Publications by authors named "David C Wedge"

100 Publications

Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes.

Nat Commun 2021 Nov 26;12(1):6946. Epub 2021 Nov 26.

Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, IL, 60637, USA.

Black women across the African diaspora experience more aggressive breast cancer with higher mortality rates than white women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast cancers, with RNA-seq in a subset, from women in Nigeria in comparison with The Cancer Genome Atlas (n = 76) reveal a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations with a 10.5-year younger age at diagnosis. We also find non-coding mutations in bona fide drivers (ZNF217 and SYPL1) and a previously unreported INDEL signature strongly associated with African ancestry proportion, underscoring the need to expand inclusion of diverse populations in biomedical research. Finally, we demonstrate that characterizing tumors for homologous recombination deficiency has significant clinical relevance in stratifying patients for potentially life-saving therapies.
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http://dx.doi.org/10.1038/s41467-021-27079-wDOI Listing
November 2021

Genomic and evolutionary classification of lung cancer in never smokers.

Nat Genet 2021 09 6;53(9):1348-1359. Epub 2021 Sep 6.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers' progenitor cells many years before tumor diagnosis. The other subtypes are characterized by specific amplifications and EGFR mutations (mezzo-forte) and whole-genome doubling (forte). No strong tobacco smoking signatures were detected, even in cases with exposure to secondhand tobacco smoke. Genes within the receptor tyrosine kinase-Ras pathway had distinct impacts on survival; five genomic alterations independently doubled mortality. These findings create avenues for personalized treatment in LCINS.
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http://dx.doi.org/10.1038/s41588-021-00920-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432745PMC
September 2021

Subclone Eradication Analysis Identifies Targets for Enhanced Cancer Therapy and Reveals L1 Retrotransposition as a Dynamic Source of Cancer Heterogeneity.

Cancer Res 2021 Oct 8;81(19):4901-4909. Epub 2021 Sep 8.

Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere, Finland.

Treatment-eradicated cancer subclones have been reported in leukemia and have recently been detected in solid tumors. Here we introduce Differential Subclone Eradication and Resistance (DSER) analysis, a method developed to identify molecular targets for improved therapy by direct comparison of genomic features of eradicated and resistant subclones in pre- and posttreatment samples from a patient with BRCA2-deficient metastatic prostate cancer. FANCI and EYA4 were identified as candidate DNA repair-related targets for converting subclones from resistant to eradicable, and RNAi-mediated depletion of FANCI confirmed it as a potential target. The EYA4 alteration was associated with adjacent L1 transposon insertion during cancer evolution upon treatment, raising questions surrounding the role of therapy in L1 activation. Both carboplatin and enzalutamide turned on L1 transposon machinery in LNCaP and VCaP but not in PC3 and 22Rv1 prostate cancer cell lines. L1 activation in LNCaP and VCaP was inhibited by the antiretroviral drug azidothymidine. L1 activation was also detected postcastration in LuCaP 77 and LuCaP 105 xenograft models and postchemotherapy in previously published time-series transcriptomic data from SCC25 head and neck cancer cells. In conclusion, DSER provides an informative intermediate step toward effective precision cancer medicine and should be tested in future studies, especially those including dramatic but temporary metastatic tumor regression. L1 transposon activation may be a modifiable source of cancer genomic heterogeneity, suggesting the potential of leveraging newly discovered triggers and blockers of L1 activity to overcome therapy resistance. SIGNIFICANCE: Differential analysis of eradicated and resistant subclones following cancer treatment identifies that L1 activity associated with resistance is induced by current therapies and blocked by the antiretroviral drug azidothymidine.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0371DOI Listing
October 2021

A Systematic Review of Prostate Cancer Heterogeneity: Understanding the Clonal Ancestry of Multifocal Disease.

Eur Urol Oncol 2021 Jun 20;4(3):358-369. Epub 2021 Apr 20.

Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; Department of Urology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Oxford NIHR Biomedical Research Centre, University of Oxford, UK. Electronic address:

Context: Studies characterising genomic changes in prostate cancer (PCa) during natural progression have greatly increased our understanding of the disease. A better understanding of the evolutionary history of PCa would allow advances in diagnostics, prognostication, and novel therapies that together will improve patient outcomes.

Objective: To review the molecular heterogeneity of PCa and assess recent efforts to profile intratumoural heterogeneity and clonal evolution.

Evidence Acquisition: We screened a total of 1313 abstracts from PubMed published between 2009 and 2020, of which we reviewed 84 full-text articles. We excluded 49, resulting in 35 studies for qualitative analysis.

Evidence Synthesis: In studies of primary disease (16 studies, 4793 specimens), there is a lack of consensus regarding the monoclonal or polyclonal origin of primary PCa. There is no consistent mutation giving rise to primary PCa. Detailed clonal analysis of primary PCa has been limited by current techniques. By contrast, clonal relationships between PCa metastases and a potentiating clone have been consistently identified (19 studies, 732 specimens). Metastatic specimens demonstrate consistent truncal genomic aberrations that suggest monoclonal metastatic progenitors.

Conclusions: The relationship between the clonal dynamics of PCa and clinical outcomes needs further investigation. It is likely that this will provide a biological rationale for whether radical treatment of the primary tumour benefits patients with oligometastatic PCa. Future studies on the mutational burden in primary disease at single-cell resolution should permit the identification of clonal patterns underpinning the origin of lethal PCa.

Patient Summary: Prostate cancers arise in different parts of the prostate because of DNA mutations that occur by chance at different times. These cancer cells and their origin can be tracked by DNA mapping. In this review we summarise the state of the art and outline what further science is needed to provide the missing answers.
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http://dx.doi.org/10.1016/j.euo.2021.02.008DOI Listing
June 2021

Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes.

Cell 2021 04 7;184(8):2239-2254.e39. Epub 2021 Apr 7.

Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.
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http://dx.doi.org/10.1016/j.cell.2021.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054914PMC
April 2021

A unified haplotype-based method for accurate and comprehensive variant calling.

Nat Biotechnol 2021 07 29;39(7):885-892. Epub 2021 Mar 29.

MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

Almost all haplotype-based variant callers were designed specifically for detecting common germline variation in diploid populations, and give suboptimal results in other scenarios. Here we present Octopus, a variant caller that uses a polymorphic Bayesian genotyping model capable of modeling sequencing data from a range of experimental designs within a unified haplotype-aware framework. Octopus combines sequencing reads and prior information to phase-called genotypes of arbitrary ploidy, including those with somatic mutations. We show that Octopus accurately calls germline variants in individuals, including single nucleotide variants, indels and small complex replacements such as microinversions. Using a synthetic tumor data set derived from clean sequencing data from a sample with known germline haplotypes and observed mutations in a large cohort of tumor samples, we show that Octopus is more sensitive to low-frequency somatic variation, yet calls considerably fewer false positives than other methods. Octopus also outputs realigned evidence BAM files to aid validation and interpretation.
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http://dx.doi.org/10.1038/s41587-021-00861-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611855PMC
July 2021

Promises and challenges of adoptive T-cell therapies for solid tumours.

Br J Cancer 2021 05 29;124(11):1759-1776. Epub 2021 Mar 29.

Ovarian Cancer Cell Laboratory, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.

Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas-cancer genomics, cancer immunology and cell-therapy manufacturing-that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours.
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http://dx.doi.org/10.1038/s41416-021-01353-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144577PMC
May 2021

Tracing Lung Cancer Risk Factors Through Mutational Signatures in Never-Smokers.

