19 results on '"Alexandrov LB"'
Search Results
2. APOBEC3B regulates R-loops and promotes transcription-associated mutagenesis in cancer.
- Author
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McCann JL, Cristini A, Law EK, Lee SY, Tellier M, Carpenter MA, Beghè C, Kim JJ, Sanchez A, Jarvis MC, Stefanovska B, Temiz NA, Bergstrom EN, Salamango DJ, Brown MR, Murphy S, Alexandrov LB, Miller KM, Gromak N, and Harris RS
- Subjects
- Humans, DNA, Single-Stranded genetics, Genome-Wide Association Study, Mutagenesis, Cytidine Deaminase genetics, Minor Histocompatibility Antigens genetics, Minor Histocompatibility Antigens metabolism, R-Loop Structures, Neoplasms genetics, Neoplasms pathology
- Abstract
The single-stranded DNA cytosine-to-uracil deaminase APOBEC3B is an antiviral protein implicated in cancer. However, its substrates in cells are not fully delineated. Here APOBEC3B proteomics reveal interactions with a surprising number of R-loop factors. Biochemical experiments show APOBEC3B binding to R-loops in cells and in vitro. Genetic experiments demonstrate R-loop increases in cells lacking APOBEC3B and decreases in cells overexpressing APOBEC3B. Genome-wide analyses show major changes in the overall landscape of physiological and stimulus-induced R-loops with thousands of differentially altered regions, as well as binding of APOBEC3B to many of these sites. APOBEC3 mutagenesis impacts genes overexpressed in tumors and splice factor mutant tumors preferentially, and APOBEC3-attributed kataegis are enriched in RTCW motifs consistent with APOBEC3B deamination. Taken together with the fact that APOBEC3B binds single-stranded DNA and RNA and preferentially deaminates DNA, these results support a mechanism in which APOBEC3B regulates R-loops and contributes to R-loop mutagenesis in cancer., (© 2023. The Author(s).)
- Published
- 2023
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3. Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity.
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Mangiante L, Alcala N, Sexton-Oates A, Di Genova A, Gonzalez-Perez A, Khandekar A, Bergstrom EN, Kim J, Liu X, Blazquez-Encinas R, Giacobi C, Le Stang N, Boyault S, Cuenin C, Tabone-Eglinger S, Damiola F, Voegele C, Ardin M, Michallet MC, Soudade L, Delhomme TM, Poret A, Brevet M, Copin MC, Giusiano-Courcambeck S, Damotte D, Girard C, Hofman V, Hofman P, Mouroux J, Cohen C, Lacomme S, Mazieres J, de Montpreville VT, Perrin C, Planchard G, Rousseau N, Rouquette I, Sagan C, Scherpereel A, Thivolet F, Vignaud JM, Jean D, Ilg AGS, Olaso R, Meyer V, Boland-Auge A, Deleuze JF, Altmuller J, Nuernberg P, Ibáñez-Costa A, Castaño JP, Lantuejoul S, Ghantous A, Maussion C, Courtiol P, Hernandez-Vargas H, Caux C, Girard N, Lopez-Bigas N, Alexandrov LB, Galateau-Salle F, Foll M, and Fernandez-Cuesta L
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- Humans, Multiomics, Biomarkers, Tumor genetics, Mesothelioma, Malignant genetics, Mesothelioma, Malignant complications, Mesothelioma genetics, Mesothelioma pathology, Pleural Neoplasms genetics, Pleural Neoplasms pathology, Lung Neoplasms pathology
- Abstract
Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that-in the case of the interdependent tumor cell morphology and adapted immune response-reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM., (© 2023. The Author(s).)
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- 2023
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4. Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence.
