An international team, including scientists from Sydney’s Garvan Institute of Medical Research and The University of Queensland, has described the mutational processes that drive tumour development in 30 of the most common cancer types.
The discovery, published in Nature, one of the world’s leading scientific journals, could help to treat and prevent a wide range of cancers.
The team analysed 7,042 tumours and identified 21 distinct mutational signatures and the cancer types in which they occur.
“All cancers are caused by genetic mutations, and in some cases we know the processes driving them, for example, tobacco smoking in lung cancer, however, our understanding of the causes of mutation in most cancers is remarkably limited,” Professor Grimmond said.
“This study allows us to pinpoint the root genetic cause of tumour development in common cancers and, in some cases, to identify the biological process that damages the DNA and gives rise to the cancer.”
“For example, we found that a family of enzymes known as APOBECs, which can be activated in response to viruses, is linked to mutations in more than half of the 30 cancer types.”
All of the cancers contained two or more signatures, reflecting the variety of processes that contribute to cancer development.
Professor Andrew Biankin from the Garvan Institute and the University of Glasgow said some of the mutational signatures are found in multiple cancer types, while others are confined to a single cancer type.
“Twenty-five of the 30 cancers we examined had signatures that arose from mutational processes related to ageing,” Professor Biankin said.
“Childhood cancers showed the fewest mutations whereas cancers that were caused by exposure to known carcinogenics such as tobacco and UV light had the highest prevalence of mutations.
“It is likely we will be able to identify more mutational signatures as more cancers are sequenced and the analysis of these data is further refined.”
The study was led by Ludmil Alexandrov and Professor Sir Mike Stratton from the Wellcome Trust Sanger Institute in London.
“We have identified the majority of the mutational signatures that explain the genetic development and history of cancers in patients,” said Ludmil Alexandrov, first author from the Wellcome Trust Sanger Institute. “We are now beginning to understand the complicated biological processes that occur over time and leave these residual mutational signatures on cancer genomes.”
Signatures of mutational processes in human cancer, Ludmil B. Alexandrov, Serena Nik-Zainal, David C. Wedge, Samuel A. J. R. Aparicio, Sam Behjati, Andrew V. Biankin, Graham R. Bignell, Niccolò Bolli, Ake Borg, Anne-Lise Børresen-Dale, Sandrine Boyault, Birgit Burkhardt, Adam P. Butler, Carlos Caldas, Helen R. Davies, Christine Desmedt, Roland Eils, Jórunn Erla Eyfjörd, John A. Foekens, Mel Greaves, Fumie Hosoda, Barbara Hutter, Tomislav Ilicic, Sandrine Imbeaud, Marcin Imielinsk et al., Nature (2013) Published online 14 August 2013, doi:10.1038/nature12477.
Australian authors included Professor Biankin and Professor Grimmond; Dr Nic Waddell and John Pearson from the Institute for Molecular Bioscience; Professor Sunil Lakhani from UQ Centre for Clinical Research; and Dr Marina Pajic from the Garvan Institute.
We wish to acknowledge the clinicians, scientists and participants of the Australian Pancreatic Cancer Genome Initiative (APGI) who have made this research possible. We would also like to thank our funding bodies which include the NHMRC, Cancer Council NSW, the Cancer Institute NSW, the Avner Nahmani Pancreatic Cancer Foundation and The Philip Hemstritch Fellowship in Pancreatic Cancer Research. Please refer to APGI website for a detailed list of contributors.
Garvan Institute of Medical Research