Am J Epidemiol 2021 06;190(6):962-976

Epidemiologic studies often rely on questionnaire data, exposure measurement tools, and/or biomarkers to identify risk factors and the underlying carcinogenic processes. An emerging and promising complementary approach to investigate cancer etiology is the study of somatic "mutational signatures" that endogenous and exogenous processes imprint on the cellular genome. These signatures can be identified from a complex web of somatic mutations thanks to advances in DNA sequencing technology and analytical algorithms. This approach is at the core of the Sherlock-Lung study (2018-ongoing), a retrospective case-only study of over 2,000 lung cancers in never-smokers (LCINS), using different patterns of mutations observed within LCINS tumors to trace back possible exposures or endogenous processes. Whole genome and transcriptome sequencing, genome-wide methylation, microbiome, and other analyses are integrated with data from histological and radiological imaging, lifestyle, demographic characteristics, environmental and occupational exposures, and medical records to classify LCINS into subtypes that could reveal distinct risk factors. To date, we have received samples and data from 1,370 LCINS cases from 17 study sites worldwide and whole-genome sequencing has been completed on 1,257 samples. Here, we present the Sherlock-Lung study design and analytical strategy, also illustrating some empirical challenges and the potential for this approach in future epidemiologic studies.
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http://dx.doi.org/10.1093/aje/kwaa234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316614PMC
June 2021

Re-evaluating experimental validation in the Big Data Era: a conceptual argument.

Genome Biol 2021 02 24;22(1):71. Epub 2021 Feb 24.

Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7LF, UK.

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http://dx.doi.org/10.1186/s13059-021-02292-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903713PMC
February 2021

A practical guide to cancer subclonal reconstruction from DNA sequencing.

Nat Methods 2021 02 4;18(2):144-155. Epub 2021 Jan 4.

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

Subclonal reconstruction from bulk tumor DNA sequencing has become a pillar of cancer evolution studies, providing insight into the clonality and relative ordering of mutations and mutational processes. We provide an outline of the complex computational approaches used for subclonal reconstruction from single and multiple tumor samples. We identify the underlying assumptions and uncertainties in each step and suggest best practices for analysis and quality assessment. This guide provides a pragmatic resource for the growing user community of subclonal reconstruction methods.
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http://dx.doi.org/10.1038/s41592-020-01013-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867630PMC
February 2021

Evolution and lineage dynamics of a transmissible cancer in Tasmanian devils.

PLoS Biol 2020 11 24;18(11):e3000926. Epub 2020 Nov 24.

Transmissible Cancer Group, Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.

Devil facial tumour 1 (DFT1) is a transmissible cancer clone endangering the Tasmanian devil. The expansion of DFT1 across Tasmania has been documented, but little is known of its evolutionary history. We analysed genomes of 648 DFT1 tumours collected throughout the disease range between 2003 and 2018. DFT1 diverged early into five clades, three spreading widely and two failing to persist. One clade has replaced others at several sites, and rates of DFT1 coinfection are high. DFT1 gradually accumulates copy number variants (CNVs), and its telomere lengths are short but constant. Recurrent CNVs reveal genes under positive selection, sites of genome instability, and repeated loss of a small derived chromosome. Cultured DFT1 cell lines have increased CNV frequency and undergo highly reproducible convergent evolution. Overall, DFT1 is a remarkably stable lineage whose genome illustrates how cancer cells adapt to diverse environments and persist in a parasitic niche.
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http://dx.doi.org/10.1371/journal.pbio.3000926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685465PMC
November 2020

Genomic copy number predicts esophageal cancer years before transformation.

Nat Med 2020 11 7;26(11):1726-1732. Epub 2020 Sep 7.

Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.