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Moody S, Senkin S, Islam SMA, Wang J, Nasrollahzadeh D, Cortez Cardoso Penha R, Fitzgerald S, Bergstrom EN, Atkins J, He Y, Khandekar A, Smith-Byrne K, Carreira C, Gaborieau V, Latimer C, Thomas E, Abnizova I, Bucciarelli PE, Jones D, Teague JW, Abedi-Ardekani B, Serra S, Scoazec JY, Saffar H, Azmoudeh-Ardalan F, Sotoudeh M, Nikmanesh A, Poustchi H, Niavarani A, Gharavi S, Eden M, Richman P, Campos LS, Fitzgerald RC, Ribeiro LF, Soares-Lima SC, Dzamalala C, Mmbaga BT, Shibata T, Menya D, Goldstein AM, Hu N, Malekzadeh R, Fazel A, McCormack V, McKay J, Perdomo S, Scelo G, Chanudet E, Humphreys L, Alexandrov LB, Brennan P, and Stratton MR
- Subjects
- APOBEC Deaminases genetics, Adult, Aged, Aged, 80 and over, Aldehyde Dehydrogenase, Mitochondrial genetics, Brazil epidemiology, China epidemiology, Female, Humans, Incidence, Iran epidemiology, Male, Middle Aged, Tumor Suppressor Protein p53 genetics, United Kingdom epidemiology, Whole Genome Sequencing, Esophageal Neoplasms epidemiology, Esophageal Neoplasms genetics, Esophageal Squamous Cell Carcinoma epidemiology, Esophageal Squamous Cell Carcinoma genetics, Mutation
- Abstract
Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. Mutational profiles were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining differences in ESCC incidence. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signatures single-base substitution (SBS)2 and SBS13 were present in 88% and 91% of cases, respectively, and accounted for 25% of the mutation burden on average, indicating that APOBEC activation is a crucial step in ESCC tumor development., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2021
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5. Genomic and evolutionary classification of lung cancer in never smokers.
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Zhang T, Joubert P, Ansari-Pour N, Zhao W, Hoang PH, Lokanga R, Moye AL, Rosenbaum J, Gonzalez-Perez A, Martínez-Jiménez F, Castro A, Muscarella LA, Hofman P, Consonni D, Pesatori AC, Kebede M, Li M, Gould Rothberg BE, Peneva I, Schabath MB, Poeta ML, Costantini M, Hirsch D, Heselmeyer-Haddad K, Hutchinson A, Olanich M, Lawrence SM, Lenz P, Duggan M, Bhawsar PMS, Sang J, Kim J, Mendoza L, Saini N, Klimczak LJ, Islam SMA, Otlu B, Khandekar A, Cole N, Stewart DR, Choi J, Brown KM, Caporaso NE, Wilson SH, Pommier Y, Lan Q, Rothman N, Almeida JS, Carter H, Ried T, Kim CF, Lopez-Bigas N, Garcia-Closas M, Shi J, Bossé Y, Zhu B, Gordenin DA, Alexandrov LB, Chanock SJ, Wedge DC, and Landi MT
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- Adult, Aged, Aged, 80 and over, ErbB Receptors genetics, Female, Genome genetics, Genome-Wide Association Study, Humans, Male, Middle Aged, Neoplastic Stem Cells pathology, Proto-Oncogene Proteins p21(ras) genetics, Receptors, Androgen genetics, Risk Factors, Smoking genetics, Ubiquitin-Activating Enzymes genetics, Whole Genome Sequencing, Young Adult, DNA Copy Number Variations genetics, Lung Neoplasms genetics, Lung Neoplasms pathology, Non-Smokers statistics & numerical data
- Abstract
Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers' progenitor cells many years before tumor diagnosis. The other subtypes are characterized by specific amplifications and EGFR mutations (mezzo-forte) and whole-genome doubling (forte). No strong tobacco smoking signatures were detected, even in cases with exposure to secondhand tobacco smoke. Genes within the receptor tyrosine kinase-Ras pathway had distinct impacts on survival; five genomic alterations independently doubled mortality. These findings create avenues for personalized treatment in LCINS., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)
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- 2021
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6. The mutational signature profile of known and suspected human carcinogens in mice.
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Riva L, Pandiri AR, Li YR, Droop A, Hewinson J, Quail MA, Iyer V, Shepherd R, Herbert RA, Campbell PJ, Sills RC, Alexandrov LB, Balmain A, and Adams DJ
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- Animals, Carcinogenesis genetics, DNA Mutational Analysis, Environmental Pollutants toxicity, Female, Genome, Humans, Male, Mice, Mutation Rate, Propane analogs & derivatives, Propane toxicity, Species Specificity, Carcinogens toxicity, Mutation
- Abstract
Epidemiological studies have identified many environmental agents that appear to significantly increase cancer risk in human populations. By analyzing tumor genomes from mice chronically exposed to 1 of 20 known or suspected human carcinogens, we reveal that most agents do not generate distinct mutational signatures or increase mutation burden, with most mutations, including driver mutations, resulting from tissue-specific endogenous processes. We identify signatures resulting from exposure to cobalt and vinylidene chloride and link distinct human signatures (SBS19 and SBS42) with 1,2,3-trichloropropane, a haloalkane and pollutant of drinking water, and find these and other signatures in human tumor genomes. We define the cross-species genomic landscape of tumors induced by an important compendium of agents with relevance to human health.
