Showing papers by "Michael R. Stratton published in 2014"
TL;DR: The current understanding of mutational patterns and mutational signatures in light of both the somatic cell paradigm of cancer research and the recent developments in the field of cancer genomics is summarized.
433 citations
Wellcome Trust Sanger Institute1, Cambridge University Hospitals NHS Foundation Trust2, University of New South Wales3, Harvard University4, Institute of Cancer Research5, University of Oxford6, University of Texas MD Anderson Cancer Center7, University of Nottingham8, National Institutes of Health9, University of North Carolina at Chapel Hill10, University of Toronto11, University of Liverpool12, University of Cambridge13, University of Tampere14, Johns Hopkins University15, Royal National Orthopaedic Hospital16, Newcastle University17
TL;DR: This study analyzed somatic alterations in mtDNA from 1675 tumors and identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand.
Abstract: Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication.
391 citations
Wellcome Trust Sanger Institute1, University of Santiago de Compostela2, University College London3, University of Bergen4, Haukeland University Hospital5, Katholieke Universiteit Leuven6, University of Cambridge7, University of Liverpool8, Institute of Cancer Research9, University of East Anglia10, University of Tampere11, Johns Hopkins University12, Netherlands Cancer Institute13, Université libre de Bruxelles14, Erasmus University Medical Center15, University of Iceland16, Royal Brisbane and Women's Hospital17, University of Queensland18, University of Lyon19, Oslo University Hospital20, Radboud University Nijmegen21, Harvard University22, Curie Institute23, Royal National Orthopaedic Hospital24, University of Texas MD Anderson Cancer Center25
TL;DR: It is found that 3′ transduction activity in a patient’s tumor was always associated with hypomethylation of that element, and in some cases transduction events can scatter exons, genes, and regulatory elements widely across the genome.
Abstract: Long interspersed nuclear element-1 (L1) retrotransposons are mobile repetitive elements that are abundant in the human genome. L1 elements propagate through RNA intermediates. In the germ line, neighboring, nonrepetitive sequences are occasionally mobilized by the L1 machinery, a process called 3' transduction. Because 3' transductions are potentially mutagenic, we explored the extent to which they occur somatically during tumorigenesis. Studying cancer genomes from 244 patients, we found that tumors from 53% of the patients had somatic retrotranspositions, of which 24% were 3' transductions. Fingerprinting of donor L1s revealed that a handful of source L1 elements in a tumor can spawn from tens to hundreds of 3' transductions, which can themselves seed further retrotranspositions. The activity of individual L1 elements fluctuated during tumor evolution and correlated with L1 promoter hypomethylation. The 3' transductions disseminated genes, exons, and regulatory elements to new locations, most often to heterochromatic regions of the genome.
338 citations
TL;DR: Differences were observed between tissues in the numbers and types of mutations accumulated by each cell, which likely reflect differences in the number of cell divisions they have undergone and varying contributions of different mutational processes.
Abstract: The somatic mutations present in the genome of a cell accumulate over the lifetime of a multicellular organism. These mutations can provide insights into the developmental lineage tree, the number of divisions that each cell has undergone and the mutational processes that have been operative. Here we describe whole genomes of clonal lines derived from multiple tissues of healthy mice. Using somatic base substitutions, we reconstructed the early cell divisions of each animal, demonstrating the contributions of embryonic cells to adult tissues. Differences were observed between tissues in the numbers and types of mutations accumulated by each cell, which likely reflect differences in the number of cell divisions they have undergone and varying contributions of different mutational processes. If somatic mutation rates are similar to those in mice, the results indicate that precise insights into development and mutagenesis of normal human cells will be possible.
315 citations
TL;DR: A remarkably parsimonious mutational process transforms ETV6-RUNX1–positive lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B cell differentiation.
Abstract: The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL) cases, is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near breakpoints, incorporation of non-templated sequence at junctions, ∼30-fold enrichment at promoters and enhancers of genes actively transcribed in B cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single-cell tracking shows that this mechanism is active throughout leukemic evolution, with evidence of localized clustering and reiterated deletions. Integration of data on point mutations and rearrangements identifies ATF7IP and MGA as two new tumor-suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1-positive lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B cell differentiation.
