Cancer Genome Complexity Made Simple

The largest investigation of whole tumor genomes to date has laid barecharacteristic DNA aberrations responsible for cancer's development and helped unravel mutational processes that shape tumor evolution.

The survey of 2,658 cancer samples and matched normal tissues across 38 different tumor types—a project of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which kicked off in 2013 and brought together more than 1,300 scientists in 37 countries—is described in a collection of nearly two dozen new articles (www.nature.com/collections/pcawg/).

“To me, 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 PCAWG Steering Committee Co-chair Peter Campbell, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK. Yet, amid all the genetic complexity are recurring and identifiable patterns of tumor evolution.

In an overview article outlining the breadth and depth of the PCAWG dataset, Campbell and his colleagues report that 91% of tumors had at least one recognizable driver mutation, with nearly half harboring five or more (Nature 2020;578:82–93). Somatic copy-number alterations and coding-variant mutations were the most common, but the researchers documented chromosomal rearrangements, pathogenic germline variants, and driver noncoding point mutations as well.

A companion article describes several recurrent and often novel noncoding driver mutations, including one in the untranslated region upstream of the well-known tumor suppressor TP53 and others in the promoter region of TERT that result in overexpression of the telomerase enzyme (Nature 2020;578:102–11). Another study of matched transcriptomes showed that, even when driver events could not be found in the DNA, RNA-level alterations were evident (Nature 2020;578:129–36).

A reconstruction of evolutionary trajectories found that driver events often occur years before a diagnosis is made, with implications for early detection and prevention, while two articles—one on smaller mutational processes and another on larger structural variation—characterized nearly 100 genetic signatures that presumably reflect the different mutagenic factors that can shape and mold the cancer genome (Nature 2020;578:122–8; Nature 2020;578:94–101; Nature 2020;578:112–21). Other studies variously focused on regulatory alterations, mitochondrial genomes, retrotransposition events, chromatin architecture, and more (Nat Comm 2020;11:736; Nat Genet 2020 Feb 5 [Epub ahead of print]; Nat Genet 2020 Feb 5 [Epub ahead of print]; Nat Genet 2020 Feb 5 [Epub ahead of print]). Several reports also describe new tools and software for analyzing and characterizing cancer genomes, all of which are now freely available along with the underlying data, notes Lincoln Stein, MD, PhD, another PCAWG Steering Committee co-chair from the Ontario Institute for Cancer Research in Toronto, Canada (Nat Biotechnol 2020 Feb 5 [Epub ahead of print]; Nat Comm 2020;11:734; Nat Comm 2020;11:735; Nat Comm 2020;11:730; http://dcc.icgc.org/pcawg).

“Of equal importance to the publications,” Stein says, “we've released all the raw, processed, and interpreted data to the research community to act as a legacy dataset that we'll continue to give to the cancer research community for years to come.”

The leaders of PCAWG—a joint initiative of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas—hope to see the resource continue to grow as more clinicians take advantage of its findings and then deposit additional patient genomes. “One then has the sort of virtuous circle that the patient both benefits from the knowledge bank and in time will contribute to it,” Campbell says.

One major limitation of the PCAWG catalogue is the lack of corresponding medical records concerning patientcare trajectories and treatment responses, note Marcin Cieslik, PhD, and Arul Chinnaiyan, MD, PhD, of the University of Michigan, Ann Arbor. “Such data would allow researchers to identify the genetic changes that can predict clinical outcomes,” they write in an accompanying commentary (Nature 2020;578:39–40).

Fortunately for the cancer community, the ICGC's latest initiative—the Accelerating Research in Genomic Oncology project—aims to address that shortcoming by sequencing cancer genomes from some 200,000 trial participants for whom full clinical records are available. –Elie Dolgin

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.