Scars in cancer cell DNA are ‘smoking gun’ of disease development

15 August 2013

Human cancer cells in culture.

Image: Human cancer cells in culture. ©  Matthew Daniels, Wellcome Images.

A comprehensive map of scars left behind on the DNA of cancer cells is helping to reveal the biological processes underlying the genetic mutations that cause disease. The findings could reveal new ways to treat and prevent a wide range of cancers.

Cancer begins when cells start to grow out of control as a result of mutations in their genetic material. We know that chemicals in tobacco smoke cause mutations in lung cells that lead to lung cancers and UV light causes mutations in skin cells that lead to skin cancers; however, we have little understanding of the biological processes that cause the mutations underlying the development of most cancers.

When genetic mutations arise in a cancer cell, the biological processes that cause it can leave behind an imprint on the cell's DNA. Now, research led by the Wellcome Trust Sanger Institute has created a comprehensive log of these scars, or 'signatures', across a range of cancer types.

The international team studied genetic material from more than 7,000 cancer samples from people with the most common forms of cancer, uncovering more than 20 signatures of biological processes that mutate DNA. For many of the signatures, they also identified the underlying biological process responsible.

Professor Sir Mike Stratton of the Wellcome Trust Sanger Institute, explained: "We have uncovered the archaeological traces within cancer genomes of the diverse mutational processes that lead to the development of most cancers. This compendium of mutational signatures and the consequent insights into the mutational processes underlying them has profound implications for the understanding of cancer development with potential applications in disease prevention and treatment."

All of the cancers studied contained two or more signatures, reflecting the variety of biological processes that work together during the development of cancer.

Different signatures were found to be involved in different cancers, however; two signatures were identified in the development of ovarian cancer, for example, but six signatures were identified in liver cancer development. Some of the signatures were found in multiple cancer types, whereas others were confined to a single cancer type.

More than half the cancer types had a signature that is linked to the activity of a family of enzymes known as APOBECs, which are involved in editing virus DNA as part of the innate immune response. The authors suggest that the actions of APOBECs to protect cells from virus infection could lead to collateral damage on human DNA, introducing mutations that lead to cancer.

"Through detailed analysis, we can start to use the overwhelming amounts of information buried deep in the DNA of cancers to our advantage in terms of understanding how and why cancers arise," says Dr Serena Nik-Zainal, also from the Wellcome Trust Sanger Institute. "Our map of the events that cause the majority of cancers in humans is an important step to discovering the processes that drive cancer formation."

Dr Michael Dunn, Head of Genetic and Molecular Sciences at the Wellcome Trust, said: "These signatures in the DNA of cancer cells are like a smoking gun at the scene of a crime: they provide vital evidence of the cellular events and causative agents that are at work in cancer and will help to uncover opportunities for new interventions to treat and prevent disease."

The paper, Signatures of mutational processes in human cancer, is published in Nature.

  • Genetic mutations in cancer cells can leave behind an imprint on the cell's DNA. Wellcome Trust scientists have now made a map of these 'scars' across a range of cancers, with the aim of finding new ways to treat and prevent them.
  • The imprints are due to the biological processes from which the mutations arise, and the research also uncovered some of these processes.
  • The Wellcome Trust has now awarded £4.3 million to researchers at the University of Cambridge, Sanger Institute and University of Dundee to explore the signatures of genetic mutations in model systems, such as yeast cells and human stem cells, in a bid to shed further light on the biological processes and causative agents of human cancer development.