Publications by authors named "Graham Bignell"

53 Publications

Functional linkage of gene fusions to cancer cell fitness assessed by pharmacological and CRISPR-Cas9 screening.

Nat Commun 2019 05 16;10(1):2198. Epub 2019 May 16.

Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, CB10 1SA, UK.

Many gene fusions are reported in tumours and for most their role remains unknown. As fusions are used for diagnostic and prognostic purposes, and are targets for treatment, it is crucial to assess their function in cancer. To systematically investigate the role of fusions in tumour cell fitness, we utilized RNA-sequencing data from 1011 human cancer cell lines to functionally link 8354 fusion events with genomic data, sensitivity to >350 anti-cancer drugs and CRISPR-Cas9 loss-of-fitness effects. Established clinically-relevant fusions were identified. Overall, detection of functional fusions was rare, including those involving cancer driver genes, suggesting that many fusions are dispensable for tumour fitness. Therapeutically actionable fusions involving RAF1, BRD4 and ROS1 were verified in new histologies. In addition, recurrent YAP1-MAML2 fusions were identified as activators of Hippo-pathway signaling in multiple cancer types. Our approach discriminates functional fusions, identifying new drivers of carcinogenesis and fusions that could have clinical implications.
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http://dx.doi.org/10.1038/s41467-019-09940-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522557PMC
May 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: 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

An integrated genomic analysis of anaplastic meningioma identifies prognostic molecular signatures.

Sci Rep 2018 09 10;8(1):13537. Epub 2018 Sep 10.

Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth University, Plymouth, Devon, PL4 8AA, UK.

Anaplastic meningioma is a rare and aggressive brain tumor characterised by intractable recurrences and dismal outcomes. Here, we present an integrated analysis of the whole genome, transcriptome and methylation profiles of primary and recurrent anaplastic meningioma. A key finding was the delineation of distinct molecular subgroups that were associated with diametrically opposed survival outcomes. Relative to lower grade meningiomas, anaplastic tumors harbored frequent driver mutations in SWI/SNF complex genes, which were confined to the poor prognosis subgroup. Aggressive disease was further characterised by transcriptional evidence of increased PRC2 activity, stemness and epithelial-to-mesenchymal transition. Our analyses discern biologically distinct variants of anaplastic meningioma with prognostic and therapeutic significance.
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http://dx.doi.org/10.1038/s41598-018-31659-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131140PMC
September 2018

The germline genetic component of drug sensitivity in cancer cell lines.

Nat Commun 2018 08 23;9(1):3385. Epub 2018 Aug 23.

European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.

Patients with seemingly the same tumour can respond very differently to treatment. There are strong, well-established effects of somatic mutations on drug efficacy, but there is at-most anecdotal evidence of a germline component to drug response. Here, we report a systematic survey of how inherited germline variants affect drug susceptibility in cancer cell lines. We develop a joint analysis approach that leverages both germline and somatic variants, before applying it to screening data from 993 cell lines and 265 drugs. Surprisingly, we find that the germline contribution to variation in drug susceptibility can be as large or larger than effects due to somatic mutations. Several of the associations identified have a direct relationship to the drug target. Finally, using 17-AAG response as an example, we show how germline effects in combination with transcriptomic data can be leveraged for improved patient stratification and to identify new markers for drug sensitivity.
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http://dx.doi.org/10.1038/s41467-018-05811-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107640PMC
August 2018

Transcription Factor Activities Enhance Markers of Drug Sensitivity in Cancer.

Cancer Res 2018 02 11;78(3):769-780. Epub 2017 Dec 11.

European Molecular Biology Laboratory - European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, United Kingdom.

