RESUMEN
Cancers develop as a result of driver mutations1,2 that lead to clonal outgrowth and the evolution of disease3,4. The discovery and functional characterization of individual driver mutations are central aims of cancer research, and have elucidated myriad phenotypes5 and therapeutic vulnerabilities6. However, the serial genetic evolution of mutant cancer genes7,8 and the allelic context in which they arise is poorly understood in both common and rare cancer genes and tumour types. Here we find that nearly one in four human tumours contains a composite mutation of a cancer-associated gene, defined as two or more nonsynonymous somatic mutations in the same gene and tumour. Composite mutations are enriched in specific genes, have an elevated rate of use of less-common hotspot mutations acquired in a chronology driven in part by oncogenic fitness, and arise in an allelic configuration that reflects context-specific selective pressures. cis-acting composite mutations are hypermorphic in some genes in which dosage effects predominate (such as TERT), whereas they lead to selection of function in other genes (such as TP53). Collectively, composite mutations are driver alterations that arise from context- and allele-specific selective pressures that are dependent in part on gene and mutation function, and which lead to complex-often neomorphic-functions of biological and therapeutic importance.
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Carcinogénesis/genética , Modelos Genéticos , Mutación , Neoplasias/genética , Oncogenes/genética , Alelos , Animales , Femenino , Genes p53/genética , Humanos , Ratones , Selección Genética , Telomerasa/genéticaRESUMEN
The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856.
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Policitemia Vera , Trombocitemia Esencial , Trombosis , Progresión de la Enfermedad , Humanos , Hidroxiurea/efectos adversos , Interferón-alfa/efectos adversos , Policitemia Vera/tratamiento farmacológico , Policitemia Vera/genética , Trombocitemia Esencial/tratamiento farmacológico , Trombocitemia Esencial/genética , Trombosis/inducido químicamente , Trombosis/prevención & controlRESUMEN
Large-scale sequencing studies of hematologic malignancies have revealed notable epistasis among high-frequency mutations. One of the most striking examples of epistasis occurs for mutations in RNA splicing factors. These lesions are among the most common alterations in myeloid neoplasms and generally occur in a mutually exclusive manner, a finding attributed to their synthetic lethal interactions and/or convergent effects. Curiously, however, patients with multiple-concomitant splicing factor mutations have been observed, challenging our understanding of one of the most common examples of epistasis in hematologic malignancies. In this study, we performed bulk and single-cell analyses of patients with myeloid malignancy who were harboring ≥2 splicing factor mutations, to understand the frequency and basis for the coexistence of these mutations. Although mutations in splicing factors were strongly mutually exclusive across 4231 patients (q < .001), 0.85% harbored 2 concomitant bona fide splicing factor mutations, â¼50% of which were present in the same individual cells. However, the distribution of mutations in patients with double mutations deviated from that in those with single mutations, with selection against the most common alleles, SF3B1K700E and SRSF2P95H/L/R, and selection for less common alleles, such as SF3B1 non-K700E mutations, rare amino acid substitutions at SRSF2P95, and combined U2AF1S34/Q157 mutations. SF3B1 and SRSF2 alleles enriched in those with double-mutations had reduced effects on RNA splicing and/or binding compared with the most common alleles. Moreover, dual U2AF1 mutations occurred in cis with preservation of the wild-type allele. These data highlight allele-specific differences as critical in regulating the molecular effects of splicing factor mutations as well as their cooccurrences/exclusivities with one another.
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Epistasis Genética , Neoplasias Hematológicas/genética , Mutación , Factores de Empalme de ARN/genética , Empalme del ARN , Alelos , Análisis Mutacional de ADN , Genómica , Humanos , Leucemia Mieloide/genética , Análisis de la Célula IndividualRESUMEN
We derived a mouse model in which a mutant form of Nbn/Nbs1mid8 (hereafter Nbnmid8) exhibits severely impaired binding to the Mre11-Rad50 core of the Mre11 complex. The Nbnmid8 allele was expressed exclusively in hematopoietic lineages (in Nbn-/mid8vav mice). Unlike Nbnflox/floxvav mice with Nbn deficiency in the bone marrow, Nbn-/mid8vav mice were viable. Nbn-/mid8vav mice hematopoiesis was profoundly defective, exhibiting reduced cellularity of thymus and bone marrow, and stage-specific blockage of B cell development. Within 6 mo, Nbn-/mid8 mice developed highly penetrant T cell leukemias. Nbn-/mid8vav leukemias recapitulated mutational features of human T cell acute lymphoblastic leukemia (T-ALL), containing mutations in NOTCH1, TP53, BCL6, BCOR, and IKZF1, suggesting that Nbnmid8 mice may provide a venue to examine the relationship between the Mre11 complex and oncogene activation in the hematopoietic compartment. Genomic analysis of Nbn-/mid8vav malignancies showed focal amplification of 9qA2, causing overexpression of MRE11 and CHK1 We propose that overexpression of MRE11 compensates for the metastable Mre11-Nbnmid8 interaction, and that selective pressure for overexpression reflects the essential role of Nbn in promoting assembly and activity of the Mre11 complex.
