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.