Transcriptional dysregulation induced by aberrant transcription factors (TF) is a key feature of cancer, but its global influence on drug sensitivity has not been examined. Here, we infer the transcriptional activity of 127 TFs through analysis of RNA-seq gene expression data newly generated for 448 cancer cell lines, combined with publicly available datasets to survey a total of 1,056 cancer cell lines and 9,250 primary tumors. Predicted TF activities are supported by their agreement with independent shRNA essentiality profiles and homozygous gene deletions, and recapitulate mutant-specific mechanisms of transcriptional dysregulation in cancer. By analyzing cell line responses to 265 compounds, we uncovered numerous TFs whose activity interacts with anticancer drugs. Importantly, combining existing pharmacogenomic markers with TF activities often improves the stratification of cell lines in response to drug treatment. Our results, which can be queried freely at dorothea.opentargets.io, offer a broad foundation for discovering opportunities to refine personalized cancer therapies. Systematic analysis of transcriptional dysregulation in cancer cell lines and patient tumor specimens offers a publicly searchable foundation to discover new opportunities to refine personalized cancer therapies. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522379PMC
February 2018

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

Nat Commun 2017 10 31;8(1):1221. Epub 2017 Oct 31.

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

Homozygous deletions are rare in cancers and often target tumour suppressor genes. Here, we build a compendium of 2218 primary tumours across 12 human cancer types and systematically screen for homozygous deletions, aiming to identify rare tumour suppressors. Our analysis defines 96 genomic regions recurrently targeted by homozygous deletions. These recurrent homozygous deletions occur either over tumour suppressors or over fragile sites, regions of increased genomic instability. We construct a statistical model that separates fragile sites from regions showing signatures of positive selection for homozygous deletions and identify candidate tumour suppressors within those regions. We find 16 established tumour suppressors and propose 27 candidate tumour suppressors. Several of these genes (including MGMT, RAD17, and USP44) show prior evidence of a tumour suppressive function. Other candidate tumour suppressors, such as MAFTRR, KIAA1551, and IGF2BP2, are novel. Our study demonstrates how rare tumour suppressors can be identified through copy number meta-analysis.
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http://dx.doi.org/10.1038/s41467-017-01355-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663922PMC
October 2017

Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations.

Genome Res 2017 04 8;27(4):613-625. Epub 2017 Feb 8.

Wellcome Trust Sanger Institute, Hinxton CB10 1SA, United Kingdom.

Drug resistance is an almost inevitable consequence of cancer therapy and ultimately proves fatal for the majority of patients. In many cases, this is the consequence of specific gene mutations that have the potential to be targeted to resensitize the tumor. The ability to uniformly saturate the genome with point mutations without chromosome or nucleotide sequence context bias would open the door to identify all putative drug resistance mutations in cancer models. Here, we describe such a method for elucidating drug resistance mechanisms using genome-wide chemical mutagenesis allied to next-generation sequencing. We show that chemically mutagenizing the genome of cancer cells dramatically increases the number of drug-resistant clones and allows the detection of both known and novel drug resistance mutations. We used an efficient computational process that allows for the rapid identification of involved pathways and druggable targets. Such a priori knowledge would greatly empower serial monitoring strategies for drug resistance in the clinic as well as the development of trials for drug-resistant patients.
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http://dx.doi.org/10.1101/gr.213546.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378179PMC
April 2017

A Landscape of Pharmacogenomic Interactions in Cancer.

Cell 2016 Jul 7;166(3):740-754. Epub 2016 Jul 7.

Genetically Defined Diseases and Genomics, Bristol-Myers Squibb Research and Development, Hopewell, NJ 08534, USA.

Systematic studies of cancer genomes have provided unprecedented insights into the molecular nature of cancer. Using this information to guide the development and application of therapies in the clinic is challenging. Here, we report how cancer-driven alterations identified in 11,289 tumors from 29 tissues (integrating somatic mutations, copy number alterations, DNA methylation, and gene expression) can be mapped onto 1,001 molecularly annotated human cancer cell lines and correlated with sensitivity to 265 drugs. We find that cell lines faithfully recapitulate oncogenic alterations identified in tumors, find that many of these associate with drug sensitivity/resistance, and highlight the importance of tissue lineage in mediating drug response. Logic-based modeling uncovers combinations of alterations that sensitize to drugs, while machine learning demonstrates the relative importance of different data types in predicting drug response. Our analysis and datasets are rich resources to link genotypes with cellular phenotypes and to identify therapeutic options for selected cancer sub-populations.
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http://dx.doi.org/10.1016/j.cell.2016.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967469PMC
July 2016

Recurrent ETNK1 mutations in atypical chronic myeloid leukemia.

