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Whole-Genome Sequencing in Cancer Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press Whole-Genome Sequencing in Cancer Eric Y. Zhao, Martin Jones, and Steven J.M. Jones Canada’s Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada Correspondence: [email protected] Genome sequencing of cancer has fundamentally advanced our understanding of the underlying biology of this disease, and more recently has provided approaches to character- ize and monitor tumors in the clinic, guiding and evaluating treatment. Although cancer research is relying more on whole-genome characterization, the clinical application of genomics is largely limited to targeted sequencing approaches, tailored to capture specific clinically relevant biomarkers. However, as sequencing costs reduce, and the tools to effec- tively analyze complex and large-scale data improve, the ability to effectively characterize whole genomes at scale in a clinically relevant time frame is now being piloted. This ability effectively blurs the line between clinical cancer research and the clinical management of the disease. This leads to a new paradigm in cancer management in which real-time analysis of an individual’s disease can have a rapid and lasting impact on our understanding of how clinical practices need to change to exploit novel therapeutic rationales. In this article, we will discuss how whole-genome sequencing (WGS), often combined with transcriptome analysis, has been used to understand cancer and how this approach is uniquely positioned to provide a comprehensive view of an evolving disease in response to therapy. EARLY APPLICATION OF WHOLE-GENOME Network 2013), only 6 months after the first hu- SEQUENCING IN ONCOLOGY man whole-genome sequence by next-genera- tion technologies was published (Wheeler et al. he application of whole-genome sequencing 2008). At that time, the bioinformatics tools T(WGS) to derive a more complete under- and genomic resources to facilitate the in-depth www.perspectivesinmedicine.org standing of cancer has been a central goal of analysis of whole-genome data could be con- cancer researchers since before the human ge- sidered in their infancy compared with today’s nome was first decoded in 2003 (Lander et al. standards. Even so, the insights gained into both 2001). It would take a further 5 years and a the approach taken to sequencing the tumor and sea change in genome-sequencing technology the biology of the tumor itself were profound before the first application of next-generation when compared with the targeted sequencing WGS to a cancer sample was described. Ley approaches commonly applied to cancer re- and colleagues reported the analysis of a cyto- search at the time. genetically normal acute myeloid leukemia Today, the resources required for WGS anal- (AML) in 2008 (The Cancer Genome Atlas ysis have decreased substantially. Alongside a Editors: W. Richard McCombie, Elaine R. Mardis, James A. Knowles, and John D. McPherson Additional Perspectives on Next-Generation Sequencing in Medicine available at www.perspectivesinmedicine.org Copyright © 2019 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a034579 Cite this article as Cold Spring Harb Perspect Med 2019;9:a034579 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press E.Y. Zhao et al. steady reduction in the cost of WGS, there have better define tumor biology and the relationship been improvements in the technologies for gen- to treatment history and response. erating and processing quality raw data as well as the tools and companion datasets that contex- WHOLE-GENOME CHARACTERIZATION tualize findings for biological and clinical inter- OF CANCERS pretation. However, a majority of cancer geno- mics efforts remain focused around targeted The number of tumor whole-genome sequences deep sequencing and whole-exome sequencing that have been published and made publicly (WES) (Morris et al. 2017; Raphael et al. 2017). available has steadily increased over the past 10 years. These analyses have led to surprising insights into cancer biology, particularly from LARGE-SCALE EFFORTS TO CHARACTERIZE the analysis of structural variants (SVs) in tumor GENOMIC EVENTS IN CANCER genomes (Chong et al. 2017). They range in Large-scale efforts using genome sequencing to scope from characterization of cancer cell lines characterize a wide variety of adult and pediatric (Pleasance et al. 2010a,b) and N-of-One case cancers began in earnest as early as 2005. This reports with rich clinical detail (Ellis et al. included projects such as The Cancer Genome 2012), to ultradeep sequencing of a single tumor Atlas (TCGA; see cancergenome.nih.gov), the to uncover clonal heterogeneity (Griffith et al. International Cancer Genome Consortium 2015). Larger scale efforts are also emerging, (ICGC; see icgc.org), Catalog of Somatic Muta- focused both at the characterization of the so- tions in Cancer (COSMIC; see cancer.sanger.ac matic mutation, including noncoding and SVs .uk), and Therapeutically Applicable Research (Banerji et al. 