Showing papers by "Michael R. Stratton published in 2017"
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Howard Hughes Medical Institute1, Broad Institute2, Massachusetts Institute of Technology3, Wellcome Trust Sanger Institute4, European Bioinformatics Institute5, University of Cambridge6, Harvard University7, Weizmann Institute of Science8, University of Zurich9, Laboratory of Molecular Biology10, Utrecht University11, École Polytechnique Fédérale de Lausanne12, University of Pennsylvania13, Heidelberg University14, German Cancer Research Center15, Ludwig Maximilian University of Munich16, John Radcliffe Hospital17, Newcastle University18, Stanford University19, University of Oxford20, University of California, San Francisco21, Allen Institute for Brain Science22, Karolinska Institutet23, Royal Institute of Technology24, Icahn School of Medicine at Mount Sinai25, University of Cape Town26, University Medical Center Groningen27, Radboud University Nijmegen28, Kettering University29, University of Edinburgh30, Babraham Institute31, New York University32, Netherlands Cancer Institute33, Ragon Institute of MGH, MIT and Harvard34, University of Texas Health Science Center at Houston35, Technische Universität München36, Technical University of Denmark37, University of California, Berkeley38, King's College London39, California Institute of Technology40
TL;DR: An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease.
Abstract: The recent advent of methods for high-throughput single-cell molecular profiling has catalyzed a growing sense in the scientific community that the time is ripe to complete the 150-year-old effort to identify all cell types in the human body. The Human Cell Atlas Project is an international collaborative effort that aims to define all human cell types in terms of distinctive molecular profiles (such as gene expression profiles) and to connect this information with classical cellular descriptions (such as location and morphology). An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease. Here we describe the idea, its potential utility, early proofs-of-concept, and some design considerations for the Human Cell Atlas, including a commitment to open data, code, and community.
1,391 citations
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TL;DR: This work adapted methods from molecular evolution and applied them to 7,664 tumors across 29 cancer types, allowing exome-wide enumeration of all driver coding mutations, including outside known cancer genes.
938 citations
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Wellcome Trust Sanger Institute1, Guy's and St Thomas' NHS Foundation Trust2, Lund University3, AstraZeneca4, Erasmus University Medical Center5, University of Queensland6, Memorial Sloan Kettering Cancer Center7, University of Iceland8, Hanyang University9, Wellcome Trust10, Radboud University Nijmegen11, University of Amsterdam12, University of Oslo13, Royal Brisbane and Women's Hospital14, Curie Institute15, Université libre de Bruxelles16, King's College London17, University of Antwerp18, Harvard University19, Cambridge University Hospitals NHS Foundation Trust20
TL;DR: In this article, a weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples with 98.7% sensitivity (area under the curve (AUC) = 0.98).
Abstract: Approximately 1-5% of breast cancers are attributed to inherited mutations in BRCA1 or BRCA2 and are selectively sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. In other cancer types, germline and/or somatic mutations in BRCA1 and/or BRCA2 (BRCA1/BRCA2) also confer selective sensitivity to PARP inhibitors. Thus, assays to detect BRCA1/BRCA2-deficient tumors have been sought. Recently, somatic substitution, insertion/deletion and rearrangement patterns, or 'mutational signatures', were associated with BRCA1/BRCA2 dysfunction. Herein we used a lasso logistic regression model to identify six distinguishing mutational signatures predictive of BRCA1/BRCA2 deficiency. A weighted model called HRDetect was developed to accurately detect BRCA1/BRCA2-deficient samples. HRDetect identifies BRCA1/BRCA2-deficient tumors with 98.7% sensitivity (area under the curve (AUC) = 0.98). Application of this model in a cohort of 560 individuals with breast cancer, of whom 22 were known to carry a germline BRCA1 or BRCA2 mutation, allowed us to identify an additional 22 tumors with somatic loss of BRCA1 or BRCA2 and 47 tumors with functional BRCA1/BRCA2 deficiency where no mutation was detected. We validated HRDetect on independent cohorts of breast, ovarian and pancreatic cancers and demonstrated its efficacy in alternative sequencing strategies. Integrating all of the classes of mutational signatures thus reveals a larger proportion of individuals with breast cancer harboring BRCA1/BRCA2 deficiency (up to 22%) than hitherto appreciated (∼1-5%) who could have selective therapeutic sensitivity to PARP inhibition.