305 citations
TL;DR: It is shown that breast cancers in carriers of the deletion show more mutations of the putative APOBEC-dependent genome-wide signatures than cancers in non-carriers, suggesting that the APOB EC3A-APOBEC3B germline deletion allele confers cancer susceptibility through increased activity of APOBec-dependent mutational processes.
Abstract: Mike Stratton and colleague show that carriers of a germline copy number polymorphism involving APOBEC3A and APOBEC3B, which has been associated with increased risk of breast cancer, show more mutations characteristic of APOBEC-dependent mutational processes than cancers in non-carriers.
263 citations
Wellcome Trust Sanger Institute1, University of Cambridge2, University of Oxford3, Katholieke Universiteit Leuven4, University College London5, Royal National Orthopaedic Hospital6, Oslo University Hospital7, The Breast Cancer Research Foundation8, Medical Research Council9, John Radcliffe Hospital10, University of Texas MD Anderson Cancer Center11, University Hospital of Basel12, Pfizer13
TL;DR: This work employed whole-genome, whole-exome and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma, and identified recurrent mutations in two genes, PTPRB and PLCG1, which are intimately linked to angiogenesis.
Abstract: Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionizing radiation or chronic lymphoedema. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signaling genes, as a key driver of angiosarcoma. Here we employed whole-genome, whole-exome and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, PTPRB and PLCG1, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harbored predominantly truncating mutations in 10 of 39 tumors (26%). PLCG1, a signal transducer of tyrosine kinases, encoded a recurrent, likely activating p.Arg707Gln missense variant in 3 of 34 cases (9%). Overall, 15 of 39 tumors (38%) harbored at least one driver mutation in angiogenesis signaling genes. Our findings inform and reinforce current therapeutic efforts to target angiogenesis signaling in angiosarcoma.
252 citations
Wellcome Trust Sanger Institute1, Newcastle University2, Salisbury NHS Foundation Trust3, University of Birmingham4, Ohio State University5, University of Alabama at Birmingham6, National Health Service7, Newcastle upon Tyne Hospitals NHS Foundation Trust8, University of Manchester9, University of Porto10, Katholieke Universiteit Leuven11, University of Cambridge12
TL;DR: It is shown that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have approximately 2,700-fold increased risk of developing iAMP21 ALL compared to the general population.
Abstract: Changes in gene dosage are a major driver of cancer, known to be caused by a finite, but increasingly well annotated, repertoire of mutational mechanisms1. This can potentially generate correlated copy-number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukaemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21)2, 3. We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL. Here we show that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have approximately 2,700-fold increased risk of developing iAMP21 ALL compared to the general population. In such cases, amplification is initiated by a chromothripsis event involving both sister chromatids of the Robertsonian chromosome, a novel mechanism for cancer predisposition. In sporadic iAMP21, breakage-fusion-bridge cycles are typically the initiating event, often followed by chromothripsis. In both sporadic and rob(15;21)c-associated iAMP21, the final stages frequently involve duplications of the entire abnormal chromosome. The end-product is a derivative of chromosome 21 or the rob(15;21)c chromosome with gene dosage optimized for leukaemic potential, showing constrained copy-number levels over multiple linked genes. Thus, dicentric chromosomes may be an important precipitant of chromothripsis, as we show rob(15;21)c to be constitutionally dicentric and breakage-fusion-bridge cycles generate dicentric chromosomes somatically. Furthermore, our data illustrate that several cancer-specific mutational processes, applied sequentially, can coordinate to fashion copy-number profiles over large genomic scales, incrementally refining the fitness benefits of aggregated gene dosage changes.
232 citations
TL;DR: Experimental model systems combined with genome sequencing can recapture and mechanistically explain mutational signatures associated with human disease.