2012; Alexandrov et al. 2013b; to Generate Effective Treatments (TARGET; Wang et al. 2014; Nik-Zainal et al. 2016) and see ocg.cancer.gov/programs/target), to name germline-specific analysis for the discovery of but a few. Not only have such efforts progressed predisposing and pharmacogenomic informa- our understanding of cancer as a genomic dis- tion (Foley et al. 2015). For example, Nik-Zainal ease, they also provide the data needed for de- et al. (2016) sequenced the whole genomes of veloping tools and resources that facilitate the 560 breast cancers, 260 supplemented with tran- rapid detection and analysis of potentially rele- scriptome sequencing. They showed how such vant genomic events (Cerami et al. 2012; Gao approaches fill gaps in our understanding of the et al. 2013; Gonzalez-Perez et al. 2013; Rubio- genome between the exons and expand the Perez et al. 2015). However, because the bulk of known repertoire of biological mechanisms un- the data produced is focused on the coding derlying tumorigenesis with potential clinical www.perspectivesinmedicine.org region of the genome, the available data are un- use (Alexandrov et al. 2013b; Alexandrov and derpowered to inform how untranslated, in- Stratton 2014; Davies et al. 2017; Zolkind and tronic, and intergenic regions might impact the Uppaluri 2017). molecular pathogenesis of disease (Nik-Zainal et al. 2016). In many cases, the data also lack WHOLE-GENOME CHARACTERIZATION comprehensive clinical annotation, which is re- OF CANCERS IN THE CLINIC quired for linking genomic events to specificcan- cer types, prognoses, and treatment responses The scope of sequencing and its applications has (Robinson et al. 2017). Furthermore, the majority also broadened into the clinic. For specific can- of samples in these cohorts are from primary cer types, the use of targeted genomic panels for untreated disease and do not offer insight into both germline susceptibility and known “action- how tumors respond to often complex and dis- able” somatic mutations is becoming routine in parate treatment regimens (Robinson et al. 2017). many cancer centers (De Leeneer et al. 2011; Additional cancer cohorts of samples from mul- Bosdet et al. 2013). The development and appli- tiple time points and biopsy sites that include rich cation of larger-scale gene panels is also seeing clinical information are therefore still required to routine use on a large number of patient samples 2 Cite this article as Cold Spring Harb Perspect Med 2019;9:a034579 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 27, 2021 - Published by Cold Spring Harbor Laboratory Press Whole-Genome Sequencing in Cancer (Zehir et al. 2017). These high-throughput ap- characterizing cancer, the unique capabilities of proaches drive discovery in the clinical context such an approach require consideration. What and quantify the frequency and prevalence of benefits could these capabilities provide if intro- both well-characterized and novel variants in duced into standard clinical practice? This is cancer-related genes. However, they capture a particularly timely given the insights over the tiny fraction of the genomic complexity that past few years into the potential clinical action- can exist in an individual tumor. ability of mutation signatures that can elicit The first published description of an attempt immune responses in the presence of immune to characterize a whole genome for a clinical checkpoint inhibitors (Rizvi et al. 2015). Here, application was in 2010 (Jones et al. 2010). In we will highlight the unique opportunities this analysis, Jones et al. sequenced an adeno- (Fig. 1) for discovery from WGS, as they relate carcinoma of the tongue, identifying genomic to the understanding of the underlying biology amplification and concurrent abundant expres- of a tumor, the potential impact on drug discov- sion of the RET oncogene as a potential driver of ery and success of clinical trials and how those the disease. This analysis led to a personalized discoveries can impact the treatment of an indi- treatment approach for the patient using kinase vidual’s disease. We also consider the resources inhibitors targeting the RET protein. Subse- needed to build the infrastructure for WGS in quent analysis of a posttreatment sample after routine clinical practice. disease progression provided comprehensive in- sight into how the tumor evolved to circumvent the treatment regimen in a way that a targeted UNIQUE CAPABILITIES OF WGS approach could not have achieved. The success Toward a Digital Karyotype: High-Resolution of this study led to a pilot for the Personalized Structural Variation OncoGenomics clinical trial, now in its fifth year, which aims to leverage whole-genome Few images are more deeply enscribed in the analysis with the intent-to-treat based on the history of human genetics than the karyotype, genomic information. Sequencing of the initial which emphasizes the functional importance of 100 patients on this trial required development genomic organization.
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