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Unprecedented Analyses of More Than 2,600 Whole Genome Sequences from 38 Different Tumor Types Results in 21 Studies Published Simultaneously in Nature Journals; One Suggests Many Cancer Mutations Occur Years Before the Cancer Develops

In a virtually unprecedented event, 21 open-access research papers arising from the monumental efforts of the ICGC/TCGA consortium on whole genome sequencing and integrative analysis of cancer have been published simultaneously online on February 5, 2020, in the following journals published by Nature: Nature Communications (8), Nature (6), Nature Genetics (5), Nature Biotechnology (1), and Communications Biology (1). The work is based on an international collaboration of over 1,300 scientists and clinicians from 37 countries known as the Pan-Cancer Analysis of Whole Genomes (PCAWG). The effort involved analysis of more than 2,600 genomes of 38 different tumor types, creating a huge resource of primary cancer genomes. The flagship paper is titled “Pan-Cancer Analysis of Whole Genomes.” In this BioQuick post, another one of the 21 articles (“The Evolutionary History of 2,658 Cancers”) is described. The the titles and links for all 21 articles are provided following description of the Evolutionary History article. In addition, related articles, including editorials and a News & Views article are provided at the end. Researchers at EMBL's European Bioinformatics Institute (EMBL-EBI) and the Francis Crick Institute in the UK have analyzed the whole genomes of over 2r,600 tumors from 38 different cancer types to determine the chronology of genomic changes during cancer development. Cancer occurs as part of a lifelong process in which our genome changes over time. As we age, our cells cannot maintain the integrity of the genome after cell division without making some errors (mutations). This process can be accelerated by various genetic predispositions and environmental factors, such as smoking. Over our lifetimes, these mutations build up and cells may be mis-programmed, leading to cancer. The scientists published their research (“The Evolutionary History of 2,658 Cancers”)in Nature as part of an international collaboration of over 1,300 scientists known as the Pan-Cancer Analysis of Whole Genomes (PCAWG). The project aims to identify and catalogue the underlying patterns of mutation that give rise to many different cancer types. Access to this resource has significant implications for aiding the understanding of tumor progression, as well as opening up possibilities for early diagnosis and clinical intervention.

"We can map out the point mutations arising throughout normal aging to create a molecular clock for the human genome, akin to tracking the rings of a tree," says Moritz Gerstung, PhD, Group Leader at EMBL-EBI. "This provides us with a yardstick to estimate the age of some alterations seen in cancer, and to measure how far a tumor has progressed."

The researchers used data from the Pan-Cancer project and The Cancer Genome Atlas (ICGC) to create tumor development timelines for several cancer types including glioblastoma, and colorectal and ovarian adenocarcinoma. Their findings suggest that tumor development can span the entire lifetime of an individual, so the mutations that initiate cancer progression may arise decades before diagnosis.

"We've observed that changes in chromosome count within tumor cells typically occur late during tumor evolution. However, in some cases, such as in glioblastoma multiforme tumors, these changes can occur decades before diagnosis," says Stefan Dentro, PhD, Postdoctoral Fellow at EMBL-EBI. "Typically, cells don't survive for very long with an odd number of chromosomes, but somehow these cells do; possibly founding a tumor that is detected many years later."

TOWARDS EARLY CANCER DETECTION

"We've developed the first timelines of genetic mutations across the spectrum of cancer types," says Peter Van Loo, PhD, co-lead author and group leader in the Cancer Genomics Laboratory at the Francis Crick Institute. "For more than 30 cancers, we now know what specific genetic changes are likely to happen, and when these are likely to take place. Unlocking these patterns means it should now be possible to develop new diagnostic tests that pick up signs of cancer much earlier."

Understanding the sequence and chronology of mutations leading to cancer may help clarify the mechanisms of cancer development, which otherwise appear convoluted due to the presence of many alterations in the final cancer cells. Being able to determine whether a mutation typically occurs early or late during cancer progression may also help to guide early detection. This would make it possible to define the sets of alterations to screen for, to detect pre-cancerous cells at different stages of transformation.

"To a large extent, cancer development is an unfortunate consequence of the normal aging of our cells," says Dr.Gerstung. "Fully understanding the molecular progression of the disease is the first step towards identifying targets for early detection and perhaps treatment. The observation that many genetic alterations were already present years before the cancer was diagnosed provides a window of opportunity to detect aberrant cells before they become fully malignant."