Recent studies show that aneuploidy and driver gene mutations precede cancer diagnosis by many years. We assess whether these genomic signals can be used for early detection and pre-emptive cancer treatment using the neoplastic precursor lesion Barrett's esophagus as an exemplar. Shallow whole-genome sequencing of 777 biopsies, sampled from 88 patients in Barrett's esophagus surveillance over a period of up to 15 years, shows that genomic signals can distinguish progressive from stable disease even 10 years before histopathological transformation. These findings are validated on two independent cohorts of 76 and 248 patients. These methods are low-cost and applicable to standard clinical biopsy samples. Compared with current management guidelines based on histopathology and clinical presentation, genomic classification enables earlier treatment for high-risk patients as well as reduction of unnecessary treatment and monitoring for patients who are unlikely to develop cancer.
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http://dx.doi.org/10.1038/s41591-020-1033-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116403PMC
November 2020

Malignant transformation and genetic alterations are uncoupled in early colorectal cancer progression.

BMC Biol 2020 09 7;18(1):116. Epub 2020 Sep 7.

Department für Diagnostik, Institut für Pathologie, Universitätsklinikum Leipzig AöR, Leipzig, Germany.

Background: Colorectal cancer (CRC) development is generally accepted as a sequential process, with genetic mutations determining phenotypic tumor progression. However, matching genetic profiles with histological transition requires the analyses of temporal samples from the same patient at key stages of progression.

Results: Here, we compared the genetic profiles of 34 early carcinomas with their respective adenomatous precursors to assess timing and heterogeneity of driver alterations accompanying the switch from benign adenoma to malignant carcinoma. In almost half of the cases, driver mutations specific to the carcinoma stage were not observed. In samples where carcinoma-specific alterations were present, TP53 mutations and chromosome 20 copy gains commonly accompanied the switch from adenomatous tissue to carcinoma. Remarkably, 40% and 50% of high-grade adenomas shared TP53 mutations and chromosome 20 gains, respectively, with their matched carcinomas. In addition, multi-regional analyses revealed greater heterogeneity of driver mutations in adenomas compared to their matched carcinomas.

Conclusion: Genetic alterations in TP53 and chromosome 20 occur at the earliest histological stage in colorectal carcinomas (pTis and pT1). However, high-grade adenomas can share these alterations despite their histological distinction. Based on the well-defined sequence of CRC development, we suggest that the timing of genetic changes during neoplastic progression is frequently uncoupled from histological progression.
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http://dx.doi.org/10.1186/s12915-020-00844-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487684PMC
September 2020

Multi-site clonality analysis uncovers pervasive heterogeneity across melanoma metastases.

Nat Commun 2020 08 27;11(1):4306. Epub 2020 Aug 27.

Experimental Cancer Genetics, The Wellcome Sanger Institute, Hinxton, Cambridgeshire, UK.

Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal evidence of diversification among metastatic lineages. UV-induced mutations dominate the trunk, whereas APOBEC-associated mutations are found in the branches of the evolutionary tree. Multi-sample analyses from a further seven patients confirmed that lineage diversification was pervasive, representing an important mode of melanoma dissemination. Our analyses demonstrate that joint analysis of cancer cell fraction estimates across multiple metastases can uncover previously unrecognised levels of tumour heterogeneity and highlight the limitations of inferring heterogeneity from a single biopsy.
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http://dx.doi.org/10.1038/s41467-020-18060-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453196PMC
August 2020

The genomic and epigenomic evolutionary history of papillary renal cell carcinomas.

Nat Commun 2020 06 18;11(1):3096. Epub 2020 Jun 18.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, 20892, USA.

Intratumor heterogeneity (ITH) and tumor evolution have been well described for clear cell renal cell carcinomas (ccRCC), but they are less studied for other kidney cancer subtypes. Here we investigate ITH and clonal evolution of papillary renal cell carcinoma (pRCC) and rarer kidney cancer subtypes, integrating whole-genome sequencing and DNA methylation data. In 29 tumors, up to 10 samples from the center to the periphery of each tumor, and metastatic samples in 2 cases, enable phylogenetic analysis of spatial features of clonal expansion, which shows congruent patterns of genomic and epigenomic evolution. In contrast to previous studies of ccRCC, in pRCC, driver gene mutations and most arm-level somatic copy number alterations (SCNAs) are clonal. These findings suggest that a single biopsy would be sufficient to identify the important genetic drivers and that targeting large-scale SCNAs may improve pRCC treatment, which is currently poor. While type 1 pRCC displays near absence of structural variants (SVs), the more aggressive type 2 pRCC and the rarer subtypes have numerous SVs, which should be pursued for prognostic significance.
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http://dx.doi.org/10.1038/s41467-020-16546-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303129PMC
June 2020

Reference bias in the Illumina Isaac aligner.