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Ácido Anhídrido Hidrolasas/genética , Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Regulación Leucémica de la Expresión Génica , Proteína Homóloga de MRE11/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Linfocitos T/inmunología , Ácido Anhídrido Hidrolasas/inmunología , Animales , Linfocitos B/inmunología , Linfocitos B/patología , Médula Ósea/inmunología , Médula Ósea/patología , Proteínas de Ciclo Celular/deficiencia , Proteínas de Ciclo Celular/inmunología , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/genética , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/inmunología , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/inmunología , Modelos Animales de Enfermedad , Inestabilidad Genómica/inmunología , Hematopoyesis/genética , Hematopoyesis/inmunología , Humanos , Factor de Transcripción Ikaros/genética , Factor de Transcripción Ikaros/inmunología , Proteína Homóloga de MRE11/inmunología , Ratones , Ratones Noqueados , Mutación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/prevención & control , Unión Proteica , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/inmunología , Receptor Notch1/genética , Receptor Notch1/inmunología , Proteínas Represoras/genética , Proteínas Represoras/inmunología , Transducción de Señal , Linfocitos T/patología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/inmunologíaRESUMEN
Certain arylsulfonamides (ArSulf) induce an interaction between the E3 ligase substrate adaptor DCAF15 and the critical splicing factor RBM39, ultimately causing its degradation. However, degradation of a splicing factor introduces complex pleiotropic effects that are difficult to untangle, since, aside from direct protein degradation, downstream transcriptional effects also influence the proteome. By overlaying transcriptional data and proteome datasets, we distinguish transcriptional from direct degradation effects, pinpointing those proteins most impacted by splicing changes. Using our workflow, we identify and validate the upregulation of the arginine-and-serine rich protein (RSRP1) and the downregulation of the key kinesin motor proteins KIF20A and KIF20B due to altered splicing in the absence of RBM39. We further show that kinesin downregulation is connected to the multinucleation phenotype observed upon RBM39 depletion by ArSulfs. Our approach should be helpful in the assessment of potential cancer drug candidates which target splicing factors. IMPLICATIONS: Our approach provides a workflow for identifying and studying the most strongly modulated proteins when splicing is altered. The work also uncovers a splicing-based approach toward pharmacologic targeting of mitotic kinesins.
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Cinesinas , Proteínas de Unión al ARN , Humanos , Cinesinas/genética , Cinesinas/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Proteoma/metabolismo , Unión Proteica , Factores de Empalme de ARN/metabolismoRESUMEN
Certain arylsulfonamides (ArSulfs) induce an interaction between the E3 ligase substrate adaptor DCAF15 and the critical splicing factor RBM39, ultimately causing its degradation. However, degradation of a splicing factor introduces complex pleiotropic effects that are difficult to untangle, since, aside from direct protein degradation, downstream transcriptional effects also influence the proteome. By overlaying transcriptional data and proteome datasets, we distinguish transcriptional from direct degradation effects, pinpointing those proteins most impacted by splicing changes. Using our workflow, we identify and validate the upregulation of the argininie-and-serine rich protein (RSRP1) and the downregulation of the key kinesin motor proteins KIF20A and KIF20B due to altered splicing in the absence of RBM39. We further show that kinesin downregulation is connected to the multinucleation phenotype observed upon RBM39 depletion by ArSulfs. Our approach should be helpful in the assessment of potential cancer drug candidates which target splicing factors. Implications: Our approach provides a workflow for identifying and studying the most strongly modulated proteins when splicing is altered; the work also uncovers a splicing-based approach toward pharmacological targeting of mitotic kinesins.
RESUMEN
Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR-Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncover a selective dependency on RNA splicing factors whose loss preferentially enhances response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augments response to venetoclax in leukemia yet is completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition leads to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. Inhibition of splicing kinase families CLKs (CDC-like kinases) and DYRKs (dual-specificity tyrosine-regulated kinases) leads to aberrant splicing of key splicing and apoptotic factors that synergize with venetoclax, and overcomes resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments.
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Leucemia Mieloide Aguda , Proteínas Proto-Oncogénicas c-bcl-2 , Humanos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Línea Celular Tumoral , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Empalme del ARN/genética , Leucemia Mieloide Aguda/genética , Proteínas Tirosina Quinasas , Apoptosis/genética , Proteínas de Unión al ARN/genéticaRESUMEN
Human cancers arise from environmental, heritable and somatic factors, but how these mechanisms interact in tumorigenesis is poorly understood. Studying 17,152 prospectively sequenced patients with cancer, we identified pathogenic germline variants in cancer predisposition genes, and assessed their zygosity and co-occurring somatic alterations in the concomitant tumors. Two major routes to tumorigenesis were apparent. In carriers of pathogenic germline variants in high-penetrance genes (5.1% overall), lineage-dependent patterns of biallelic inactivation led to tumors exhibiting mechanism-specific somatic phenotypes and fewer additional somatic oncogenic drivers. Nevertheless, 27% of cancers in these patients, and most tumors in patients with pathogenic germline variants in lower-penetrance genes, lacked particular hallmarks of tumorigenesis associated with the germline allele. The dependence of tumors on pathogenic germline variants is variable and often dictated by both penetrance and lineage, a finding with implications for clinical management.