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- 2020
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7. Genomic evidence supports a clonal diaspora model for metastases of esophageal adenocarcinoma.
- Author
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Noorani A, Li X, Goddard M, Crawte J, Alexandrov LB, Secrier M, Eldridge MD, Bower L, Weaver J, Lao-Sirieix P, Martincorena I, Debiram-Beecham I, Grehan N, MacRae S, Malhotra S, Miremadi A, Thomas T, Galbraith S, Petersen L, Preston SD, Gilligan D, Hindmarsh A, Hardwick RH, Stratton MR, Wedge DC, and Fitzgerald RC
- Subjects
- Adenocarcinoma genetics, Adolescent, Adult, Aged, Aged, 80 and over, Child, Esophageal Neoplasms genetics, Esophageal Neoplasms secondary, Humans, Male, Middle Aged, Phylogeny, Whole Genome Sequencing, Young Adult, Adenocarcinoma secondary, Clonal Evolution, Esophageal Neoplasms pathology, Genomics methods, Models, Statistical
- Abstract
The poor outcomes in esophageal adenocarcinoma (EAC) prompted us to interrogate the pattern and timing of metastatic spread. Whole-genome sequencing and phylogenetic analysis of 388 samples across 18 individuals with EAC showed, in 90% of patients, that multiple subclones from the primary tumor spread very rapidly from the primary site to form multiple metastases, including lymph nodes and distant tissues-a mode of dissemination that we term 'clonal diaspora'. Metastatic subclones at autopsy were present in tissue and blood samples from earlier time points. These findings have implications for our understanding and clinical evaluation of EAC.
- Published
- 2020
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8. Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets.
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Wedge DC, Gundem G, Mitchell T, Woodcock DJ, Martincorena I, Ghori M, Zamora J, Butler A, Whitaker H, Kote-Jarai Z, Alexandrov LB, Van Loo P, Massie CE, Dentro S, Warren AY, Verrill C, Berney DM, Dennis N, Merson S, Hawkins S, Howat W, Lu YJ, Lambert A, Kay J, Kremeyer B, Karaszi K, Luxton H, Camacho N, Marsden L, Edwards S, Matthews L, Bo V, Leongamornlert D, McLaren S, Ng A, Yu Y, Zhang H, Dadaev T, Thomas S, Easton DF, Ahmed M, Bancroft E, Fisher C, Livni N, Nicol D, Tavaré S, Gill P, Greenman C, Khoo V, Van As N, Kumar P, Ogden C, Cahill D, Thompson A, Mayer E, Rowe E, Dudderidge T, Gnanapragasam V, Shah NC, Raine K, Jones D, Menzies A, Stebbings L, Teague J, Hazell S, Corbishley C, de Bono J, Attard G, Isaacs W, Visakorpi T, Fraser M, Boutros PC, Bristow RG, Workman P, Sander C, Hamdy FC, Futreal A, McDermott U, Al-Lazikani B, Lynch AG, Bova GS, Foster CS, Brewer DS, Neal DE, Cooper CS, and Eeles RA
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- Adult, Aged, Aged, 80 and over, BRCA2 Protein genetics, Disease Progression, Hepatocyte Nuclear Factor 3-alpha genetics, High-Throughput Nucleotide Sequencing methods, Humans, Male, Middle Aged, Mutation, Oncogenes, Prostatic Neoplasms pathology, Prostatic Neoplasms genetics
- Abstract
Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials.
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- 2018
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9. Corrigendum: A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers.
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Glodzik D, Morganella S, Davies H, Simpson PT, Li Y, Zou X, Diez-Perez J, Staaf J, Alexandrov LB, Smid M, Brinkman AB, Rye IH, Russnes H, Raine K, Purdie CA, Lakhani SR, Thompson AM, Birney E, Stunnenberg HG, van de Vijver MJ, Martens JWM, Børresen-Dale AL, Richardson AL, Kong G, Viari A, Easton D, Evan G, Campbell PJ, Stratton MR, and Nik-Zainal S
- Abstract
This corrects the article DOI: 10.1038/ng.3771.
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- 2017
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10. A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers.