Blood 2015 Jan 24;125(3):499-503. Epub 2014 Oct 24.

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.

Despite the recent identification of recurrent SETBP1 mutations in atypical chronic myeloid leukemia (aCML), a complete description of the somatic lesions responsible for the onset of this disorder is still lacking. To find additional somatic abnormalities in aCML, we performed whole-exome sequencing on 15 aCML cases. In 2 cases (13.3%), we identified somatic missense mutations in the ETNK1 gene. Targeted resequencing on 515 hematological clonal disorders revealed the presence of ETNK1 variants in 6 (8.8%) of 68 aCML and 2 (2.6%) of 77 chronic myelomonocytic leukemia samples. These mutations clustered in a small region of the kinase domain, encoding for H243Y and N244S (1/8 H243Y; 7/8 N244S). They were all heterozygous and present in the dominant clone. The intracellular phosphoethanolamine/phosphocholine ratio was, on average, 5.2-fold lower in ETNK1-mutated samples (P < .05). Similar results were obtained using myeloid TF1 cells transduced with ETNK1 wild type, ETNK1-N244S, and ETNK1-H243Y, where the intracellular phosphoethanolamine/phosphocholine ratio was significantly lower in ETNK1-N244S (0.76 ± 0.07) and ETNK1-H243Y (0.37 ± 0.02) than in ETNK1-WT (1.37 ± 0.32; P = .01 and P = .0008, respectively), suggesting that ETNK1 mutations may inhibit the catalytic activity of the enzyme. In summary, our study shows for the first time the evidence of recurrent somatic ETNK1 mutations in the context of myeloproliferative/myelodysplastic disorders.
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http://dx.doi.org/10.1182/blood-2014-06-579466DOI Listing
January 2015

Processed pseudogenes acquired somatically during cancer development.

Nat Commun 2014 Apr 9;5:3644. Epub 2014 Apr 9.

Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.

Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5' truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context.
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http://dx.doi.org/10.1038/ncomms4644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996531PMC
April 2014

Heterogeneity of genomic evolution and mutational profiles in multiple myeloma.

Nat Commun 2014 ;5:2997

Department of Hematology, University Hospital and CRCT, INSERM U1037, Toulouse 31400, France.

Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment.
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http://dx.doi.org/10.1038/ncomms3997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905727PMC
October 2015

Signatures of mutational processes in human cancer.

Nature 2013 Aug 14;500(7463):415-21. Epub 2013 Aug 14.

Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.

All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
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http://dx.doi.org/10.1038/nature12477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776390PMC
August 2013

Whole exome sequencing of adenoid cystic carcinoma.

J Clin Invest 2013 Jul 17;123(7):2965-8. Epub 2013 Jun 17.

Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom.

Adenoid cystic carcinoma (ACC) is a rare malignancy that can occur in multiple organ sites and is primarily found in the salivary gland. While the identification of recurrent fusions of the MYB-NFIB genes have begun to shed light on the molecular underpinnings, little else is known about the molecular genetics of this frequently fatal cancer. We have undertaken exome sequencing in a series of 24 ACC to further delineate the genetics of the disease. We identified multiple mutated genes that, combined, implicate chromatin deregulation in half of cases. Further, mutations were identified in known cancer genes, including PIK3CA, ATM, CDKN2A, SF3B1, SUFU, TSC1, and CYLD. Mutations in NOTCH1/2 were identified in 3 cases, and we identify the negative NOTCH signaling regulator, SPEN, as a new cancer gene in ACC with mutations in 5 cases. Finally, the identification of 3 likely activating mutations in the tyrosine kinase receptor FGFR2, analogous to those reported in ovarian and endometrial carcinoma, point to potential therapeutic avenues for a subset of cases.
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http://dx.doi.org/10.1172/JCI67201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3999050PMC
July 2013

The relative timing of mutations in a breast cancer genome.

