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1.
Cell ; 184(3): 596-614.e14, 2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-33508232

RESUMEN

Checkpoint inhibitors (CPIs) augment adaptive immunity. Systematic pan-tumor analyses may reveal the relative importance of tumor-cell-intrinsic and microenvironmental features underpinning CPI sensitization. Here, we collated whole-exome and transcriptomic data for >1,000 CPI-treated patients across seven tumor types, utilizing standardized bioinformatics workflows and clinical outcome criteria to validate multivariable predictors of CPI sensitization. Clonal tumor mutation burden (TMB) was the strongest predictor of CPI response, followed by total TMB and CXCL9 expression. Subclonal TMB, somatic copy alteration burden, and histocompatibility leukocyte antigen (HLA) evolutionary divergence failed to attain pan-cancer significance. Dinucleotide variants were identified as a source of immunogenic epitopes associated with radical amino acid substitutions and enhanced peptide hydrophobicity/immunogenicity. Copy-number analysis revealed two additional determinants of CPI outcome supported by prior functional evidence: 9q34 (TRAF2) loss associated with response and CCND1 amplification associated with resistance. Finally, single-cell RNA sequencing (RNA-seq) of clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs), combined with bulk RNA-seq analysis of CPI-responding tumors, identified CCR5 and CXCL13 as T-cell-intrinsic markers of CPI sensitivity.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias/inmunología , Linfocitos T/inmunología , Biomarcadores de Tumor/metabolismo , Antígenos CD8/metabolismo , Quimiocina CXCL13/metabolismo , Cromosomas Humanos Par 9/genética , Estudios de Cohortes , Ciclina D1/genética , Variaciones en el Número de Copia de ADN/genética , Exoma/genética , Amplificación de Genes , Humanos , Evasión Inmune/efectos de los fármacos , Análisis Multivariante , Mutación/genética , Neoplasias/patología , Polimorfismo de Nucleótido Simple/genética , Receptores CCR5/metabolismo , Linfocitos T/efectos de los fármacos , Carga Tumoral/genética
2.
Cell ; 184(8): 2239-2254.e39, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33831375

RESUMEN

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.


Asunto(s)
Heterogeneidad Genética , Neoplasias/genética , Variaciones en el Número de Copia de ADN , ADN de Neoplasias/química , ADN de Neoplasias/metabolismo , Bases de Datos Genéticas , Resistencia a Antineoplásicos/genética , Humanos , Neoplasias/patología , Polimorfismo de Nucleótido Simple , Secuenciación Completa del Genoma
3.
Cell ; 173(3): 595-610.e11, 2018 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-29656894

RESUMEN

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.


Asunto(s)
Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Neoplasias Renales/genética , Neoplasias Renales/patología , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Biomarcadores de Tumor , Cromosomas , Evolución Clonal , Progresión de la Enfermedad , Evolución Molecular , Femenino , Heterogeneidad Genética , Variación Genética , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Mutación , Metástasis de la Neoplasia , Fenotipo , Filogenia , Pronóstico , Estudios Prospectivos , Análisis de Secuencia de ADN
4.
Cell ; 173(3): 581-594.e12, 2018 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-29656895

RESUMEN

Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.


Asunto(s)
Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Neoplasias Renales/genética , Neoplasias Renales/patología , Mutación , Metástasis de la Neoplasia , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Biopsia , Mapeo Cromosómico , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 9 , Progresión de la Enfermedad , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Fenotipo , Estudios Prospectivos , Trombosis , Resultado del Tratamiento
5.
Cell ; 171(6): 1259-1271.e11, 2017 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-29107330

RESUMEN

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. VIDEO ABSTRACT.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/inmunología , Antígenos HLA/genética , Neoplasias Pulmonares/inmunología , Escape del Tumor , Adulto , Anciano , Anciano de 80 o más Años , Presentación de Antígeno , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Estudios de Cohortes , Femenino , Antígenos HLA/inmunología , Humanos , Pérdida de Heterocigocidad , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Masculino , Persona de Mediana Edad , Mutación , Polimorfismo de Nucleótido Simple
6.
Nat Immunol ; 19(4): 397-406, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29531339