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Glodzik D, Morganella S, Davies H, Simpson PT, Li Y, Zou X, Diez-Perez J, Staaf J, Alexandrov LB, Smid M, Brinkman AB, Rye IH, Russnes H, Raine K, Purdie CA, Lakhani SR, Thompson AM, Birney E, Stunnenberg HG, van de Vijver MJ, Martens JW, Børresen-Dale AL, Richardson AL, Kong G, Viari A, Easton D, Evan G, Campbell PJ, Stratton MR, and Nik-Zainal S
- Subjects
- DNA Breaks, Double-Stranded, DNA Repair genetics, Female, Gene Expression genetics, Genome genetics, Humans, Transcriptome genetics, Breast Neoplasms genetics, Genetic Loci genetics, Mutation genetics, Regulatory Sequences, Nucleic Acid genetics
- 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.
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- 2017
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11. Timing, rates and spectra of human germline mutation.
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Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, and Hurles ME
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- CpG Islands, Female, Humans, Male, Mosaicism, Paternal Age, Pedigree, Germ-Line Mutation
- Abstract
Germline mutations are a driving force behind genome evolution and genetic disease. We investigated genome-wide mutation rates and spectra in multi-sibling families. The mutation rate increased with paternal age in all families, but the number of additional mutations per year differed by more than twofold between families. Meta-analysis of 6,570 mutations showed that germline methylation influences mutation rates. In contrast to somatic mutations, we found remarkable consistency in germline mutation spectra between the sexes and at different paternal ages. In parental germ line, 3.8% of mutations were mosaic, resulting in 1.3% of mutations being shared by siblings. The number of these shared mutations varied significantly between families. Our data suggest that the mutation rate per cell division is higher during both early embryogenesis and differentiation of primordial germ cells but is reduced substantially during post-pubertal spermatogenesis. These findings have important consequences for the recurrence risks of disorders caused by de novo mutations.
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- 2016
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12. Clock-like mutational processes in human somatic cells.
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Alexandrov LB, Jones PH, Wedge DC, Sale JE, Campbell PJ, Nik-Zainal S, and Stratton MR
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- Embryo, Mammalian metabolism, Gene Expression Regulation, Neoplastic, Humans, Mutation Rate, Neoplasms classification, Biological Clocks genetics, Cell Lineage genetics, Cell Transformation, Neoplastic genetics, Embryo, Mammalian cytology, Genome, Human, Mutation genetics, Neoplasms genetics
- Abstract
During the course of a lifetime, somatic cells acquire mutations. Different mutational processes may contribute to the mutations accumulated in a cell, with each imprinting a mutational signature on the cell's genome. Some processes generate mutations throughout life at a constant rate in all individuals, and the number of mutations in a cell attributable to these processes will be proportional to the chronological age of the person. Using mutations from 10,250 cancer genomes across 36 cancer types, we investigated clock-like mutational processes that have been operating in normal human cells. Two mutational signatures show clock-like properties. Both exhibit different mutation rates in different tissues. However, their mutation rates are not correlated, indicating that the underlying processes are subject to different biological influences. For one signature, the rate of cell division may influence its mutation rate. This study provides the first survey of clock-like mutational processes operating in human somatic cells.
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- 2015
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13. Corrigendum: analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.
- Author
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Cooper CS, Eeles R, Wedge DC, Van Loo P, Gundem G, Alexandrov LB, Kremeyer B, Butler A, Lynch AG, Camacho N, Massie CE, Kay J, Luxton HJ, Edwards S, Kote-Jarai Z, Dennis N, Merson S, Leongamornlert D, Zamora J, Corbishley C, Thomas S, Nik-Zainal S, Ramakrishna M, O'Meara S, Matthews L, Clark J, Hurst R, Mithen R, Bristow RG, Boutros PC, Fraser M, Cooke S, Raine K, Jones D, Menzies A, Stebbings L, Hinton J, Teague J, McLaren S, Mudie L, Hardy C, Anderson E, Joseph O, Goody V, Robinson B, Maddison M, Gamble S, Greenman C, Berney D, Hazell S, Livni N, Fisher C, Ogden C, Kumar P, Thompson A, Woodhouse C, Nicol D, Mayer E, Dudderidge T, Shah NC, Gnanapragasam V, Voet T, Campbell P, Futreal A, Easton D, Warren AY, Foster CS, Stratton MR, Whitaker HC, McDermott U, Brewer DS, and Neal DE
- Published
- 2015
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14. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.