PLoS One 2013 10;8(6):e64991. Epub 2013 Jun 10.

Hutchison/MRC Research Centre and Department of Pathology, University of Cambridge, Cambridge, United Kingdom.

Many tumors have highly rearranged genomes, but a major unknown is the relative importance and timing of genome rearrangements compared to sequence-level mutation. Chromosome instability might arise early, be a late event contributing little to cancer development, or happen as a single catastrophic event. Another unknown is which of the point mutations and rearrangements are selected. To address these questions we show, using the breast cancer cell line HCC1187 as a model, that we can reconstruct the likely history of a breast cancer genome. We assembled probably the most complete map to date of a cancer genome, by combining molecular cytogenetic analysis with sequence data. In particular, we assigned most sequence-level mutations to individual chromosomes by sequencing of flow sorted chromosomes. The parent of origin of each chromosome was assigned from SNP arrays. We were then able to classify most of the mutations as earlier or later according to whether they occurred before or after a landmark event in the evolution of the genome, endoreduplication (duplication of its entire genome). Genome rearrangements and sequence-level mutations were fairly evenly divided earlier and later, suggesting that genetic instability was relatively constant throughout the life of this tumor, and chromosome instability was not a late event. Mutations that caused chromosome instability would be in the earlier set. Strikingly, the great majority of inactivating mutations and in-frame gene fusions happened earlier. The non-random timing of some of the mutations may be evidence that they were selected.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0064991PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677865PMC
February 2014

Single-cell paired-end genome sequencing reveals structural variation per cell cycle.

Nucleic Acids Res 2013 Jul 29;41(12):6119-38. Epub 2013 Apr 29.

Department of Human Genetics, KU Leuven, Leuven, 3000, Belgium.

The nature and pace of genome mutation is largely unknown. Because standard methods sequence DNA from populations of cells, the genetic composition of individual cells is lost, de novo mutations in cells are concealed within the bulk signal and per cell cycle mutation rates and mechanisms remain elusive. Although single-cell genome analyses could resolve these problems, such analyses are error-prone because of whole-genome amplification (WGA) artefacts and are limited in the types of DNA mutation that can be discerned. We developed methods for paired-end sequence analysis of single-cell WGA products that enable (i) detecting multiple classes of DNA mutation, (ii) distinguishing DNA copy number changes from allelic WGA-amplification artefacts by the discovery of matching aberrantly mapping read pairs among the surfeit of paired-end WGA and mapping artefacts and (iii) delineating the break points and architecture of structural variants. By applying the methods, we capture DNA copy number changes acquired over one cell cycle in breast cancer cells and in blastomeres derived from a human zygote after in vitro fertilization. Furthermore, we were able to discover and fine-map a heritable inter-chromosomal rearrangement t(1;16)(p36;p12) by sequencing a single blastomere. The methods will expedite applications in basic genome research and provide a stepping stone to novel approaches for clinical genetic diagnosis.
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http://dx.doi.org/10.1093/nar/gkt345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695511PMC
July 2013

Recurrent SETBP1 mutations in atypical chronic myeloid leukemia.

Nat Genet 2013 Jan 9;45(1):18-24. Epub 2012 Dec 9.

Department of Health Sciences, University of Milano-Bicocca, Monza, Italy.

Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16-35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases.
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http://dx.doi.org/10.1038/ng.2495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3588142PMC
January 2013

The landscape of cancer genes and mutational processes in breast cancer.

Nature 2012 May 16;486(7403):400-4. Epub 2012 May 16.

Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.