Abstract: Mutation is associated with developmental and hereditary disorders, aging, and cancer. While we understand some mutational processes operative in human disease, most remain mysterious. We used Caenorhabditis elegans whole-genome sequencing to model mutational signatures, analyzing 183 worm populations across 17 DNA repair-deficient backgrounds propagated for 20 generations or exposed to carcinogens. The baseline mutation rate in C. elegans was approximately one per genome per generation, not overtly altered across several DNA repair deficiencies over 20 generations. Telomere erosion led to complex chromosomal rearrangements initiated by breakage–fusion–bridge cycles and completed by simultaneously acquired, localized clusters of breakpoints. Aflatoxin B1 induced substitutions of guanines in a GpC context, as observed in aflatoxin-induced liver cancers. Mutational burden increased with impaired nucleotide excision repair. Cisplatin and mechlorethamine, DNA crosslinking agents, caused dose- and genotype-dependent signatures among indels, substitutions, and rearrangements. Strikingly, both agents induced clustered rearrangements resembling “chromoanasynthesis,” a replication-based mutational signature seen in constitutional genomic disorders, suggesting that interstrand crosslinks may play a pathogenic role in such events. Cisplatin mutagenicity was most pronounced in xpf-1 mutants, suggesting that this gene critically protects cells against platinum chemotherapy. Thus, experimental model systems combined with genome sequencing can recapture and mechanistically explain mutational signatures associated with human disease.
167 citations
TL;DR: Although CTVT has acquired a massive number of genomic alterations, including hundreds of times more somatic mutations than are normally found in human cancers, the tumor cell genome has remained diploid and stable.
Abstract: Canine transmissible venereal tumor (CTVT) is the oldest known somatic cell lineage. It is a transmissible cancer that propagates naturally in dogs. We sequenced the genomes of two CTVT tumors and found that CTVT has acquired 1.9 million somatic substitution mutations and bears evidence of exposure to ultraviolet light. CTVT is remarkably stable and lacks subclonal heterogeneity despite thousands of rearrangements, copy-number changes, and retrotransposon insertions. More than 10,000 genes carry nonsynonymous variants, and 646 genes have been lost. CTVT first arose in a dog with low genomic heterozygosity that may have lived about 11,000 years ago. The cancer spawned by this individual dispersed across continents about 500 years ago. Our results provide a genetic identikit of an ancient dog and demonstrate the robustness of mammalian somatic cells to survive for millennia despite a massive mutation burden.
157 citations
TL;DR: The dynamics of protein and mRNA expression levels across a minimally perturbed cell cycle in human myeloid leukemia cells are chronicled using centrifugal elutriation combined with mass spectrometry-based proteomics and RNA-Seq, avoiding artificial synchronization procedures.
Abstract: Technological advances have enabled the analysis of cellular protein and RNA levels with unprecedented depth and sensitivity, allowing for an unbiased re-evaluation of gene regulation during fundamental biological processes. Here, we have chronicled the dynamics of protein and mRNA expression levels across a minimally perturbed cell cycle in human myeloid leukemia cells using centrifugal elutriation combined with mass spectrometry-based proteomics and RNA-Seq, avoiding artificial synchronization procedures. We identify myeloid-specific gene expression and variations in protein abundance, isoform expression and phosphorylation at different cell cycle stages. We dissect the relationship between protein and mRNA levels for both bulk gene expression and for over ∼6000 genes individually across the cell cycle, revealing complex, gene-specific patterns. This data set, one of the deepest surveys to date of gene expression in human cells, is presented in an online, searchable database, the Encyclopedia of Proteome Dynamics (http://www.peptracker.com/epd/). DOI: http://dx.doi.org/10.7554/eLife.01630.001.
Wellcome Trust Sanger Institute1, University College London2, Johns Hopkins University3, University of Nottingham4, University of Toronto5, Harvard University6, Royal National Orthopaedic Hospital7, Peter MacCallum Cancer Centre8, Université libre de Bruxelles9, Memorial Sloan Kettering Cancer Center10, National Institutes of Health11, University of North Carolina at Chapel Hill12
TL;DR: Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications, consensus TTTTAA sites at insertion points, inverted rearrangements and polyA tails, and transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes.
Abstract: 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.
TL;DR: A 2 years old child presenting with three separate cancers over a 6 month period; two soft tissue mesenchymal tumors and an aggressive metastatic neuroblastoma demonstrates pathogenic mosaicim, detected by next generation deep sequencing, that arose in the early stages of embryogenesis.
