Biopsies from one tumour have more genetic differences than similarities, finds study

BMJ 2012; 344 doi: (Published 08 March 2012) Cite this as: BMJ 2012;344:e1714
  1. Susan Mayor
  1. 1London

Taking a single biopsy from just one part of a tumour may fail to provide a full picture of its genetic landscape, indicates the first study to analyse the full genome in different regions of the same tumour, which shows much greater variation in mutations than previously thought.

Two thirds (66-69%) of mutations identified in the study were not shared by different biopsies taken from the same tumour. This may help to explain why using single biopsies to identify biomarkers used to direct treatment with molecular targeted therapies has often proved unsuccessful in improving long term survival from cancer.

Researchers at Cancer Research UK’s London Research Institute and University College London’s Cancer Institute analysed the complete genome in biopsies taken from different regions of four separate kidney tumours and also from metastases located near and at a distance from the patients’ primary tumours.

They identified 118 different mutations in the tumour samples—40 of which were “ubiquitous mutations” found in all biopsies, 53 “shared mutations” that occurred in most but not all biopsies, and 25 “private mutations” that were detected in only a single biopsy (New England Journal of Medicine 2012;366:883-92).

Charles Swanton, professor of personalised medicine at the UCL Cancer Institute and the study’s lead author, said, “We’ve known for some time that tumours are a ‘patchwork’ of faults, but this is the first time we’ve been able to use cutting edge genome sequencing technology to map out the genetic landscape of a tumour in such exquisite detail.

“This has revealed an extraordinary amount of diversity, with more differences between biopsies from the same tumour at the genetic level than there are similarities,” he said, adding that a similar degree of genetic heterogeneity has been found in other solid tumours.

By analysing the location of shared mutations across the whole tumour the team was able to trace the origins of particular subtypes of cancer cells back to key driver mutations. This enabled them to create a map of how the pattern of mutations within a tumour may have evolved over time.

Comparing the branching of new mutations from the initial mutations in the primary tumour to the “tree of life” model that Darwin used to show how different species evolved, Professor Swanton said that the study results could track the evolution of different populations of cancer cells.

“It will be important to target common mutations found in the ‘trunk’ of the tree as opposed to those in the ‘branches,’ which may occur in only a small number of cells,” he suggested, adding that anticancer drug targets, including EGFR, KRAS, and HER2 mutations, may fall into this category of common ‘trunk’ mutations. “Early events that drive tumour biology may be good targets.”

He added that the study findings might explain why surgery to remove a primary tumour can significantly improve survival, by reducing the likelihood that resistant cells remain in the body to regrow.

Professor Swanton concluded that the findings were only a start in pointing to a new direction for unravelling the complexity of cancer growth and designing novel treatments. “The next step will be to understand what’s driving the diversity in mutations in different cancers and to identify the key driver mutations that are common throughout all parts of a tumour,” he said.

The research group now plans to see whether the findings can be replicated in a larger group of patients with different cancers, including breast and lung cancer.


Cite this as: BMJ 2012;344:e1714