All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease.
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http://dx.doi.org/10.1038/nature11017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428862PMC
May 2012

Mutational processes molding the genomes of 21 breast cancers.

Cell 2012 May 17;149(5):979-93. Epub 2012 May 17.

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.

All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis," was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed.
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http://dx.doi.org/10.1016/j.cell.2012.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3414841PMC
May 2012

The life history of 21 breast cancers.

Cell 2012 May 17;149(5):994-1007. Epub 2012 May 17.

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.

Cancer evolves dynamically as clonal expansions supersede one another driven by shifting selective pressures, mutational processes, and disrupted cancer genes. These processes mark the genome, such that a cancer's life history is encrypted in the somatic mutations present. We developed algorithms to decipher this narrative and applied them to 21 breast cancers. Mutational processes evolve across a cancer's lifespan, with many emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, and most mutations are found in just a fraction of tumor cells. Every tumor has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent cell lineages capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may therefore represent the final rate-limiting step in a breast cancer's development, triggering diagnosis.
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http://dx.doi.org/10.1016/j.cell.2012.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428864PMC
May 2012

Systematic identification of genomic markers of drug sensitivity in cancer cells.

Nature 2012 Mar 28;483(7391):570-5. Epub 2012 Mar 28.

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.
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http://dx.doi.org/10.1038/nature11005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349233PMC
March 2012

Genome sequencing and analysis of the Tasmanian devil and its transmissible cancer.

Cell 2012 Feb;148(4):780-91

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

The Tasmanian devil (Sarcophilus harrisii), the largest marsupial carnivore, is endangered due to a transmissible facial cancer spread by direct transfer of living cancer cells through biting. Here we describe the sequencing, assembly, and annotation of the Tasmanian devil genome and whole-genome sequences for two geographically distant subclones of the cancer. Genomic analysis suggests that the cancer first arose from a female Tasmanian devil and that the clone has subsequently genetically diverged during its spread across Tasmania. The devil cancer genome contains more than 17,000 somatic base substitution mutations and bears the imprint of a distinct mutational process. Genotyping of somatic mutations in 104 geographically and temporally distributed Tasmanian devil tumors reveals the pattern of evolution and spread of this parasitic clonal lineage, with evidence of a selective sweep in one geographical area and persistence of parallel lineages in other populations.
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http://dx.doi.org/10.1016/j.cell.2011.11.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281993PMC
February 2012

Large duplications at reciprocal translocation breakpoints that might be the counterpart of large deletions and could arise from stalled replication bubbles.

Genome Res 2011 Apr 20;21(4):525-34. Epub 2011 Jan 20.

Hutchison/MRC Research Centre and Department of Pathology, University of Cambridge, Cambridge, UK.

Reciprocal chromosome translocations are often not exactly reciprocal. Most familiar are deletions at the breakpoints, up to megabases in extent. We describe here the opposite phenomenon-duplication of tens or hundreds of kilobases at the breakpoint junction, so that the same sequence is present on both products of a translocation. When the products of the translocation are mapped on the genome, they overlap. We report several of these "overlapping-breakpoint" duplications in breast cancer cell lines HCC1187, HCC1806, and DU4475. These lines also had deletions and essentially balanced translocations. In HCC1187 and HCC1806, we identified five cases of duplication ranging between 46 kb and 200 kb, with the partner chromosome showing deletions between 29 bp and 31 Mb. DU4475 had a duplication of at least 200 kb. Breakpoints were mapped using array painting, i.e., hybridization of chromosomes isolated by flow cytometry to custom oligonucleotide microarrays. Duplications were verified by fluorescent in situ hybridization (FISH), PCR on isolated chromosomes, and cloning of breakpoints. We propose that these duplications are the counterpart of deletions and that they are produced at a replication bubble, comprising two replication forks with the duplicated sequence in between. Both copies of the duplicated sequence would go to one daughter cell, on different products of the translocation, while the other daughter cell would show deletion. These duplications may have been overlooked because they may be missed by FISH and array-CGH and may be interpreted as insertions by paired-end sequencing. Such duplications may therefore be quite frequent.
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http://dx.doi.org/10.1101/gr.114116.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065700PMC
April 2011

Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma.

