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1.
Nucleic Acids Res ; 49(2): 891-901, 2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33347579

RESUMO

An abnormally high rate of UV-light related mutations appears at transcription factor binding sites (TFBS) across melanomas. The binding of transcription factors (TFs) to the DNA impairs the repair of UV-induced lesions and certain TFs have been shown to increase the rate of generation of these lesions at their binding sites. However, the precise contribution of these two elements to the increase in mutation rate at TFBS in these malignant cells is not understood. Here, exploiting nucleotide-resolution data, we computed the rate of formation and repair of UV-lesions within the binding sites of TFs of different families. We observed, at certain dipyrimidine positions within the binding site of TFs in the Tryptophan Cluster family, an increased rate of formation of UV-induced lesions, corroborating previous studies. Nevertheless, across most families of TFs, the observed increased mutation rate within the entire DNA region covered by the protein results from the decreased repair efficiency. While the rate of mutations across all TFBS does not agree with the amount of UV-induced lesions observed immediately after UV exposure, it strongly agrees with that observed after 48 h. This corroborates the determinant role of the impaired repair in the observed increase of mutation rate.


Assuntos
Dano ao DNA , Reparo do DNA , DNA de Neoplasias/efeitos da radiação , Melanoma/genética , Mutagênese , Neoplasias Cutâneas/genética , Fatores de Transcrição/metabolismo , Raios Ultravioleta/efeitos adversos , Sítios de Ligação , Mapeamento Cromossômico , DNA de Neoplasias/genética , Humanos , Mutação , Dímeros de Pirimidina/genética , Dímeros de Pirimidina/metabolismo , Sequenciamento Completo do Genoma
2.
Genome Biol ; 21(1): 284, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33225950

RESUMO

BACKGROUND: Adult T cell acute lymphoblastic leukemia (T-ALL) is a rare disease that affects less than 10 individuals in one million. It has been less studied than its cognate pediatric malignancy, which is more prevalent. A higher percentage of the adult patients relapse, compared to children. It is thus essential to study the mechanisms of relapse of adult T-ALL cases. RESULTS: We profile whole-genome somatic mutations of 19 primary T-ALLs from adult patients and the corresponding relapse malignancies and analyze their evolution upon treatment in comparison with 238 pediatric and young adult ALL cases. We compare the mutational processes and driver mutations active in primary and relapse adult T-ALLs with those of pediatric patients. A precise estimation of clock-like mutations in leukemic cells shows that the emergence of the relapse clone occurs several months before the diagnosis of the primary T-ALL. Specifically, through the doubling time of the leukemic population, we find that in at least 14 out of the 19 patients, the population of relapse leukemia present at the moment of diagnosis comprises more than one but fewer than 108 blasts. Using simulations, we show that in all patients the relapse appears to be driven by genetic mutations. CONCLUSIONS: The early appearance of a population of leukemic cells with genetic mechanisms of resistance across adult T-ALL cases constitutes a challenge for treatment. Improving early detection of the malignancy is thus key to prevent its relapse.

3.
Nat Genet ; 52(11): 1137-1138, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33128047
4.
Nat Rev Cancer ; 20(10): 555-572, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778778

RESUMO

A fundamental goal in cancer research is to understand the mechanisms of cell transformation. This is key to developing more efficient cancer detection methods and therapeutic approaches. One milestone towards this objective is the identification of all the genes with mutations capable of driving tumours. Since the 1970s, the list of cancer genes has been growing steadily. Because cancer driver genes are under positive selection in tumorigenesis, their observed patterns of somatic mutations across tumours in a cohort deviate from those expected from neutral mutagenesis. These deviations, which constitute signals of positive selection, may be detected by carefully designed bioinformatics methods, which have become the state of the art in the identification of driver genes. A systematic approach combining several of these signals could lead to a compendium of mutational cancer genes. In this Review, we present the Integrative OncoGenomics (IntOGen) pipeline, an implementation of such an approach to obtain the compendium of mutational cancer drivers. Its application to somatic mutations of more than 28,000 tumours of 66 cancer types reveals 568 cancer genes and points towards their mechanisms of tumorigenesis. The application of this approach to the ever-growing datasets of somatic tumour mutations will support the continuous refinement of our knowledge of the genetic basis of cancer.