710 citations
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Wellcome Trust Sanger Institute1, University of Bergen2, Haukeland University Hospital3, University of Oxford4, University of Cambridge5, European Bioinformatics Institute6, Los Alamos National Laboratory7, University of New Mexico8, Francis Crick Institute9, Katholieke Universiteit Leuven10, Memorial Sloan Kettering Cancer Center11, King's College London12, Université libre de Bruxelles13, Erasmus University Medical Center14, Harvard University15, Brigham and Women's Hospital16, Institute of Cancer Research17
TL;DR: Several lines of analysis indicate that clones seeding metastasis or relapse disseminate late from primary tumors, but continue to acquire mutations, mostly accessing the same mutational processes active in the primary tumor.
481 citations
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Wellcome Trust Sanger Institute1, KAIST2, European Bioinformatics Institute3, Los Alamos National Laboratory4, Memorial Sloan Kettering Cancer Center5, Akershus University Hospital6, King's College London7, Ninewells Hospital8, Lund University9, Radboud University Nijmegen10, Singapore General Hospital11, University of Cambridge12, Breast Cancer Now13, University of Texas MD Anderson Cancer Center14, University of California, San Francisco15, Erasmus University Medical Center16, Institut Jules Bordet17, University of Iceland18, Oslo University Hospital19, The Breast Cancer Research Foundation20, Johns Hopkins University21
TL;DR: Insight is provided into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis and it is demonstrated that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio.
Abstract: Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis.
234 citations
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University of Cambridge1, Wellcome Trust2, Wellcome Trust Sanger Institute3, Francis Crick Institute4, Royal National Orthopaedic Hospital5, Los Alamos National Laboratory6, University College London7, Wellcome Trust Centre for Human Genetics8, UCL Institute of Child Health9, University of Texas Health Science Center at Houston10, University Hospital of Basel11, Oslo University Hospital12, Katholieke Universiteit Leuven13
TL;DR: This study presents the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes and identifies distinct rearrangement profiles including a process characterized by chromothripsis and amplification.
Abstract: Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike.
172 citations
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Wellcome Trust Sanger Institute1, University of Cambridge2, Los Alamos National Laboratory3, UCL Institute of Child Health4, University of Texas Health Science Center at Houston5, University of British Columbia6, University Hospital of Basel7, UCL Institute of Neurology8, Mount Sinai Hospital, Toronto9, Durham University10, University of California, San Francisco11, Royal National Orthopaedic Hospital12, University College London13
TL;DR: The somatic driver landscape of 104 cases of sporadic chordoma is defined, revealing duplications in notochordal transcription factor brachyury (T), PI3K signalling mutations, and mutations in LYST, a potential novel cancer gene in chordoma.
Abstract: Chordoma is a malignant, often incurable bone tumour showing notochordal differentiation. Here, we defined the somatic driver landscape of 104 cases of sporadic chordoma. We reveal somatic duplications of the notochordal transcription factor brachyury (T) in up to 27% of cases. These variants recapitulate the rearrangement architecture of the pathogenic germline duplications of T that underlie familial chordoma. In addition, we find potentially clinically actionable PI3K signalling mutations in 16% of cases. Intriguingly, one of the most frequently altered genes, mutated exclusively by inactivating mutation, was LYST (10%), which may represent a novel cancer gene in chordoma.Chordoma is a rare often incurable malignant bone tumour. Here, the authors investigate driver mutations of sporadic chordoma in 104 cases, revealing duplications in notochordal transcription factor brachyury (T), PI3K signalling mutations, and mutations in LYST, a potential novel cancer gene in chordoma.
98 citations
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TL;DR: This study builds a compendium of 2218 primary tumours across 12 human cancer types and systematically screen for homozygous deletions and proposes 27 candidate tumour suppressors, including MAFTRR, KIAA1551, and IGF2BP2.
Abstract: 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.
74 citations
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Wellcome Trust Sanger Institute1, University of Queensland2, Lund University3, Los Alamos National Laboratory4, Erasmus University Medical Center5, Radboud University Nijmegen6, Oslo University Hospital7, The Breast Cancer Research Foundation8, University of Dundee9, Royal Brisbane and Women's Hospital10, European Bioinformatics Institute11, Harvard University12, Hanyang University13, French Institute for Research in Computer Science and Automation14, University of Cambridge15, Cambridge University Hospitals NHS Foundation Trust16
TL;DR: A somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.
Abstract: Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.
72 citations
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Wellcome Trust Sanger Institute1, Ninewells Hospital2, University of Ulsan3, Oslo University Hospital4, University of Oslo5, French Institute for Research in Computer Science and Automation6, Harvard University7, University of Texas MD Anderson Cancer Center8, University of Iceland9, Hanyang University10, Cambridge University Hospitals NHS Foundation Trust11
TL;DR: Patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, are utilized to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients.