RESUMEN

The hallmark function of αß T cell antigen receptors (TCRs) involves the highly specific co-recognition of a major histocompatibility complex molecule and its carried peptide. However, the molecular basis of the interactions of TCRs with the lipid antigen-presenting molecule CD1c is unknown. We identified frequent staining of human T cells with CD1c tetramers across numerous subjects. Whereas TCRs typically show high specificity for antigen, both tetramer binding and autoreactivity occurred with CD1c in complex with numerous, chemically diverse self lipids. Such extreme polyspecificity was attributable to binding of the TCR over the closed surface of CD1c, with the TCR covering the portal where lipids normally protrude. The TCR essentially failed to contact lipids because they were fully seated within CD1c. These data demonstrate the sequestration of lipids within CD1c as a mechanism of autoreactivity and point to small lipid size as a determinant of autoreactive T cell responses.


Asunto(s)
Antígenos CD1/inmunología , Autoantígenos/inmunología , Autoinmunidad/inmunología , Glicoproteínas/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Presentación de Antígeno/inmunología , Humanos , Lípidos/inmunología , Activación de Linfocitos/inmunología
7.
Nature ; 616(7957): 543-552, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37046093

RESUMEN

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic-transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary-metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.


Asunto(s)
Evolución Molecular , Genoma Humano , Neoplasias Pulmonares , Metástasis de la Neoplasia , Transcriptoma , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Genómica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Metástasis de la Neoplasia/genética , Transcriptoma/genética , Alelos , Aprendizaje Automático , Genoma Humano/genética
8.
Nature ; 616(7957): 534-542, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37046095

RESUMEN

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Evolución Clonal , Células Clonales , Evolución Molecular , Neoplasias Pulmonares , Metástasis de la Neoplasia , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Células Clonales/patología , Estudios de Cohortes , Progresión de la Enfermedad , Neoplasias Pulmonares/patología , Metástasis de la Neoplasia/diagnóstico , Metástasis de la Neoplasia/patología , Recurrencia Local de Neoplasia
9.
Nature ; 616(7957): 525-533, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37046096

RESUMEN

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Adenocarcinoma del Pulmón/etiología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Carcinoma de Pulmón de Células no Pequeñas/etiología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/etiología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Recurrencia Local de Neoplasia/genética , Filogenia , Resultado del Tratamiento , Fumar/genética , Fumar/fisiopatología , Mutagénesis , Variaciones en el Número de Copia de ADN
10.
Nature ; 616(7957): 563-573, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37046094

RESUMEN

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response.


Asunto(s)
Retrovirus Endógenos , Inmunoterapia , Neoplasias Pulmonares , Animales , Humanos , Ratones , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/terapia , Adenocarcinoma del Pulmón/virología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/virología , Modelos Animales de Enfermedad , Retrovirus Endógenos/inmunología , Inmunoterapia/métodos , Pulmón/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/virología , Microambiente Tumoral , Linfocitos B/inmunología , Estudios de Cohortes , Anticuerpos/inmunología , Anticuerpos/uso terapéutico
11.
Nature ; 616(7957): 553-562, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37055640

RESUMEN

Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy.


Asunto(s)
Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Neoplasias Pulmonares , Mutación , Metástasis de la Neoplasia , Carcinoma Pulmonar de Células Pequeñas , Humanos , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Estudios de Cohortes , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Metástasis de la Neoplasia/diagnóstico , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Filogenia , Carcinoma Pulmonar de Células Pequeñas/patología , Biopsia Líquida
12.
Nature ; 597(7877): 555-560, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34497419