5.
Bioinformatics ; 36(19): 4854-4859, 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-32592465

RESUMO

MOTIVATION: The high resolution of single-cell DNA sequencing (scDNA-seq) offers great potential to resolve intratumor heterogeneity (ITH) by distinguishing clonal populations based on their mutation profiles. However, the increasing size of scDNA-seq datasets and technical limitations, such as high error rates and a large proportion of missing values, complicate this task and limit the applicability of existing methods. RESULTS: Here, we introduce BnpC, a novel non-parametric method to cluster individual cells into clones and infer their genotypes based on their noisy mutation profiles. We benchmarked our method comprehensively against state-of-the-art methods on simulated data using various data sizes, and applied it to three cancer scDNA-seq datasets. On simulated data, BnpC compared favorably against current methods in terms of accuracy, runtime and scalability. Its inferred genotypes were the most accurate, especially on highly heterogeneous data, and it was the only method able to run and produce results on datasets with 5000 cells. On tumor scDNA-seq data, BnpC was able to identify clonal populations missed by the original cluster analysis but supported by Supplementary Experimental Data. With ever growing scDNA-seq datasets, scalable and accurate methods such as BnpC will become increasingly relevant, not only to resolve ITH but also as a preprocessing step to reduce data size. AVAILABILITY AND IMPLEMENTATION: BnpC is freely available under MIT license at https://github.com/cbg-ethz/BnpC. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

6.
Nature ; 578(7793): 102-111, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32025015

RESUMO

The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.


Assuntos
Genoma Humano/genética , Mutação/genética , Neoplasias/genética , Quebras de DNA , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Mutação INDEL
7.
Nat Genet ; 51(12): 1732-1740, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31740835

RESUMO

Some cancer therapies damage DNA and cause mutations in both cancerous and healthy cells. Therapy-induced mutations may underlie some of the long-term and late side effects of treatments, such as mental disabilities, organ toxicity and secondary neoplasms. Nevertheless, the burden of mutation contributed by different chemotherapies has not been explored. Here we identify the mutational signatures or footprints of six widely used anticancer therapies across more than 3,500 metastatic tumors originating from different organs. These include previously known and new mutational signatures generated by platinum-based drugs as well as a previously unknown signature of nucleoside metabolic inhibitors. Exploiting these mutational footprints, we estimate the contribution of different treatments to the mutation burden of tumors and their risk of contributing coding and potential driver mutations in the genome. The mutational footprints identified here allow for precise assessment of the mutational risk of different cancer therapies to understand their long-term side effects.


Assuntos
Antineoplásicos/efeitos adversos , Mutação , Neoplasias/genética , Neoplasias/terapia , Radioterapia/efeitos adversos , Antineoplásicos/uso terapêutico , Humanos , Neoplasias/patologia , Fatores de Risco
8.
Eur J Cancer ; 120: 54-64, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31491604

