‘Genome doubling’ linked to worse prognosis in colorectal cancer

01 February 2014

A genome doubled cell, showing all the chromosomes present. Two different coloured fluorescent probes were used to detect two different chromosome arms - showing that there are two copies of each.

Image: A genome doubled cell, showing all the chromosomes present. Two different coloured fluorescent probes were used to detect two different chromosome arms - showing that there are two copies of each.

Genome doubling is a common type of genetic mutation in colorectal cancer in which tumour cells obtain an extra copy of their whole genome.

Scientists at Cancer Research UK's London Research Institute (LRI; now part of the Francis Crick Institute) have now found that genome doubling may be linked to poor prognosis.

It's hoped that the discovery will help doctors make more informed decisions about colorectal cancer treatment strategies and, in particular, which patients should receive additional chemotherapy.

Colorectal cancer, also called bowel, colon or rectal cancer, is the third most common cancer in both men and women in the UK. It affects around 41,000 people and causes more than 15,000 deaths a year.

In Professor Charles Swanton's lab at LRI, Sally Dewhurst, Nicky McGranahan worked with a team of international collaborators to compare normal cancer cells with genome-doubled cells, both grown in the lab for over two years. This gave them insight into how the genomes of these cells evolved over time.

The team also used bioinformatics tools to identify which tumours might have doubled their genome at some point in the past - allowing them to compare the changes they observed in the lab-grown cells with changes that occurred in cells taken from patients' tumours.

They found that when genome-doubling had occurred, it was linked to accelerated evolution of the tumour. In addition, the genome-doubled cells were better able to tolerate further changes to their genome, which could mean that genome doubling contributes to tumour cell diversity and makes tumours more resilient.

Most importantly, the team found that identifying the genome-doubling event in early-stage patient tumours predicted significantly worse outcomes.

Professor Swanton, of LRI and the UCL Cancer Institute, said: "Our work gives us insights into how tumours change over time, and, in particular, the importance of genome doubling as a major event within the cancer genome that fosters tumour evolution.

"Genome doubling often occurs early in tumour development and could be a very useful biomarker of poor prognosis in early stage colorectal cancer. Identifying biomarkers at early disease stage is of great importance as important decisions about treatment strategies need to be made - in particular, whether or not patients should undergo additional chemotherapy."

The paper, Tolerance of Whole-Genome Doubling Propagates Chromosomal Instability and Accelerates Cancer Genome Evolution, is published in Cancer Discovery.

  • Scientists have found that in colorectal cancer, the presence of cells with an extra copy of their whole genome - known as genome-doubled cells - is linked to a worse prognosis. The findings are hoped to inform future treatment strategies.
  • Chromosomal instability means the continual loss or gain of whole and/or part of chromosomes. It is a common feature of cancer cells and is associated with poor prognosis and drug resistance. This research shows that genome-doubled cells in colorectal cancer undergo further rapid genetic changes (after the genome doubling) and repeat the genetic changes seen in chromosomally unstable cells.
  • The research was funded by Cancer Research UK, the Medical Research  Council, EU Framework 7, cancer and medical research charities and the Australian National Health and Medical Research Council, and was supported by researchers at UCL.