Unprecedented exploration generates comprehensive map of cancer genome

An international team has completed the most comprehensive study of whole cancer genomes to date, significantly improving our fundamental understanding of cancer and signposting new directions for its diagnosis and treatment.

The Pan-Cancer Project, a collaboration involving more than 1,300 scientists and clinicians from 37 countries, analysed more than 2,600 genomes of 38 different tumour types, creating a huge resource of primary cancer genomes. This was then the launch-point for 16 working groups studying multiple aspects of cancer’s development, cause, progression and classification.

Members from our Markowetz Group, Dr Geoff Macintyre and Ruben Drews, formed part of the evolution and tumour heterogeneity working group, involved on the papers “Inferring structural variant cancer cell fraction” and “The evolutionary history of 2,658 cancers“.

Previous studies focused on the 1% of the genome that codes for proteins. The Pan-Cancer Project explored in considerably greater detail the remaining 99% of the genome, including key regions that control switching genes on and off.

The Pan-Cancer Project has made available a comprehensive resource for cancer genomics research, including the raw genome sequencing data, software for cancer genome analysis, and multiple interactive websites exploring various aspects of the Pan-Cancer Project data.

The Pan-Cancer Project extended and advanced methods for analyzing cancer genomes which included cloud computing, and by applying these methods to its large dataset, discovered new knowledge about cancer biology and confirmed important findings of previous studies.

In 23 papers published today in Nature and its affiliated journals, the Pan-Cancer Project reports that:

• The cancer genome is finite and knowable, but enormously complicated. By combining sequencing of the whole cancer genome with a suite of analysis tools, we can characterize every genetic change found in a cancer, all the processes that have generated those mutations, and even the order of key events during a cancer’s life history.

• Researchers are close to cataloguing all of the biological pathways involved in cancer and having a fuller picture of their actions in the genome. At least one causal mutation was found in virtually all of the cancers analyzed and the processes that generate mutations were found to be hugely diverse — from changes in single DNA letters to the reorganization of whole chromosomes. Multiple novel regions of the genome controlling how genes switch on and off were identified as targets of cancer-causing mutations.

• Through a new method of “carbon dating,” Pan-Cancer researchers discovered that it is possible to identify mutations which occurred years, sometimes even decades, before the tumour appears. This opens, theoretically, a window of opportunity for early cancer detection.

• Tumour types can be identified accurately according to the patterns of genetic changes seen throughout the genome, potentially aiding the diagnosis of a patient’s cancer where conventional clinical tests could not identify its type. Knowledge of the exact tumour type could also help tailor treatments.

“The findings we have shared with the world today are the culmination of an unparalleled, decade-long collaboration that explored the entire cancer genome,” says Dr Lincoln Stein, Head of Adaptive Oncology at the Ontario Institute for Cancer Research (OICR). “With the knowledge, we have gained about the origins and evolution of tumours, we can develop new tools and therapies to detect cancer earlier, develop more targeted therapies and treat patients more successfully.”

“This work is helping to answer a long-standing medical difficulty, why two patients with what appear to be the same cancer can have very different outcomes to the same drug treatment. We show that the reasons for these different behaviours are written in the DNA.  The genome of each patient’s cancer is unique, but there are a finite set of recurring patterns, so with large enough studies we can identify all these patterns to optimize diagnosis and treatment.” said Dr Peter Campbell, Head of Cancer, Ageing and Somatic Mutation at the Wellcome Sanger Institute in the UK.

“This study provides the most complete picture to date of cancer-causing mutations in all parts of the genome. It was a massive team science effort involving researchers spanning the globe,” said steering committee member Josh Stuart, a professor of biomolecular engineering at UC Santa Cruz. “At UC Santa Cruz, our strengths in systems biology and RNA expression helped us connect findings in the previously unexplored noncoding genome with the pathways that lead to cancer. Like a charted map, this new work creates a reference and resource that researchers can use to interpret future data and physicians can use to guide treatment.”

”With the continuing drop in sequencing costs and accumulation of genomic data across increasing numbers of patients worldwide, the comprehensive analyses performed in this project will serve as a template for future work and will enable new discoveries in cancer,” said steering committee member, Dr Gad Getz, professor of pathology at the Massachusetts General Hospital and the Broad Institute of MIT and Harvard.