RESUMO

BACKGROUND: Changes in the clinical subtype (CS) and intrinsic subtype (IS) between breast cancer (BC) metastases and corresponding primary tumours have been reported. However, their relationship with tumour genomic changes remains poorly characterised. Here, we analysed the association between genomic remodelling and subtype conversion in paired primary and metastatic BC samples. METHODS: A total of 57 paired primary and metastatic tumours from GEICAM/2009-03 (ConvertHER, NCT01377363) study participants with centrally assessed CS (n = 57) and IS (n = 46) were analysed. Targeted capture and next-generation sequencing of 202 genes on formalin-fixed paraffin-embedded samples was performed. The cancer cell fraction (CCF) of mutations in primary and metastatic pairs was estimated as a surrogate of tumour clonal architecture. Changes in mutation CCF between matched primary and metastatic tumours were analysed in the presence or absence of subtype conversion. FINDINGS: CS conversion occurred in 24.6% and IS conversion occurred in 36.9% of metastases. Primary tumours and metastases had a median of 11 (range, 3-29) and 9 (range, 1-38) mutations, respectively (P = 0.05). Overall, mutations in metastases showed a higher estimated CCF than in primary tumours (median CCF, 0.51 and 0.47, respectively; P = 0.042), consistent with increased clonal homogeneity. The increase in mutation CCF was significant in CS-converted (P = 0.04) but not in IS-converted (P = 0.48) metastases. Clonal remodelling was highest in metastases from hormone receptor-positive and human epidermal growth factor 2 (HER2)-positive tumours (P = 0.006). CONCLUSIONS: Mutations in BC metastases showed significantly higher estimated CCF than primary tumours. CCF changes were more prominent in metastases with CS conversion. Our findings suggest that changes in BC subtypes are linked to clonal remodelling during BC evolution.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/secundário , Neoplasias da Mama/classificação , Neoplasias da Mama/patologia , Mutação , Neoplasias Cutâneas/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/genética , Neoplasias Encefálicas/genética , Neoplasias da Mama/genética , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Prospectivos , Neoplasias Cutâneas/genética
10.
Bioinformatics ; 35(22): 4788-4790, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31228182

RESUMO

MOTIVATION: Identification of the genomic alterations driving tumorigenesis is one of the main goals in oncogenomics research. Given the evolutionary principles of cancer development, computational methods that detect signals of positive selection in the pattern of tumor mutations have been effectively applied in the search for cancer genes. One of these signals is the abnormal clustering of mutations, which has been shown to be complementary to other signals in the detection of driver genes. RESULTS: We have developed OncodriveCLUSTL, a new sequence-based clustering algorithm to detect significant clustering signals across genomic regions. OncodriveCLUSTL is based on a local background model derived from the simulation of mutations accounting for the composition of tri- or penta-nucleotide context substitutions observed in the cohort under study. Our method can identify known clusters and bona-fide cancer drivers across cohorts of tumor whole-exomes, outperforming the existing OncodriveCLUST algorithm and complementing other methods based on different signals of positive selection. Our results indicate that OncodriveCLUSTL can be applied to the analysis of non-coding genomic elements and non-human mutations data. AVAILABILITY AND IMPLEMENTATION: OncodriveCLUSTL is available as an installable Python 3.5 package. The source code and running examples are freely available at https://bitbucket.org/bbglab/oncodriveclustl under GNU Affero General Public License. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Neoplasias , Software , Análise por Conglomerados , Genômica , Humanos
11.
Cell ; 177(1): 101-114, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30901533

RESUMO

Large-scale chromatin features, such as replication time and accessibility influence the rate of somatic and germline mutations at the megabase scale. This article reviews how local chromatin structures -e.g., DNA wrapped around nucleosomes, transcription factors bound to DNA- affect the mutation rate at a local scale. It dissects how the interaction of some mutagenic agents and/or DNA repair systems with these local structures influence the generation of mutations. We discuss how this local mutation rate variability affects our understanding of the evolution of the genomic sequence, and the study of the evolution of organisms and tumors.


Assuntos
Cromatina/genética , Genoma Humano/genética , Mutação/genética , Mapeamento Cromossômico/métodos , DNA/química , Reparo do DNA/genética , Evolução Molecular , Genômica , Mutação em Linhagem Germinativa/genética , Humanos , Mutagênese/genética , Taxa de Mutação , Nucleossomos/genética , Fatores de Transcrição/genética
12.
Clin Cancer Res ; 25(5): 1535-1545, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30523021