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Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S, Couchy G, Meiller C, Shinde J, Soysouvanh F, Calatayud AL, Pinyol R, Pelletier L, Balabaud C, Laurent A, Blanc JF, Mazzaferro V, Calvo F, Villanueva A, Nault JC, Bioulac-Sage P, Stratton MR, Llovet JM, and Zucman-Rossi J
- Subjects
- Aged, Antineoplastic Agents pharmacology, Benzoquinones pharmacology, Carcinoma, Hepatocellular drug therapy, Cell Line, Tumor, DNA Mutational Analysis, Female, Genetic Association Studies, HSP90 Heat-Shock Proteins antagonists & inhibitors, Humans, Lactams, Macrocyclic pharmacology, Liver Neoplasms drug therapy, Male, Molecular Targeted Therapy, NAD(P)H Dehydrogenase (Quinone) genetics, NAD(P)H Dehydrogenase (Quinone) metabolism, Risk Factors, Sequence Deletion, Carcinoma, Hepatocellular genetics, Exome, Liver Neoplasms genetics
- Abstract
Genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. Analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereas FGF3, FGF4, FGF19 or CCND1 amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)-approved drugs. In conclusion, we identified risk factor-specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy.
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- 2015
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15. Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.
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Cooper CS, Eeles R, Wedge DC, Van Loo P, Gundem G, Alexandrov LB, Kremeyer B, Butler A, Lynch AG, Camacho N, Massie CE, Kay J, Luxton HJ, Edwards S, Kote-Jarai Z, Dennis N, Merson S, Leongamornlert D, Zamora J, Corbishley C, Thomas S, Nik-Zainal S, O'Meara S, Matthews L, Clark J, Hurst R, Mithen R, Bristow RG, Boutros PC, Fraser M, Cooke S, Raine K, Jones D, Menzies A, Stebbings L, Hinton J, Teague J, McLaren S, Mudie L, Hardy C, Anderson E, Joseph O, Goody V, Robinson B, Maddison M, Gamble S, Greenman C, Berney D, Hazell S, Livni N, Fisher C, Ogden C, Kumar P, Thompson A, Woodhouse C, Nicol D, Mayer E, Dudderidge T, Shah NC, Gnanapragasam V, Voet T, Campbell P, Futreal A, Easton D, Warren AY, Foster CS, Stratton MR, Whitaker HC, McDermott U, Brewer DS, and Neal DE
- Subjects
- Case-Control Studies, Cell Lineage genetics, Clone Cells pathology, Humans, Male, Mutation, Phylogeny, Clonal Evolution genetics, DNA Mutational Analysis, Neoplasms, Multiple Primary genetics, Prostate cytology, Prostate pathology, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology
- Abstract
Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.
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- 2015
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16. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers.
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Shlien A, Campbell BB, de Borja R, Alexandrov LB, Merico D, Wedge D, Van Loo P, Tarpey PS, Coupland P, Behjati S, Pollett A, Lipman T, Heidari A, Deshmukh S, Avitzur N, Meier B, Gerstung M, Hong Y, Merino DM, Ramakrishna M, Remke M, Arnold R, Panigrahi GB, Thakkar NP, Hodel KP, Henninger EE, Göksenin AY, Bakry D, Charames GS, Druker H, Lerner-Ellis J, Mistry M, Dvir R, Grant R, Elhasid R, Farah R, Taylor GP, Nathan PC, Alexander S, Ben-Shachar S, Ling SC, Gallinger S, Constantini S, Dirks P, Huang A, Scherer SW, Grundy RG, Durno C, Aronson M, Gartner A, Meyn MS, Taylor MD, Pursell ZF, Pearson CE, Malkin D, Futreal PA, Stratton MR, Bouffet E, Hawkins C, Campbell PJ, and Tabori U
- Subjects
- DNA Repair, DNA-Directed DNA Polymerase genetics, Exons, Germ-Line Mutation, Humans, Microsatellite Instability, Base Pair Mismatch, Brain Neoplasms genetics, DNA Mismatch Repair, DNA Replication genetics
- Abstract
DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ɛ or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10(-13)). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in <6 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.
- Published
- 2015
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17. Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer.