Abstract: Mismatch repair (MMR)–deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR-related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. Cancer Res; 77(18); 4755–62. ©2017 AACR.
71 citations
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Broad Institute1, Wellcome Trust Sanger Institute2, Weizmann Institute of Science3, Harvard University4, European Bioinformatics Institute5, University of Zurich6, University of Cambridge7, École Polytechnique Fédérale de Lausanne8, University of Pennsylvania9, Ludwig Maximilian University of Munich10, John Radcliffe Hospital11, Newcastle University12, Stanford University13, University of California, San Francisco14, Allen Institute for Artificial Intelligence15, Karolinska Institutet16, Royal Institute of Technology17, Mount Sinai Hospital18, University of Cape Town19, University Medical Center Groningen20, Radboud University Nijmegen21, Kettering University22, University of Edinburgh23, Babraham Institute24, New York University25, Netherlands Cancer Institute26, Ragon Institute of MGH, MIT and Harvard27, University of Texas MD Anderson Cancer Center28, University of California, Berkeley29, King's College London30, California Institute of Technology31
TL;DR: A comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, as well as provide a framework for understanding cellular dysregulation in human disease.
Abstract: The recent advent of methods for high-throughput single-cell molecular profiling has catalyzed a growing sense in the scientific community that the time is ripe to complete the 150-year-old effort to identify all cell types in the human body, by undertaking a Human Cell Atlas Project as an international collaborative effort. The aim would be to define all human cell types in terms of distinctive molecular profiles (e.g., gene expression) and connect this information with classical cellular descriptions (e.g., location and morphology). A comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, as well as provide a framework for understanding cellular dysregulation in human disease. Here we describe the idea, its potential utility, early proofs-of-concept, and some design considerations for the Human Cell Atlas.
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TL;DR: Methods from evolutionary genomics are applied to 7,664 human cancers across 29 tumor types to identify novel cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.
Abstract: Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We applied methods from evolutionary genomics to 7,664 human cancers across 29 tumor types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, 10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We identify novel cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.
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TL;DR: It is shown that SIRs confer an increase in localized mutability in breast cancer, which is domain-dependent with the greatest mutability observed within spacer sequences (∼1.35-fold above background).
Abstract: Selected repetitive sequences termed short inverted repeats (SIRs) have the propensity to form secondary DNA structures called hairpins. SIRs comprise palindromic arm sequences separated by short spacer sequences that form the hairpin stem and loop respectively. Here, we show that SIRs confer an increase in localized mutability in breast cancer, which is domain-dependent with the greatest mutability observed within spacer sequences (∼1.35-fold above background). Mutability is influenced by factors that increase the likelihood of formation of hairpins such as loop lengths (of 4-5 bp) and stem lengths (of 7-15 bp). Increased mutability is an intrinsic property of SIRs as evidenced by how almost all mutational processes demonstrate a higher rate of mutagenesis of spacer sequences. We further identified 88 spacer sequences showing enrichment from 1.8- to 90-fold of local mutability distributed across 283 sites in the genome that intriguingly, can be used to inform the biological status of a tumor.
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TL;DR: It is shown 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.
Abstract: 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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Massachusetts Institute of Technology1, Broad Institute2, Howard Hughes Medical Institute3, University of Cambridge4, European Bioinformatics Institute5, Wellcome Trust Sanger Institute6, Harvard University7, Weizmann Institute of Science8, University of Zurich9, Laboratory of Molecular Biology10, Utrecht University11, École Polytechnique Fédérale de Lausanne12, University of Pennsylvania13, German Cancer Research Center14, Heidelberg University15, Ludwig Maximilian University of Munich16, John Radcliffe Hospital17, Newcastle University18, Stanford University19, University of Oxford20, University of California, San Francisco21, Allen Institute for Brain Science22, Karolinska Institutet23, Royal Institute of Technology24, Icahn School of Medicine at Mount Sinai25, University of Cape Town26, University Medical Center Groningen27, Radboud University Nijmegen28, Kettering University29, University of Edinburgh30, Babraham Institute31, New York University32, Netherlands Cancer Institute33, Ragon Institute of MGH, MIT and Harvard34, University of Texas Health Science Center at Houston35, Technische Universität München36, Technical University of Denmark37, University of California, Berkeley38, King's College London39, California Institute of Technology40
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TL;DR: It is shown 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.
Abstract: 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 and re-sensitize the tumor. The means therefore to saturate the genome with point mutations and that avoids chromosome or nucleotide sequence context bias would open the door to identify all possible 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 have developed 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.