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Large-Scale Pan-Cancer Analysis Expands Set of Alterations Disrupting Key Genes, Pathways

NEW YORK – Members of the International Cancer Genome Consortium (ICGC)'s Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium have integrated and analyzed whole-genome sequence data for thousands of tumors spanning 38 cancer types generated through ICGC and the Cancer Genome Atlas project (TCGA), getting a closer look at the point mutations, chromosomal rearrangements, and other alterations contributing to cancer development and behavior. 

Although they did not see large numbers of new cancer-related genes and pathways, the investigators put together "a broad and comprehensive portrait of cancer-related mutations in both the coding and the non-coding portions of the genome," said co-lead author Lincoln Stein, a researcher at the University of Toronto and head of adaptive oncology at the Ontario Institute for Cancer Research, during a conference call on Tuesday to discuss the results of the project.

"We found the same pathways that had been identified by [tumor] exome sequencing, but many more ways to change those pathways," Stein explained. "What we've been able to do is increase our ability to identify which pathways and genes are altered in a particular cancer, so that … we can more accurately diagnose what changes have occurred in a patient's tumor, identify the dysregulated pathways in that patient, and assign that patient to the therapy most likely to be effective and least likely to have toxic effects."

Over the past few decades, the cancer research community has been systematically sifting through the many mutations that may occur in the human genome to narrow in on those with the ability to prompt cancer development. But while tens of thousands of cancer exomes that have now been sequenced have offered insights into potential drivers in protein-coding portions of the genome, Stein noted, far less work has been done to bring together information on whole-genome sequences across cancer types.

For a series of pan-cancer analyses, outlined in nearly two dozen articles published in Nature and Nature-family journals on Wednesday, Stein and his colleagues — more than 1,300 investigators from teams around the world — attempted to uniformly analyze whole-genome sequence data for 2,658 cancer cases previously profiled for the ICGC and TCGA efforts, unearthing new insights into the biology and potential vulnerabilities of tumors from diverse cancer types.

"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," Peter Campbell, head of the cancer, aging, and somatic mutation program at the Wellcome Sanger Institute and co-leader of the pan-cancer steering committee, said during the call.

Along with clues for better classifying primary and metastatic cancers, including "carcinoma of unknown primary" (CUP) cases, members of the team uncovered molecular insights that may eventually help find and thwart some of the early events that set cells on the path to becoming cancer.

In one of the papers, for example, a team led by researchers at the European Molecular Biology Laboratory took a tumor archeology approach to dig into the mutations accumulating in a patient's tumor over time to identify driver events occurring long before cancer diagnoses in some cases.

Still other papers tallied mutational signatures in tumor genomes and exomes, delved into alterations found with transcriptomic approaches, searched for informative structural variants in tumor genomes, profiled potential regulation-related changes in tumors, and more.

"What this analysis — the pan-cancer analysis — has done is really laid bare the reasons for … unpredictability in clinical outcomes: the reasons are written in the genome," Campbell said, noting that the goal is to one day tailor treatment for each individual patient based on their tumor genome and other molecular insights.

"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," he explained. "That leads to very different shapes and patterns in the genomes that result: some of these processes reflect the wear and tear of aging, some of them reflect inherited causes, some reflect the lifestyles that people have engaged in, and all of these shape and mold the genome during cancer's development."

The PCAWG team is making raw, processed, and interpretative data used for the newly-published analyses available to other members of the research community through an ICGC Data Portal, Stein noted, in the hopes of leaving a "legacy dataset that will continue to give to the cancer research community for years to come."

Although sequencing is more frequently being used as a clinical tool, cancer genome sequencing is still at a relatively early stage, and access to it "remains patchy," Campbell cautioned. Still, he suggested that the current pan-cancer analyses may serve as a resource for existing and anticipated sequencing programs in different parts of the world.

In addition to "illustrating all the manifold ways that a cancer genome can be analyzed and the insights that emerge," he said, the work demonstrates the feasibility of coming up with "portable, stable, and reproducible" data analysis pipelines and strategies for building even larger cancer genome collections that can be used by investigators around the world.

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