Abstract: Background
Li-Fraumeni syndrome is caused by germline TP53 mutations and is clinically characterized by a predisposition to a range of cancers, most commonly sarcoma, brain tumours and leukemia. Pathogenic mosaic TP53 mutations have only rarely been described.
Methods and Findings
We describe a 2 years old child presenting with three separate cancers over a 6 month period; two soft tissue mesenchymal tumors and an aggressive metastatic neuroblastoma. As conventional testing of blood DNA by Sanger sequencing for mutations in TP53, ALK, and SDH was negative, whole exome sequencing of the blood DNA of the patient and both parents was performed to screen more widely for cancer predisposing mutations. In the patient's but not the parents' DNA we found a c.743 G>A, p.Arg248Gln (CCDS11118.1) TP53 mutation in 3–20% of sequencing reads, a level that would not generally be detectable by Sanger sequencing. Homozygosity for this mutation was detected in all tumor samples analyzed, and germline mosaicism was demonstrated by analysis of the child's newborn blood spot DNA. The occurrence of separate tumors derived from different germ layers suggests that this de novo mutation occurred early in embryogenesis, prior to gastrulation.
Conclusion
The case demonstrates pathogenic mosaicim, detected by next generation deep sequencing, that arose in the early stages of embryogenesis.
01 Jan 2014
TL;DR: All analysed strains originate from single hybridisation event, as most of LOH events are shared by all strains, and some selected duplications and deletions among those longer than 5Kb are represented.
Abstract: Candida metapsilosis chromosomes graphs For each chromosome we have plotted: i) coding genes for +/-strand (grey bars) and GC-content in 1kb windows (blue plot) in the bottom track and log2 of observed vs expected value in 1kb windows for depth of coverage (blue) in the top fourteen tracks. In the bottom panel, the X axis reflects the genomic position given in bp (from 0 up to 3.25Mb for the longest chromosome), while the Y axis the GC% content (0-100%). In the other panels the Y axis reflect the log2 of observed vs expected depth-of-coverage (from-4 to +4). In addition, loss of heterozygosity (LOH) regions have been marked in grey, if the same genotype as reference was kept (hapA), and orange, if alternative genotype was kept (hapB). Four replicas (pe300, pe600, mp500 and pe400ov) were analysed for PL429. C. metapsilosis genome is a mixture of heterozygous (light grey), haplotype B (dark grey) and haplotype A (orange) regions. We suspect all analysed strains originate from single hybridisation event, as most of LOH events are shared by all strains. Examples of large LOH, duplications and deletions have been annotated ie. rDNA cluster (scaffold5), scaffold5 triploidy in PL448, partial scaffold2 triploidy in SZMC21154 and PL448, and complete LOH in scaffold6 in PL448. For the sake of simplicity, only some selected duplications and deletions among those longer than 5Kb are represented (annotated as such in Supplementary table S4). rDNA cluster is found on the edge of the largest LOH (over 350kb, scaffold5). Interestingly, we have also found rDNA cluster in long (200kb) LOH track in C. orthopsilosis MCO448 (PMID: 24747362).
Wellcome Trust Sanger Institute1, University of Cambridge2, Cambridge University Hospitals NHS Foundation Trust3, University of New South Wales4, National University of Singapore5, Harvard University6, Institute of Cancer Research7, University of Oxford8, University of Texas MD Anderson Cancer Center9, University of Nottingham10, National Institutes of Health11, University of North Carolina at Chapel Hill12, University of Toronto13, University of Liverpool14, University of East Anglia15, University of Tampere16, Johns Hopkins University17, University College London18, Royal National Orthopaedic Hospital19, Newcastle University20
TL;DR: These findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria, and is fundamentally linked to mtDNA replication.
Abstract: Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA
Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of human cancers. Although mitochondria in cancer cells have important roles in energy metabolism and survival, the origins and impact of somatic mutations in mitochondrial DNA (mtDNA) are unclear. Here, we provide a comprehensive analysis of somatic alterations in cancer mitochondria from 1,675 genome sequences across 31 tumor types. We identified 1,907 somatic substitutions which were mainly C:G>T:A and T:A>C:G. These mutations exhibited dramatic replicative strand bias, being almost all C>T and A>G on the mitochondrial heavy strand. This strand-asymmetric mitochondrial mutational signature is different from those found in nuclear cancer genomes but is similar to processes shaping human mtDNA sequence over evolutionary time. The number of mtDNA mutations showed considerable heterogeneity across tumor types, being significantly higher in tumors from gastrointestinal and hepatobiliary systems. With respect to selection, observed missense mutations were nearly neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation showed evidence of negative selection and were more frequently heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria, and is fundamentally linked to mtDNA replication.