Bioinformatics 2020 11;36(17):4671-4672

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SM2 5NG 2, UK.

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http://dx.doi.org/10.1093/bioinformatics/btaa514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653636PMC
November 2020

Genetic and epigenetic intratumor heterogeneity impacts prognosis of lung adenocarcinoma.

Nat Commun 2020 05 18;11(1):2459. Epub 2020 May 18.

Integrative Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA.

Intratumor heterogeneity (ITH) of genomic alterations may impact prognosis of lung adenocarcinoma (LUAD). Here, we investigate ITH of somatic copy number alterations (SCNAs), DNA methylation, and point mutations in lung cancer driver genes in 292 tumor samples from 84 patients with LUAD. LUAD samples show substantial SCNA and methylation ITH, and clonal architecture analyses present congruent evolutionary trajectories for SCNAs and DNA methylation aberrations. Methylation ITH mapping to gene promoter areas or tumor suppressor genes is low. Moreover, ITH composed of genetic and epigenetic mechanisms altering the same cancer driver genes is shown in several tumors. To quantify ITH for valid statistical association analyses, we develope an average pairwise ITH index (APITH), which does not depend on the number of samples per tumor. Both APITH indexes for SCNAs and methylation aberrations show significant associations with poor prognosis. This study further establishes the important clinical implications of genetic and epigenetic ITH in LUAD.
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http://dx.doi.org/10.1038/s41467-020-16295-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235245PMC
May 2020

DNA copy number motifs are strong and independent predictors of survival in breast cancer.

Commun Biol 2020 04 2;3(1):153. Epub 2020 Apr 2.

Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Ullernchausseen 70 N-0310, Oslo, Norway.

Somatic copy number alterations are a frequent sign of genome instability in cancer. A precise characterization of the genome architecture would reveal underlying instability mechanisms and provide an instrument for outcome prediction and treatment guidance. Here we show that the local spatial behavior of copy number profiles conveys important information about this architecture. Six filters were defined to characterize regional traits in copy number profiles, and the resulting Copy Aberration Regional Mapping Analysis (CARMA) algorithm was applied to tumors in four breast cancer cohorts (n = 2919). The derived motifs represent a layer of information that complements established molecular classifications of breast cancer. A score reflecting presence or absence of motifs provided a highly significant independent prognostic predictor. Results were consistent between cohorts. The nonsite-specific occurrence of the detected patterns suggests that CARMA captures underlying replication and repair defects and could have a future potential in treatment stratification.
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http://dx.doi.org/10.1038/s42003-020-0884-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118095PMC
April 2020

The evolutionary history of 2,658 cancers.

Nature 2020 02 6;578(7793):122-128. Epub 2020 Feb 6.

University of Toronto, Toronto, Ontario, Canada.

Cancer develops through a process of somatic evolution. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.
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http://dx.doi.org/10.1038/s41586-019-1907-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054212PMC
February 2020

Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition.

Nat Genet 2020 03 5;52(3):306-319. Epub 2020 Feb 5.

Cancer Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Cambridge, UK.

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.
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http://dx.doi.org/10.1038/s41588-019-0562-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058536PMC
March 2020

A community effort to create standards for evaluating tumor subclonal reconstruction.

Nat Biotechnol 2020 01 9;38(1):97-107. Epub 2020 Jan 9.

Big Data Institute, University of Oxford, Oxford, UK.