RESUMO

PURPOSE: We investigated the value of tumor-infiltrating NK (TI-NK) cells and HLA class I tumor expression as biomarkers of response to neoadjuvant anti-HER2 antibody-based treatment in breast cancer. EXPERIMENTAL DESIGN: TI-NK cells and HLA-I were determined by IHC in pretreatment tumor biopsies from two cohorts of patients with HER2-positive breast cancer [discovery cohort (n = 42) and validation cohort (n = 71)]. Tumor-infiltrating lymphocytes (TIL) were scored according to international guidelines. Biomarker association with pathologic complete response (pCR) and disease-free survival (DFS) was adjusted for prognostic factors. Gene set variation analysis was used for determining immune cell populations concomitant to NK-cell enrichment in HER2-positive tumors from the Cancer Genome Atlas (n = 190). RESULTS: TI-NK cells were significantly associated with pCR in the discovery cohort as well as in the validation cohort (P < 0.0001), independently of clinicopathologic factors. A ≥3 TI-NK cells/50x high-power field (HPF) cutoff predicted pCR in the discovery and validation cohort [OR, 188 (11-3154); OR, 19.5 (5.3-71.8)]. Presence of TI-NK cells associated with prolonged DFS in both patient cohorts [HR, 0.07 (0.01-0.6); P = 0.01; HR, 0.3 (0.08-1.3); P = 0.1]. NK-, activated dendritic- and CD8 T-cell gene expression signatures positively correlated in HER2-positive tumors, supporting the value of NK cells as surrogates of effective antitumor immunity. Stratification of patients by tumor HLA-I expression identified patients with low and high relapse risk independently of pCR. CONCLUSIONS: This study identifies baseline TI-NK cells as an independent biomarker with great predictive value for pCR to anti-HER2 antibody-based treatment and points to the complementary value of tumor HLA-I status for defining patient prognosis independently of pCR.


Assuntos
Neoplasias da Mama/etiologia , Neoplasias da Mama/mortalidade , Antígenos de Histocompatibilidade Classe I/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Receptor ErbB-2/genética , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Prognóstico , Receptor ErbB-2/metabolismo , Espanha/epidemiologia
13.
Cell ; 175(4): 1074-1087.e18, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388444

RESUMO

Mutation rates along the genome are highly variable and influenced by several chromatin features. Here, we addressed how nucleosomes, the most pervasive chromatin structure in eukaryotes, affect the generation of mutations. We discovered that within nucleosomes, the somatic mutation rate across several tumor cohorts exhibits a strong 10 base pair (bp) periodicity. This periodic pattern tracks the alternation of the DNA minor groove facing toward and away from the histones. The strength and phase of the mutation rate periodicity are determined by the mutational processes active in tumors. We uncovered similar periodic patterns in the genetic variation among human and Arabidopsis populations, also detectable in their divergence from close species, indicating that the same principles underlie germline and somatic mutation rates. We propose that differential DNA damage and repair processes dependent on the minor groove orientation in nucleosome-bound DNA contribute to the 10-bp periodicity in AT/CG content in eukaryotic genomes.


Assuntos
DNA/genética , Mutação em Linhagem Germinativa , Taxa de Mutação , Nucleossomos/genética , Arabidopsis/genética , DNA/química , Sequência Rica em GC , Variação Genética , Conformação de Ácido Nucleico , Nucleossomos/química
14.
Front Genet ; 9: 412, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319692

RESUMO

Understanding the mechanisms underlying drug therapeutic action and toxicity is crucial for the prevention and management of drug adverse reactions, and paves the way for a more efficient and rational drug design. The characterization of drug targets, drug metabolism proteins, and proteins associated to side effects according to their expression patterns, their tolerance to genomic variation and their role in cellular networks, is a necessary step in this direction. In this contribution, we hypothesize that different classes of proteins involved in the therapeutic effect of drugs and in their adverse effects have distinctive transcriptomics, genomics and network features. We explored the properties of these proteins within global and organ-specific interactomes, using multi-scale network features, evaluated their gene expression profiles in different organs and tissues, and assessed their tolerance to loss-of-function variants leveraging data from 60K subjects. We found that drug targets that mediate side effects are more central in cellular networks, more intolerant to loss-of-function variation, and show a wider breadth of tissue expression than targets not mediating side effects. In contrast, drug metabolizing enzymes and transporters are less central in the interactome, more tolerant to deleterious variants, and are more constrained in their tissue expression pattern. Our findings highlight distinctive features of proteins related to drug action, which could be applied to prioritize drugs with fewer probabilities of causing side effects.