Citation Format: Young Seok Ju, Ludmil Alexandrov, Moritz Gerstung, Inigo Martincorena, ICGC Breast Cancer Group; ICGC Chronic Myeloid Disorders Group; ICGC Prostate Cancer Group, Mike Stratton, Peter J. Campbell. The landscape of mitochondrial DNA mutations in human cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4322. doi:10.1158/1538-7445.AM2014-4322
TL;DR: In this paper, distinct H3F3A and H 3F3B driver mutations were defined for chondroblastoma and giant cell tumor of bone, respectively, and they were shown to be useful for diagnosis of bone cancer.
Abstract: Corrigendum: Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone
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01 Jan 2014
TL;DR: Nucleic composition comparison baseon NatAnaerobicFreq NCBAnaerilicFreq NatAeroAnaeroFreqRatio NCBAerobicFreQ NatBacteriaFreq 1 A 1 28.46 28.79 28.32 28.64 26.74 6 T 2 30.32 30.09 31.74 1.14 1.12 8 23.91 1.17 1.00 10 24.74 0.99 0.86 0.
Abstract: Nucleic composition comparison base codon NatAnaerobicFreq NCBAnaerobicFreq NatAerobicFreq NCBAerobicFreq NatBacteriaFreq 1 A 1 28.46 28.76 22.29 23.65 24.88 2 T 1 17.34 17.49 14.44 16.03 15.92 3 G 1 34.53 34.53 38.07 38.07 36.28 4 C 1 19.67 19.22 25.21 22.25 22.92 5 A 2 31.09 31.09 26.64 26.70 28.74 6 T 2 30.32 30.32 28.79 28.79 29.58 7 G 2 16.98 16.90 19.29 18.99 17.99 8 C 2 21.61 21.69 25.28 25.52 23.69 9 A 3 22.75 24.42 12.87 24.42 17.89 10 T 3 26.74 24.95 16.15 24.71 21.91 11 G 3 24.00 25.66 32.72 26.15 28.55 12 C 3 26.52 24.98 38.26 24.72 31.65 NCBBacteriaFreq NatAeroAnaeroFreqRatio NCBAeroAnaeroFreqRatio 1 25.84 0.78 0.82 2 16.63 0.83 0.92 3 36.28 1.10 1.10 4 21.24 1.28 1.16 5 28.77 0.86 0.86 6 29.58 0.95 0.95 7 17.74 1.14 1.12 8 23.91 1.17 1.18 9 24.48 0.57 1.00 10 24.74 0.60 0.99 11 26.03 1.36 1.02 12 24.74 1.44 0.99
TL;DR: The 67th COSMIC release includes copy number mutations integrated into the database and major web page views, and is building systems to better highlight known or putative functional mutations, improving the signal-to-noise ratio of cancer genome resequencing.
Abstract: Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA
COSMIC, the Catalogue Of Somatic Mutations In Cancer (http://cancer.sanger.ac.uk) is the world's largest and most comprehensive online resource for exploring the impact of somatic mutations in human cancer. Now running for over 10 years, the 67th release (Oct 2013) describes 1592109 mutations in 947213 tumour samples across 25606 genes. This information is curated manually from the scientific literature, and automatically from genome resequencing consortium data portals. Full curation of the scientific literature provides in-depth understanding of the impact that each gene has in human cancer, and this has been achieved for 127 point-mutated cancer genes, and 185 fusion gene pairs. Curated genes are selected from the Cancer Gene Census (http://cancer.sanger.ac.uk/census), a listing of all genes with substantial evidence implicating them in cancer promotion, currently numbering 513 and updated frequently.