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Nik-Zainal S, Wedge DC, Alexandrov LB, Petljak M, Butler AP, Bolli N, Davies HR, Knappskog S, Martin S, Papaemmanuil E, Ramakrishna M, Shlien A, Simonic I, Xue Y, Tyler-Smith C, Campbell PJ, and Stratton MR
- Subjects
- Female, Genetic Markers genetics, Humans, Minor Histocompatibility Antigens, Mutagenesis, Breast Neoplasms genetics, Cytidine Deaminase genetics, DNA Copy Number Variations genetics, Genetic Predisposition to Disease genetics, Proteins genetics, Sequence Deletion genetics
- Abstract
The somatic mutations in a cancer genome are the aggregate outcome of one or more mutational processes operative through the lifetime of the individual with cancer. Each mutational process leaves a characteristic mutational signature determined by the mechanisms of DNA damage and repair that constitute it. A role was recently proposed for the APOBEC family of cytidine deaminases in generating particular genome-wide mutational signatures and a signature of localized hypermutation called kataegis. A germline copy number polymorphism involving APOBEC3A and APOBEC3B, which effectively deletes APOBEC3B, has been associated with modestly increased risk of breast cancer. Here we show that breast cancers in carriers of the deletion show more mutations of the putative APOBEC-dependent genome-wide signatures than cancers in non-carriers. The results suggest that the APOBEC3A-APOBEC3B germline deletion allele confers cancer susceptibility through increased activity of APOBEC-dependent mutational processes, although the mechanism by which this increase in activity occurs remains unknown.
- Published
- 2014
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18. RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia.
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Papaemmanuil E, Rapado I, Li Y, Potter NE, Wedge DC, Tubio J, Alexandrov LB, Van Loo P, Cooke SL, Marshall J, Martincorena I, Hinton J, Gundem G, van Delft FW, Nik-Zainal S, Jones DR, Ramakrishna M, Titley I, Stebbings L, Leroy C, Menzies A, Gamble J, Robinson B, Mudie L, Raine K, O'Meara S, Teague JW, Butler AP, Cazzaniga G, Biondi A, Zuna J, Kempski H, Muschen M, Ford AM, Stratton MR, Greaves M, and Campbell PJ
- Subjects
- Base Sequence, Basic Helix-Loop-Helix Transcription Factors genetics, DNA Copy Number Variations genetics, Gene Library, Genes, Tumor Suppressor, Humans, Molecular Sequence Data, Repressor Proteins, Sequence Analysis, DNA, Sequence Deletion genetics, Transcription Factors genetics, V(D)J Recombination genetics, Core Binding Factor Alpha 2 Subunit genetics, Gene Expression Regulation, Neoplastic genetics, Gene Rearrangement genetics, Genetic Variation, Homeodomain Proteins genetics, Oncogene Proteins, Fusion genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Recombination, Genetic genetics
- 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.
- Published
- 2014
- Full Text
- View/download PDF
19. Inactivating CUX1 mutations promote tumorigenesis.
- Author
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Wong CC, Martincorena I, Rust AG, Rashid M, Alifrangis C, Alexandrov LB, Tiffen JC, Kober C, Green AR, Massie CE, Nangalia J, Lempidaki S, Döhner H, Döhner K, Bray SJ, McDermott U, Papaemmanuil E, Campbell PJ, and Adams DJ
- Subjects
- Animals, DNA Transposable Elements, Drosophila genetics, Female, Homeodomain Proteins metabolism, Humans, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Inbred C57BL, Mice, Transgenic, Mutagenesis, Insertional, Neoplasms, Experimental genetics, Neoplasms, Experimental pathology, Nuclear Proteins metabolism, PTEN Phosphohydrolase genetics, Phosphatidylinositol 3-Kinases metabolism, Repressor Proteins metabolism, Signal Transduction genetics, Transcription Factors, Xenograft Model Antitumor Assays, Genes, Tumor Suppressor, Homeodomain Proteins genetics, Mutation, Neoplasms genetics, Nuclear Proteins genetics, Repressor Proteins genetics
- Abstract
A major challenge in cancer genetics is to determine which low-frequency somatic mutations are drivers of tumorigenesis. Here we interrogate the genomes of 7,651 diverse human cancers and find inactivating mutations in the homeodomain transcription factor gene CUX1 (cut-like homeobox 1) in ~1-5% of various tumors. Meta-analysis of CUX1 mutational status in 2,519 cases of myeloid malignancies reveals disruptive mutations associated with poor survival, highlighting the clinical significance of CUX1 loss. In parallel, we validate CUX1 as a bona fide tumor suppressor using mouse transposon-mediated insertional mutagenesis and Drosophila cancer models. We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. Thus, our complementary approaches identify CUX1 as a pan-driver of tumorigenesis and uncover a potential strategy for treating CUX1-mutant tumors.
- Published
- 2014
- Full Text
- View/download PDF
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