THE PAN-CANCER PROJECT

The Pan-Cancer Analysis of Whole Genomes project is a collaboration involving more than 1,300 scientists and clinicians from 37 countries. It involved analysis of more than 2,600 genomes of 38 different tumor types, creating a huge resource of primary cancer genomes. This was the starting point for 16 working groups to study multiple aspects of cancer development, causation, progression, and classification. This massive effort has culminated in the simultaneous publication of 21 open-access articles in Nature journals, and related articles including an introductory piece, two editorials, and one News & Views article. A list of all these articls is provided below.

IMAGE

An artist's interpretation of pinpointing the onset of cancer progression. (Credit: Spencer Phillips/EMBL-EBI).

"Pan-Cancer Analysis of Whole Genomes"
Nature
https://www.nature.com/articles/s41586-020-1969-6

"Patterns of Somatic Structural Variation in Human Cancer Genomes"
Nature
https://www.nature.com/articles/s41586-019-1913-9

"The Repertoire of Mutational Signatures in Human Cancer"
Nature
https://www.nature.com/articles/s41586-020-1943-3

"The Evolutionary History of 2,658 Cancers"
Nature
https://www.nature.com/articles/s41586-019-1907-7

"Genomic Basis for RNA Alterations in Cancer"
Nature
https://www.nature.com/articles/s41586-020-1970-0

"Analyses of Non-Coding Somatic Drivers in 2,658 Cancer Whole Genomes"
Nature
https://www.nature.com/articles/s41586-020-1965-x

"Comprehensive Molecular Characterization of Mitochondrial Genomes in Human Cancers"
Nature Genetics
https://www.nature.com/articles/s41588-019-0557-x

"Disruption of Chromatin Folding Domains by Somatic Genomic Rearrangements in Human Cancer"
Nature Genetics
https://www.nature.com/articles/s41588-019-0564-y

"Pan-Cancer Analysis of Whole Genomes Identifies Driver Rearrangements Promoted by LINE-1 Retrotransposition"
Nature Genetics
https://www.nature.com/articles/s41588-019-0562-0

"The Landscape of Viral Associations In Human Cancers"
Nature Genetics
https://www.nature.com/articles/s41588-019-0558-9

"Comprehensive Analysis of Chromothripsis in 2,658 Human Cancers Using Whole-Genome Sequencing"
Nature Genetics
https://www.nature.com/articles/s41588-019-0576-7

"Butler Enables Rapid Cloud-Based Analysis of Thousands of Human Genomes"
Nature Biotechnology
https://www.nature.com/articles/s41587-019-0360-3

"Cancer LncRNA Census Reveals Evidence for Deep Functional Conservation of Long Noncoding RNAs In Tumorigenesis"
Communications Biology
https://www.nature.com/articles/s42003-019-0741-7

"Integrative Pathway Enrichment Analysis of Multivariate Omics Data"
Nature Communications
https://www.nature.com/articles/s41467-019-13983-9

"Pathway and Network Analysis of More Than 2500 Whole Cancer Genomes"
Nature Communications
https://www.nature.com/articles/s41467-020-14367-0

"A Deep Learning System Accurately Classifies Primary and Metastatic Cancers Using Passenger Mutation Patterns"
Nature Communications
https://www.nature.com/articles/s41467-019-13825-8

"High-Coverage Whole-Genome Analysis of 1220 Cancers Reveals Hundreds of Genes Deregulated by Rearrangement-Mediated Cis-Regulatory Alterations"
Nature Communications
https://www.nature.com/articles/s41467-019-13885-w

"Genomic Footprints of Activated Telomere Maintenance Mechanisms in Cancer"
Nature Communications
https://www.nature.com/articles/s41467-019-13824-9

"Combined Burden and Functional Impact Tests for Cancer Driver Discovery Using DriverPower"
Nature Communications
https://www.nature.com/articles/s41467-019-13929-1

"Inferring Structural Variant Cancer Cell Fraction"
Nature Communications
https://www.nature.com/articles/s41467-020-14351-8

"Divergent Mutational Processes Distinguish Hypoxic And Normoxic Tumours"
Nature Communications
https://www.nature.com/articles/s41467-019-14052-x

RELATED

"Pan-Cancer Analysis of Whole Genomes"
Nature Introduction
https://www.nature.com/immersive/d42859-020-00001-y/index.html

"The Era of Massive Cancer Sequencing Projects Has Reached a Turning Point"
Nature Editorial
https://www.nature.com/articles/d41586-020-00308-w

"Genomics: Data Sharing Needs an International Code of Conduct"
Nature Editorial
https://www.nature.com/articles/d41586-020-00082-9

"Global Genomics Project Unravels Cancer’s Complexity at Unprecedented Scale"
Nature News & Views
https://www.nature.com/articles/d41586-020-00213-2
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