Tumor DNA sequencing data can be interpreted by computational methods that analyze genomic heterogeneity to infer evolutionary dynamics. A growing number of studies have used these approaches to link cancer evolution with clinical progression and response to therapy. Although the inference of tumor phylogenies is rapidly becoming standard practice in cancer genome analyses, standards for evaluating them are lacking. To address this need, we systematically assess methods for reconstructing tumor subclonality. First, we elucidate the main algorithmic problems in subclonal reconstruction and develop quantitative metrics for evaluating them. Then we simulate realistic tumor genomes that harbor all known clonal and subclonal mutation types and processes. Finally, we benchmark 580 tumor reconstructions, varying tumor read depth, tumor type and somatic variant detection. Our analysis provides a baseline for the establishment of gold-standard methods to analyze tumor heterogeneity.
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http://dx.doi.org/10.1038/s41587-019-0364-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956735PMC
January 2020

Genomic evidence supports a clonal diaspora model for metastases of esophageal adenocarcinoma.

Nat Genet 2020 01 6;52(1):74-83. Epub 2020 Jan 6.

MRC Cancer Unit, University of Cambridge, Cambridge, UK.

The poor outcomes in esophageal adenocarcinoma (EAC) prompted us to interrogate the pattern and timing of metastatic spread. Whole-genome sequencing and phylogenetic analysis of 388 samples across 18 individuals with EAC showed, in 90% of patients, that multiple subclones from the primary tumor spread very rapidly from the primary site to form multiple metastases, including lymph nodes and distant tissues-a mode of dissemination that we term 'clonal diaspora'. Metastatic subclones at autopsy were present in tissue and blood samples from earlier time points. These findings have implications for our understanding and clinical evaluation of EAC.
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http://dx.doi.org/10.1038/s41588-019-0551-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100916PMC
January 2020

Embryonal precursors of Wilms tumor.

Science 2019 12;366(6470):1247-1251

Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.

Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. We also found hypermethylation of the locus, a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. These findings reveal embryonal precursors from which unilateral and multifocal cancers develop.
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http://dx.doi.org/10.1126/science.aax1323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914378PMC
December 2019

Genomic landscape and chronological reconstruction of driver events in multiple myeloma.

Nat Commun 2019 08 23;10(1):3835. Epub 2019 Aug 23.

The Cancer, Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Hinxton, Cambridgeshire, CB10 1SA, UK.

The multiple myeloma (MM) genome is heterogeneous and evolves through preclinical and post-diagnosis phases. Here we report a catalog and hierarchy of driver lesions using sequences from 67 MM genomes serially collected from 30 patients together with public exome datasets. Bayesian clustering defines at least 7 genomic subgroups with distinct sets of co-operating events. Focusing on whole genome sequencing data, complex structural events emerge as major drivers, including chromothripsis and a novel replication-based mechanism of templated insertions, which typically occur early. Hyperdiploidy also occurs early, with individual trisomies often acquired in different chronological windows during evolution, and with a preferred order of acquisition. Conversely, positively selected point mutations, whole genome duplication and chromoplexy events occur in later disease phases. Thus, initiating driver events, drawn from a limited repertoire of structural and numerical chromosomal changes, shape preferred trajectories of evolution that are biologically relevant but heterogeneous across patients.
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http://dx.doi.org/10.1038/s41467-019-11680-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707220PMC
August 2019

Profiling molecular regulators of recurrence in chemorefractory triple-negative breast cancers.

Breast Cancer Res 2019 08 5;21(1):87. Epub 2019 Aug 5.

Department of Surgery, Indiana University School of Medicine, 980 W. Walnut St. Room C312, Indianapolis, IN, 46202, USA.

Background: Approximately two thirds of patients with localized triple-negative breast cancer (TNBC) harbor residual disease (RD) after neoadjuvant chemotherapy (NAC) and have a high risk-of-recurrence. Targeted therapeutic development for TNBC is of primary significance as no targeted therapies are clinically indicated for this aggressive subset. In view of this, we conducted a comprehensive molecular analysis and correlated molecular features of chemorefractory RD tumors with recurrence for the purpose of guiding downstream therapeutic development.