RESUMEN

The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy1,2. However, measurements of tumour infiltrating lymphocytes (TILs) are limited by a shortage of appropriate data. Whole-exome sequencing (WES) of DNA is frequently performed to calculate tumour mutational burden and identify actionable mutations. Here we develop T cell exome TREC tool (T cell ExTRECT), a method for estimation of T cell fraction from WES samples using a signal from T cell receptor excision circle (TREC) loss during V(D)J recombination of the T cell receptor-α gene (TCRA (also known as TRA)). TCRA T cell fraction correlates with orthogonal TIL estimates and is agnostic to sample type. Blood TCRA T cell fraction is higher in females than in males and correlates with both tumour immune infiltrate and presence of bacterial sequencing reads. Tumour TCRA T cell fraction is prognostic in lung adenocarcinoma. Using a meta-analysis of tumours treated with immunotherapy, we show that tumour TCRA T cell fraction predicts immunotherapy response, providing value beyond measuring tumour mutational burden. Applying T cell ExTRECT to a multi-sample pan-cancer cohort reveals a high diversity of the degree of immune infiltration within tumours. Subclonal loss of 12q24.31-32, encompassing SPPL3, is associated with reduced TCRA T cell fraction. T cell ExTRECT provides a cost-effective technique to characterize immune infiltrate alongside somatic changes.


Asunto(s)
Inmunoterapia , Neoplasias/inmunología , Neoplasias/terapia , Linfocitos T/citología , Linfocitos T/metabolismo , Adenocarcinoma del Pulmón/diagnóstico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/terapia , Ácido Aspártico Endopeptidasas/genética , Estudios de Cohortes , Exoma/genética , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Mutación , Neoplasias/diagnóstico , Neoplasias/genética , Pronóstico , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Secuenciación del Exoma/economía
13.
Nature ; 583(7818): 807-812, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32669708

RESUMEN

The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are directed against oncogenic drivers that are more prevalent in patients with light exposure to tobacco smoke1-3. As this group represents around 20% of all patients with lung cancer, the discovery of stratified medicine options for tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline the investigation of genotype-based treatments by screening tumours for multiple genomic alterations and triaging patients to one of several genotype-matched therapeutic agents. Here we report the current outcomes of 19 drug-biomarker cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial in NSCLC. We use next-generation sequencing to match patients to appropriate targeted therapies on the basis of their tumour genotype. The Bayesian trial design enables outcome data from open cohorts that are still recruiting to be reported alongside data from closed cohorts. Of the 5,467 patients that were screened, 2,007 were molecularly eligible for entry into the trial, and 302 entered the trial to receive genotype-matched therapy-including 14 that re-registered to the trial for a sequential trial drug. Despite pre-clinical data supporting the drug-biomarker combinations, current evidence shows that a limited number of combinations demonstrate clinically relevant benefits, which remain concentrated in patients with lung cancers that are associated with minimal exposure to tobacco smoke.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Marcadores Genéticos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Terapia Molecular Dirigida , Medicina de Precisión , Fumar/genética , Teorema de Bayes , Carcinoma de Pulmón de Células no Pequeñas/etiología , Protocolos Clínicos , Ensayos Clínicos como Asunto , Estudios de Cohortes , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Pulmonares/etiología , Oncogenes/genética , Selección de Paciente , Humo/efectos adversos , Triaje
15.
Nature ; 587(7832): 126-132, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32879494

RESUMEN

Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes1,2. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution1,3,4. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9, MCL1, ARNT (also known as HIF1B), TERT and MYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1) in HER2+ breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.


Asunto(s)
Inestabilidad Cromosómica/genética , Evolución Molecular , Cariotipo , Metástasis de la Neoplasia/genética , Neoplasias/genética , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 8/genética , Células Clonales/metabolismo , Células Clonales/patología , Ciclina E/genética , Variaciones en el Número de Copia de ADN/genética , Femenino , Humanos , Pérdida de Heterocigocidad/genética , Masculino , Mutagénesis , Metástasis de la Neoplasia/patología , Neoplasias/patología , Proteínas Oncogénicas/genética
16.
Immunity ; 45(2): 333-45, 2016 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-27533014

RESUMEN

Many pathogens, including Plasmodium spp., exploit the interaction of programmed death-1 (PD-1) with PD-1-ligand-1 (PD-L1) to "deactivate" T cell functions, but the role of PD-L2 remains unclear. We studied malarial infections to understand the contribution of PD-L2 to immunity. Here we have shown that higher PD-L2 expression on blood dendritic cells, from Plasmodium falciparum-infected individuals, correlated with lower parasitemia. Mechanistic studies in mice showed that PD-L2 was indispensable for establishing effective CD4(+) T cell immunity against malaria, because it not only inhibited PD-L1 to PD-1 activity but also increased CD3 and inducible co-stimulator (ICOS) expression on T cells. Importantly, administration of soluble multimeric PD-L2 to mice with lethal malaria was sufficient to dramatically improve immunity and survival. These studies show immuno-regulation by PD-L2, which has the potential to be translated into an effective treatment for malaria and other diseases where T cell immunity is ineffective or short-lived due to PD-1-mediated signaling.