16.
Nat Commun ; 9(1): 2992, 2018 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-30065304

RESUMO

Delta ligands regulate Notch signaling in normal intestinal stem cells, while Jagged1 activates Notch in intestinal adenomas carrying active ß-catenin. We used the ApcMin/+ mouse model, tumor spheroid cultures, and patient-derived orthoxenografts to address this divergent ligand-dependent Notch function and its implication in disease. We found that intestinal-specific Jag1 deletion or antibody targeting Jag1 prevents tumor initiation in mice. Addiction to Jag1 is concomitant with the absence of Manic Fringe (MFNG) in adenoma cells, and its ectopic expression reverts Jag1 dependence. In 239 human colorectal cancer patient samples, MFNG imposes a negative correlation between Jag1 and Notch, being high Jag1 in the absence of MFNG predictive of poor prognosis. Jag1 antibody treatment reduces patient-derived tumor orthoxenograft growth without affecting normal intestinal mucosa. Our data provide an explanation to Jag1 dependence in cancer, and reveal that Jag1-Notch1 interference provides therapeutic benefit in a subset of colorectal cancer and FAP syndrome patients.


Assuntos
Hexosiltransferases/metabolismo , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína Jagged-1/metabolismo , Proteínas de Membrana/metabolismo , Proteínas/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Proliferação de Células , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Glucosiltransferases , Humanos , Ligantes , Camundongos , Modelos Biológicos , Prognóstico , Receptor Notch1/metabolismo , Transdução de Sinais , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Células-Tronco/metabolismo , Transcrição Genética
17.
Nat Genet ; 50(8): 1196, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29973711

RESUMO

In the version of this article initially published, the x axis on the fourth plot in Fig. 2e was incorrectly labeled "H3K36me3 exon-to-intron ratio (lower to higher)." The x axis on this plot should read "Genic H3K36me3 coverage bins (higher to lower)".

18.
Rev. Fac. Med. (Guatemala) ; 1(25 Segunda Época): 56-63, Jun - Dic 2018.
Artigo em Espanhol | LILACS-Express | LILACS | ID: biblio-1128256

RESUMO

Introducción: El paracetamol intravenoso fue autorizado en el año 2001 para Europa, en el 2016 se autoriza en Guatemala. Esta presentación ha generado diferentes expectativas alrededor del mundo, por lo que se evaluó su administración al agregarse al tratamiento de analgesia postoperatoria multimodal. Objetivo: Evaluar el efecto analgésico en el tratamiento multimodal de dolor agudo postoperatorio con paracetamol IV en la población guatemalteca. Métodos: Estudio retrospectivo caso-control para la evaluación del dolor postoperatorio inmediato (24 horas) al agregar paracetamol IV al protocolo de analgesia estándar. En pacientes de ambos géneros, entre 18 y 70 años de edad, con peso mayor o igual a 50 Kg. con una cirugía electiva abierta o por vía laparoscópica, en una muestra de 110 pacientes dividida en dos grupos. Se comparó el número de pacientes que necesitaron dosis de rescate y el nivel de dolor según la Escala Visual Análoga (EVA) durante 4 evaluaciones en el postoperatorio agudo. Para determinar la correlación entre las variables se utilizó la prueba de independencia de Ji cuadrado. Resultados: Se demostró que agregar paracetamol IV al tratamiento estándar disminuye la cantidad de pacientes que requieren dosis de rescate y mejoran su analgesia durante el postoperatorio agudo. Conclusiones: El paracetamol IV es de beneficio al ser agregado al tratamiento de analgesia multimodal convencional de un hospital privado de Z.10. Palabras clave: Analgesia, anestesia, Escala Visual Análoga, multimodal, paracetamol, control post operativo del dolor