Methods: We assembled DNA and RNA sequencing data from RD tumors as well as pre-operative biopsies, lymphocytic infiltrate, and survival data as part of a molecular correlative to a phase II post-neoadjuvant clinical trial. Matched somatic mutation, gene expression, and lymphocytic infiltrate were assessed before and after chemotherapy to understand how tumors evolve during chemotherapy. Kaplan-Meier survival analyses were conducted categorizing cancers with TP53 mutations by the degree of loss as well as by the copy number of a locus of 18q corresponding to the SMAD2, SMAD4, and SMAD7 genes.

Results: Analysis of matched somatic genomes pre-/post-NAC revealed chaotic acquisition of copy gains and losses including amplification of prominent oncogenes. In contrast, significant gains in deleterious point mutations and insertion/deletions were not observed. No trends between clonal evolution and recurrence were identified. Gene expression data from paired biopsies revealed enrichment of actionable regulators of stem cell-like behavior and depletion of immune signaling, which was corroborated by total lymphocytic infiltrate, but was not associated with recurrence. Novel characterization of TP53 mutation revealed prognostically relevant subgroups, which were linked to MYC-driven transcriptional amplification. Finally, somatic gains in 18q were associated with poor prognosis, likely driven by putative upregulation of TGFß signaling through the signal transducer SMAD2.

Conclusions: We conclude TNBCs are dynamic during chemotherapy, demonstrating complex plasticity in subclonal diversity, stem-like qualities, and immune depletion, but somatic alterations of TP53/MYC and TGFß signaling in RD samples are prominent drivers of recurrence, representing high-yield targets for additional interrogation.
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http://dx.doi.org/10.1186/s13058-019-1171-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683504PMC
August 2019

Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis.

Cell 2019 03;176(6):1282-1294.e20

Cytometry Core Facility, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.

Multiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed most common mutational signatures, indicating past activity of the underlying processes, usually in appropriate cancer types. To investigate ongoing patterns of mutational-signature generation, cell lines were cultured for extended periods and subsequently DNA sequenced. Signatures of discontinued exposures, including tobacco smoke and ultraviolet light, were not generated in vitro. Signatures of normal and defective DNA repair and replication continued to be generated at roughly stable mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing exhibited substantial fluctuations in mutation rate over time with episodic bursts of mutations. The initiating factors for the bursts are unclear, although retrotransposon mobilization may contribute. The examined cell lines constitute a resource of live experimental models of mutational processes, which potentially retain patterns of activity and regulation operative in primary human cancers.
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http://dx.doi.org/10.1016/j.cell.2019.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424819PMC
March 2019

Author Correction: Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors.

Nat Commun 2019 01 28;10(1):525. Epub 2019 Jan 28.

The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK.

The original version of this Article omitted a declaration from the competing interests statement, which should have included the following: 'K.P.W. is President of Tempus Lab, Inc., Chicago, IL, USA'. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-019-08512-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349916PMC
January 2019

Author Correction: Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

Nature 2019 02;566(7742):E1

Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.

In the Methods section of this Article, 'greater than' should have been 'less than' in the sentence 'Putative regions of clustered rearrangements were identified as having an average inter-rearrangement distance that was at least 10 times greater than the whole-genome average for the individual sample. '. The Article has not been corrected.
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http://dx.doi.org/10.1038/s41586-019-0883-2DOI Listing
February 2019

Author Correction: Pan-cancer analysis of homozygous deletions in primary tumours uncovers rare tumour suppressors.

Nat Commun 2018 12 17;9(1):5397. Epub 2018 Dec 17.

The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.

The original version of this Article contained an error in the author affiliations. The affiliation of Kevin P. White with Tempus Labs, Inc., Chicago, IL, USA was inadvertently omitted.This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-07842-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297227PMC
December 2018
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