Asunto(s)
Antígeno B7-H1/metabolismo , Linfocitos T CD4-Positivos/inmunología , Células Dendríticas/inmunología , Malaria Falciparum/inmunología , Plasmodium falciparum/inmunología , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Adamantano/análogos & derivados , Adamantano/uso terapéutico , Adulto , Animales , Antimaláricos/uso terapéutico , Antígeno B7-H1/genética , Células Cultivadas , Ensayos Clínicos como Asunto , Células Dendríticas/parasitología , Femenino , Humanos , Inmunidad Celular , Activación de Linfocitos , Malaria Falciparum/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Parasitemia/inmunología , Peróxidos/uso terapéutico , Proteína 2 Ligando de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/genética , Pirimidinas/uso terapéutico , Triazoles/uso terapéutico , Adulto Joven
18.
Transfusion ; 64 Suppl 2: S27-S33, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38251751

RESUMEN

BACKGROUND: Whole blood (WB) collections can occur downrange for immediate administration. An important aspect of these collections is determining when the unit is sufficiently full. This project tested a novel method for determining when a field collection is complete. METHODS: The amount of empty space at the top of WB units, destined to become LTOWB or separated into components, that were collected at blood centers or hospitals was measured by holding a WB unit off the ground and placing the top of a piece of string where the donor tubing entered the bag. The string was marked where it intersected the top of the column of blood in the bag and measured from the top. The WB units were also weighed. RESULTS: A total of 15 different bags, two of which were measured in two different filling volumes, from 15 hospitals or blood centers were measured and weighed. The most commonly used blood bag, Terumo Imuflex SP, had a median string length of 9 mm (range: 2-24 mm) and weighed a median of 565.1 g (range: 524.8-636.7 g). CONCLUSION: Pieces of string can be precut to the appropriate length depending on the type of bag before a mission where field WB collections might be required and a mark placed on the bag before the collection commences to indicate when the unit is full.


Asunto(s)
Donantes de Sangre , Humanos , Bancos de Sangre , Recolección de Muestras de Sangre/métodos , Recolección de Muestras de Sangre/instrumentación
19.
PLoS Comput Biol ; 19(10): e1011379, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37871126

RESUMEN

Most computational methods that infer somatic copy number alterations (SCNAs) from bulk sequencing of DNA analyse tumour samples individually. However, the sequencing of multiple tumour samples from a patient's disease is an increasingly common practice. We introduce Refphase, an algorithm that leverages this multi-sampling approach to infer haplotype-specific copy numbers through multi-sample phasing. We demonstrate Refphase's ability to infer haplotype-specific SCNAs and characterise their intra-tumour heterogeneity, to uncover previously undetected allelic imbalance in low purity samples, and to identify parallel evolution in the context of whole genome doubling in a pan-cancer cohort of 336 samples from 99 tumours.


Asunto(s)
Variaciones en el Número de Copia de ADN , Neoplasias , Humanos , Variaciones en el Número de Copia de ADN/genética , Haplotipos/genética , Neoplasias/genética , Neoplasias/patología , Algoritmos
20.
Nature ; 553(7689): 467-472, 2018 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-29342134

RESUMEN

Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.


Asunto(s)
Inestabilidad Cromosómica , Citosol/metabolismo , ADN de Neoplasias/metabolismo , Metástasis de la Neoplasia/genética , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/secundario , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Línea Celular , Inestabilidad Cromosómica/genética , Segregación Cromosómica , Citosol/enzimología , Femenino , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Humanos , Inflamación/genética , Inflamación/metabolismo , Proteínas de la Membrana/metabolismo , Mesodermo/metabolismo , Ratones , Micronúcleos con Defecto Cromosómico , FN-kappa B/metabolismo , Nucleotidiltransferasas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
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