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Uncovering the Genetic “Fingerprints” Driving Cancer

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Almost two thousand seven hundred whole-genomes of cancer have now been sequenced and analyzed as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium – the most comprehensive study of whole-genomes to date. This international project aims to provide us with a more thorough understanding of the genetic alternations responsible for driving cancer development. Newly discovered genetic “fingerprints” will help researchers identify previously unknown causes of cancer and will help guide future strategies to diagnose and treat this extremely complex disease.

“More than 1000 researchers have assembled a broad and comprehensive portrait of cancer related mutations in both the coding and the non-coding portions of the genome, and have used this information to predict the effects of the mutations discovered on biological pathways across 38 major tumor types,” explains Prof. Lincoln Stein from the University of Toronto, Canada, and member of the project steering committee.

“Over the last two decades, the scientific community has come to realize that cancer is fundamentally a disease of the genome. It's driven by the gradual accumulation of mutations in the cell that alter how the cell regulates its growth and interacts with the environment. There are literally billions of possible mutations, but only a small number of them, called driver mutations, give rise to cancer. Cataloging and understanding these driver mutations has been a major goal of the cancer research community for the past two decades,” says Stein.

Whilst sequencing data obtained from a single tumor biopsy can provide a snapshot of the alterations that occur in a specific location at a specific point in time, the ability to perform whole-genome sequencing of many tumor samples enables the generation of a more “complete picture” of the key genetic alterations that contribute to cancer development.

Dr Peter Campbell, from the Welcome Trust Sanger Institute and co-leader of the Pan-Cancer steering committee touches on the significance of the study, drawing on his past experiences as a clinician: “When I used to treat patients with cancer, I was always completely amazed and puzzled by how two patients could have what looked like the same tumor. They would look the same under the microscope, be the same size, and the two patients would receive exactly the same treatment, but those two patients would have completely opposite outcomes, one would survive, and one would die.”

Campbell explains that the Pan-Cancer project has enabled them to identify the reasons behind the unpredictability and resulting clinical outcomes. “The most striking finding out of all of the suite of papers is just how different one person’s cancer genome is from another person's,” says Campbell.

Study specifics and findings

  • A total of 2,658 whole-genomes of cancer along with their matched normal tissues across 38 types of tumors were analyzed.

  • On average 4–5 driver mutations can be found within a cancer genome.

  • At least one cancer driver gene was discovered in 91% of all cancer samples analyzed.

  • In 5% of cancer samples analyzed no drivers could be identified – suggesting follow up analysis may be required.


“We see thousands of different combinations of mutations that can cause the cancer and more than 80 different underlying processes generating the mutations in a cancer and that leads to very different shapes and patterns in the genome that results,” says Campbell. These processes reflect the “wear and tear” of aging, they may be due to inherited causes, lifestyle choices, and these in combination shape the state of the genome during the development of cancer.

Campbell continues: “Many of the tumor types that we've studied in this project show that the first key events in cancer development occur often decades before the patient presents with a tumor, sometimes even as far back as childhood.”

This insight provides healthcare professionals with potentially a much wider window of opportunity for diagnosis and treatment than previously thought, which could in turn improve prognosis.

“This Pan-Cancer study provides a blueprint for these national programs illustrating all the manifold ways that a cancer genome can be analyzed and the insights that emerge and showing how we can make data analysis pipelines, portable, stable, reproducible, and really looking to build and comprehensive knowledge bank of cancer genomes, that will be the foundation for future data sharing and international collaboration,” concludes Campbell.

The raw, processed and interpreted data in its entirety has been made available to the research community so that it may act as a legacy data set that will continue to act as a key resource for those working the field in future.

The insights provided by Dr Lucan Stein from the University of Toronto, Canada, and Dr Peter Campbell from the Wellcome Trust Sanger Institute, UK, were obtained from a press briefing related to the six papers published in Nature this week.

References:

Overview paper outlining key findings: The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. (2020) Pan-cancer analysis of whole genomes. Nature. DOI: 10.1038/s41586-020-1969-6

Further research papers and related content are available here.