The mutations discovered in the re-sequencing of over 8000 tumour genomes are now present in COSMIC (viewable in isolation from the genic curations, http://cancer.sanger.ac.uk/wgs). In addition, the Sanger has now fully exome sequenced 1015 common cancer cell lines, identifying 1146874 coding mutations annotated for functional significance, and this is available exclusively in COSMIC at (http://cancer.sanger.ac.uk/cell_lines). While COSMIC has focused on point mutations and gene fusions, many other mutation mechanisms cause oncogenesis and these are now being integrated. The 67th COSMIC release includes copy number mutations integrated into the database and major web page views. To allow easy graphical examination of this data, copy number information was reduced to ‘gain’ and ‘loss’ annotations for inclusion in histograms and tables, with much more precise detail available with a further click. Copy number data is available in detail for every gene in COSMIC, and also for every tissue. Exploring cancer via COSMIC’s Cancer Browser (http://cancer.sanger.ac.uk/cosmic/browse/tissue), results not just in a plot of the most mutated genes, but now also a circular genome plot summarizing the copy number gains and losses across all the samples from that tumour type, all explorable in more detail via clicks on the pictures.
As the genomic data increases in COSMIC, it is becoming more important to qualitatively annotate the information, indicating which is more important or significant to oncogenesis. We are now building systems to better highlight known or putative functional mutations, improving the signal-to-noise ratio of cancer genome resequencing.
Citation Format: C Boutselakis, S A. Forbes, P Gunasekaran, M Jia, D Beare, N Bindal, C Y. Kok, K Leung, D Minjie, R Shepherd, S Bamford, S Ward, C Cole, J W. Teague, M Stratton, P Campbell, U McDermott. COSMIC: Enhancing the world's knowledge of somatic mutations in human cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5326. doi:10.1158/1538-7445.AM2014-5326
TL;DR: The diversity between multiple samples from 49 patient’s primary breast tumors is explored, finding branching heterogeneity in 11/13 surgical samples (including ER positive, triple negative and HER2+ subtypes).
Abstract: 11004 Background: The targeting of new cancer therapeutics will be driven by genomic analysis of an individual’s tumor. It is questionable that standard sampling approaches that utilize slices from...
TL;DR: The genomic characterisation of 1015 cancer cell lines currently being used as reagents in a high-throughput screen of anti-cancer agents is presented, aiding in identifying the underlying genetics of drug sensitivity and allow for identification of biomarkers with which to stratify patients.
Abstract: Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA
Over the last twenty years there has been a paradigm shift in cancer treatment, moving away from the cytotoxic effects of chemicals targeting all cells going through cell division to a more targeted approach aimed at inactivating specific cellular components upon which the cancers rely to drive cell growth, a process termed oncogene addiction. The ‘poster child’ for such therapies is ‘imatinib' a small molecule inhibitor of ABL kinase activity targeting the BCR-ABL fusion protein in CML.
We present the genomic characterisation of 1015 cancer cell lines currently being used as reagents in a high-throughput screen of anti-cancer agents. Future analysis combining these genomic and drug resistance data will aid in identifying the underlying genetics of drug sensitivity and allow for identification of biomarkers with which to stratify patients, identifying those most likely to respond to specific cancer therapies. To characterise the cell lines we performed exome sequencing and copy number analysis. Since most cell lines are unmatched we screened out germline variants by comparison to ∼8000 normal exomes, giving a set of ∼500,000 putative somatic non-synonymous variants. To reduce the ‘genetic space’ for the subsequent downstream correlation to drug response data we further filtered the variants to identify those most likely to have a functional effect or contribute to carcinogenesis. Two such filters were applied, the ‘Functional Analysis through Hidden Markov Models’ (FATHMM) algorithm and a series of checks identifying recurrence of variants in the ‘systematic screening data' held in the COSMIC database. Application of these filters reduced the number of variants to be taken forward to ∼115,000 and 30,000 respectively. The variant data for the cancer cell lines is available via the COSMIC web portal.
Citation Format: Graham R. Bignell, Francesco Iorio, Andrew Futreal, Michael R. Stratton, Peter Campbell, Ultan McDermott. Genomic characterisation of 1015 cancer cell-lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2218. doi:10.1158/1538-7445.AM2014-2218