Nature 2011 Jan 19;469(7331):539-42. Epub 2011 Jan 19.

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.

The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ∼3,500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.
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http://dx.doi.org/10.1038/nature09639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030920PMC
January 2011

Massive genomic rearrangement acquired in a single catastrophic event during cancer development.

Cell 2011 Jan;144(1):27-40

Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

Cancer is driven by somatically acquired point mutations and chromosomal rearrangements, conventionally thought to accumulate gradually over time. Using next-generation sequencing, we characterize a phenomenon, which we term chromothripsis, whereby tens to hundreds of genomic rearrangements occur in a one-off cellular crisis. Rearrangements involving one or a few chromosomes crisscross back and forth across involved regions, generating frequent oscillations between two copy number states. These genomic hallmarks are highly improbable if rearrangements accumulate over time and instead imply that nearly all occur during a single cellular catastrophe. The stamp of chromothripsis can be seen in at least 2%-3% of all cancers, across many subtypes, and is present in ∼25% of bone cancers. We find that one, or indeed more than one, cancer-causing lesion can emerge out of the genomic crisis. This phenomenon has important implications for the origins of genomic remodeling and temporal emergence of cancer.
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http://dx.doi.org/10.1016/j.cell.2010.11.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065307PMC
January 2011

GLO1-A novel amplified gene in human cancer.

Genes Chromosomes Cancer 2010 Aug;49(8):711-25

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

To identify a novel amplified cancer gene a systematic screen of 975 human cancer DNA samples, 750 cell lines and 225 primary tumors, using the Affymetrix 10K SNP microarray was undertaken. The screen identified 193 amplicons. A previously uncharacterized amplicon located on 6p21.2 whose 1 Mb minimal common amplified region contained eight genes (GLO1, DNAH8, GLP1R, C6orf64, KCNK5, KCNK17, KCNK16, and C6orf102) was further investigated to determine which gene(s) are the biological targets of this amplicon. Real time quantitative PCR (qPCR) analysis of all amplicon 6p21.2 genes in 618 human cancer cell lines identified GLO1, encoding glyoxalase 1, to be the most frequently amplified gene [twofold or greater amplification in 8.4% (49/536) of cancers]. Also the association between amplification and overexpression was greatest for GLO1. RNAi knockdown of GLO1 had the greatest and most consistent impact on cell accumulation and apoptosis. Cell lines with GLO1 amplification were more sensitive to inhibition of GLO1 by bromobenzylglutathione cyclopentyl diester (BBGC). Subsequent qPCR of 520 primary tumor samples identified twofold and greater amplification of GLO1 in 8/37 (22%) of breast, 12/71 (17%) of sarcomas, 6/53 (11.3%) of nonsmall cell lung, 2/23 (8.7%) of bladder, 6/93 (6.5%) of renal and 5/83 (6%) of gastric cancers. Amplification of GLO1 was rare in colon cancer (1/35) and glioma (1/94). Collectively the results indicate that GLO1 is at least one of the targets of gene amplification on 6p21.2 and may represent a useful target for therapy in cancers with GLO1 amplification.
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http://dx.doi.org/10.1002/gcc.20784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398139PMC
August 2010

Signatures of mutation and selection in the cancer genome.