Background: In 2001 was authorized IV paracetamol for its use in Europe. In Guatemala it was used for the first time until 2016. This formulation has awakened different expectations around the world, for this reason its administration was evaluated when added to the multimodal postoperative analgesia treatment to demonstrate its efficiency. Objective: The aim of this study is to evaluate the analgesic effect in the multimodal treatment for acute postoperative pain with IV paracetamol in a group of Guatemalans patients. Methods: Retrospective case-control study for the evaluation of acute postoperative pain (24 hours) by adding IV paracetamol to the standard analgesic protocol. Patients of both sexes, between 18 and 70 years old, with a weight greater than or equal to 50 kg with open or laparoscopically elective surgery, in a sample of 110 patients divided into two groups. The number of patients needing rescue dose and the level of pain according to the Visual Analogue Scale (VAS) were compared during 4 evaluations in the acute postoperative period. To determine the correlation between the variables, the chi square independence test was used. Results: Adding IV paracetamol to standard treatment decreases the number of patients who require rescue doses with opioids and improves their analgesia during the acute postoperative period. Conclusions: IV paracetamol is of benefit when added to the conventional multimodal postoperative analgesia treatment of a private hospital. Keywords: Analgesia, anesthesia, Visual Analogue Scale, multimodal, paracetamol, postoperative pain control

19.
Clin Cancer Res ; 24(15): 3717-3728, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29666300

RESUMO

Purpose: Throughout their development, tumors are challenged by the immune system, and they acquire features to evade its surveillance. A systematic view of these traits, which shed light on how tumors respond to immunotherapies, is still lacking.Experimental Design: Here, we computed the relative abundance of an array of immune cell populations to measure the immune infiltration pattern of 9,174 tumors of 29 solid cancers. We then clustered tumors with similar infiltration pattern to define immunophenotypes. Finally, we identified genomic and transcriptomic traits associated to these immunophenotypes across cancer types.Results: In highly cytotoxic immunophenotypes, we found tumors with low clonal heterogeneity enriched for alterations of genes involved in epigenetic regulation, ubiquitin-mediated proteolysis, antigen presentation, and cell-cell communication, which may drive resistance in combination with the ectopic expression of negative immune checkpoints. Tumors with immunophenotypes of intermediate cytotoxicity are characterized by an upregulation of processes involved in neighboring tissue invasion and remodeling that may foster the recruitment of immunosuppressive cells. Tumors with poorly cytotoxic immunophenotype tend to be of more advanced stages and bear a greater burden of copy number alterations and frequent alterations of cell cycle, hedgehog, ß-catenin, and TGFß pathways, which may cause immune depletion.Conclusions: We provide a comprehensive landscape of the characteristics of solid tumors that may influence (or be influenced by) the characteristics of their immune infiltrate. These results may help interpret the response of solid tumors to immunotherapies and guide the development of novel drug combination strategies. Clin Cancer Res; 24(15); 3717-28. ©2018 AACR.


Assuntos
Epigênese Genética/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/imunologia , Transcriptoma/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Variações do Número de Cópias de DNA/genética , Variações do Número de Cópias de DNA/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Genômica , Humanos , Imunofenotipagem , Imunoterapia , Linfócitos do Interstício Tumoral/patologia , Neoplasias/genética , Neoplasias/patologia , Transcriptoma/imunologia
20.
Cell ; 173(2): 371-385.e18, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29625053

RESUMO

Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%-85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD-L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors.


Assuntos
Neoplasias/patologia , Algoritmos , Antígeno B7-H1/genética , Biologia Computacional , Bases de Dados Genéticas , Entropia , Humanos , Instabilidade de Microssatélites , Mutação , Neoplasias/genética , Neoplasias/imunologia , Análise de Componente Principal , Receptor de Morte Celular Programada 1/genética
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