr Adams and Dr Wong talk about their ground-breaking research in this video, or click here to go to YouTube:

The samples were collected and sequenced by the International Cancer Genome Constortium (ICGC), which is a global initiative to catalogue the genetic code of 50 different cancers, and other groups.

‘Data collected from large consortia such the ICGC, provides us with a new and broader way to identify genes that can underlie the development of cancers,’ says Professor David Tuveson from Cold Spring Harbor Laboratory. ‘We can now look at cancers as groups of diseases according to their tissues of origin and collectively examine and compare their genomes.’

The team, led by the Welcome Trust Sanger Institute working in collaboration with the University of Cambridge, and the Universities of Würzberg and Ulm in Germany, silenced CUX1 in cultured cells to understand how inactivating it might lead to the development of tumours. They found that when CUX1 is deactivated, it had a knock-on effect on a biological inhibitor, PIK3IP1, reducing its inhibitory effects. This mobilises an enzyme responsible for cell growth, phosphoinositide 3-kinase (PI3K), increasing the rate of tumour progression. The research is published online in Nature Genetics.

The team has already identified several dozen other genes that when mutated at a low frequency could promote cancer development. They plan to silence these genes in mice to fully understand how their inactivation may lead to cancer development and the mechanisms by which this occurs.

‘Drugs that inhibit PI3K signalling are currently undergoing clinical trial,’ says Professor Paul Workman, Deputy Chief Executive and Head of Cancer Therapeutics at The Institute of Cancer Research, London. ‘This discovery will help us to target these drugs to a new group of patients who will benefit from them and could have a dramatic effect on the lives of many cancer sufferers.’

9 Dec 2013