Nature 2010 Feb;463(7283):893-8

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

The cancer genome is moulded by the dual processes of somatic mutation and selection. Homozygous deletions in cancer genomes occur over recessive cancer genes, where they can confer selective growth advantage, and over fragile sites, where they are thought to reflect an increased local rate of DNA breakage. However, most homozygous deletions in cancer genomes are unexplained. Here we identified 2,428 somatic homozygous deletions in 746 cancer cell lines. These overlie 11% of protein-coding genes that, therefore, are not mandatory for survival of human cells. We derived structural signatures that distinguish between homozygous deletions over recessive cancer genes and fragile sites. Application to clusters of unexplained homozygous deletions suggests that many are in regions of inherent fragility, whereas a small subset overlies recessive cancer genes. The results illustrate how structural signatures can be used to distinguish between the influences of mutation and selection in cancer genomes. The extensive copy number, genotyping, sequence and expression data available for this large series of publicly available cancer cell lines renders them informative reagents for future studies of cancer biology and drug discovery.
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http://dx.doi.org/10.1038/nature08768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145113PMC
February 2010

Novel candidate cancer genes identified by a large-scale cross-species comparative oncogenomics approach.

Cancer Res 2010 Feb 26;70(3):883-95. Epub 2010 Jan 26.

The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom.

Comparative genomic hybridization (CGH) can reveal important disease genes but the large regions identified could sometimes contain hundreds of genes. Here we combine high-resolution CGH analysis of 598 human cancer cell lines with insertion sites isolated from 1,005 mouse tumors induced with the murine leukemia virus (MuLV). This cross-species oncogenomic analysis revealed candidate tumor suppressor genes and oncogenes mutated in both human and mouse tumors, making them strong candidates for novel cancer genes. A significant number of these genes contained binding sites for the stem cell transcription factors Oct4 and Nanog. Notably, mice carrying tumors with insertions in or near stem cell module genes, which are thought to participate in cell self-renewal, died significantly faster than mice without these insertions. A comparison of the profile we identified to that induced with the Sleeping Beauty (SB) transposon system revealed significant differences in the profile of recurrently mutated genes. Collectively, this work provides a rich catalogue of new candidate cancer genes for functional analysis.
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http://dx.doi.org/10.1158/0008-5472.CAN-09-1737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880710PMC
February 2010

Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes.

Nature 2010 Jan 6;463(7279):360-3. Epub 2010 Jan 6.

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.

Clear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer, characterized by the presence of inactivating mutations in the VHL gene in most cases, and by infrequent somatic mutations in known cancer genes. To determine further the genetics of ccRCC, we have sequenced 101 cases through 3,544 protein-coding genes. Here we report the identification of inactivating mutations in two genes encoding enzymes involved in histone modification-SETD2, a histone H3 lysine 36 methyltransferase, and JARID1C (also known as KDM5C), a histone H3 lysine 4 demethylase-as well as mutations in the histone H3 lysine 27 demethylase, UTX (KMD6A), that we recently reported. The results highlight the role of mutations in components of the chromatin modification machinery in human cancer. Furthermore, NF2 mutations were found in non-VHL mutated ccRCC, and several other probable cancer genes were identified. These results indicate that substantial genetic heterogeneity exists in a cancer type dominated by mutations in a single gene, and that systematic screens will be key to fully determining the somatic genetic architecture of cancer.
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http://dx.doi.org/10.1038/nature08672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820242PMC
January 2010

A comprehensive catalogue of somatic mutations from a human cancer genome.

Nature 2010 Jan 16;463(7278):191-6. Epub 2009 Dec 16.

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

All cancers carry somatic mutations. A subset of these somatic alterations, termed driver mutations, confer selective growth advantage and are implicated in cancer development, whereas the remainder are passengers. Here we have sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person, providing the first comprehensive catalogue of somatic mutations from an individual cancer. The catalogue provides remarkable insights into the forces that have shaped this cancer genome. The dominant mutational signature reflects DNA damage due to ultraviolet light exposure, a known risk factor for malignant melanoma, whereas the uneven distribution of mutations across the genome, with a lower prevalence in gene footprints, indicates that DNA repair has been preferentially deployed towards transcribed regions. The results illustrate the power of a cancer genome sequence to reveal traces of the DNA damage, repair, mutation and selection processes that were operative years before the cancer became symptomatic.
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http://dx.doi.org/10.1038/nature08658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145108PMC
January 2010