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Mutación de Línea Germinal , Neoplasias/genética , Carcinogénesis/genética , Variaciones en el Número de Copia de ADN , Reparación de la Incompatibilidad de ADN/genética , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , FenotipoRESUMEN
TAFRO syndrome, a clinical subtype of idiopathic multicentric Castleman disease (iMCD), consists of a constellation of symptoms/signs including thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, and organomegaly. The etiology of iMCD-TAFRO and the basis for cytokine hypersecretion commonly seen in iMCD-TAFRO patients has not been elucidated. Here, we identified a somatic MEK2P128L mutation and a germline RUNX1G60C mutation in two patients with iMCD-TAFRO, respectively. The MEK2P128L mutation, which has been identified previously in solid tumor and histiocytosis patients, caused hyperactivated MAP kinase signaling, conferred IL-3 hypersensitivity and sensitized the cells to various MEK inhibitors. The RUNX1G60C mutation abolished the transcriptional activity of wild-type RUNX1 and functioned as a dominant negative form of RUNX1, resulting in enhanced self-renewal activity in hematopoietic stem/progenitor cells. Interestingly, ERK was heavily activated in both patients, highlighting a potential role for activation of MAPK signaling in iMCD-TAFRO pathogenesis and a rationale for exploring inhibition of the MAPK pathway as a therapy for iMCD-TAFRO. Moreover, these data suggest that iMCD-TAFRO might share pathogenetic features with clonal inflammatory disorders bearing MEK and RUNX1 mutations such as histiocytoses and myeloid neoplasms.
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Enfermedad de Castleman/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , MAP Quinasa Quinasa 2/genética , Adulto , Enfermedad de Castleman/patología , Preescolar , Análisis Mutacional de ADN , Humanos , Ganglios Linfáticos/patología , Sistema de Señalización de MAP Quinasas/genética , Masculino , Adulto JovenRESUMEN
BACKGROUND: The median overall survival of patients with high-risk myelodysplastic syndromes refractory to hypomethylating agents is less than 6 months. Currently, no standard therapy for such patients exists. Preclinical studies have shown that inhibition of the nuclear export protein exportin 1 (XPO1) causes nuclear accumulation of p53 and disruption of NF-κB signalling, both relevant targets for myelodysplastic syndromes. We therefore aimed to assess the safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents. METHODS: We did a single-centre, single-arm, phase 2 trial at the Memorial Sloan Kettering Cancer Center in the USA. We included patients 18 years or older with high-risk myelodysplastic syndromes or oligoblastic acute myeloid leukaemia (defined as blasts ≥20% but ≤30%) refractory to hypomethylating agents and with an Eastern Cooperative Oncology Group performance status score of 0-2. Eligible patients received 3-week long cycles of oral selinexor (60 mg twice per week for 2 weeks, followed by 1 week off). The primary outcome was overall response rate. Complete remission, partial remission, marrow complete remission, or haematological improvement were included in the response categories for assessing the primary endpoint. The activity analysis included all patients who completed at least one full-scheduled post-treatment disease assessment. All patients who were given selinexor were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT02228525. FINDINGS: Between Sept 23, 2014, and March 13, 2018, 25 patients were enrolled on this study. The median follow-up was 8·5 months (IQR 3·1-12·2). Two patients did not meet the full eligibility criteria after baseline assessment; therefore, 23 patients were evaluable for activity assessment. In the 23 evaluable patients, overall response rate was 26% (95% CI 10-48) in six patients with marrow complete remission, with an additional 12 patients (52%, 95% CI 31-73) achieving stable disease. The most common grade 3 or 4 adverse events were thrombocytopenia (eight [32%] of 25 patients) and hyponatraemia (five [20%]). There were no drug-related serious adverse events and no treatment-related deaths. INTERPRETATION: Selinexor showed responses in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents. Adverse events were manageable with supportive care implementation. Further studies are needed to compare selinexor with supportive care alone, and to identify patient subgroups that might benefit the most from selinexor treatment. FUNDING: Karyopharm Therapeutics.
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Azacitidina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Hidrazinas/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Triazoles/uso terapéutico , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/farmacología , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Síndromes Mielodisplásicos/patología , Seguridad del Paciente , Pronóstico , Tasa de SupervivenciaRESUMEN
Surgery is the only curative option for stage I/II pancreatic cancer; nonetheless, most patients will experience a recurrence after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer, we performed whole-exome or targeted sequencing of 10 resected primary cancers and matched intrapancreatic recurrences or distant metastases. We identified that recurrent disease after adjuvant or first-line platinum therapy corresponds to an increased mutational burden. Recurrent disease is enriched for genetic alterations predicted to activate MAPK/ERK and PI3K-AKT signaling and develops from a monophyletic or polyphyletic origin. Treatment-induced genetic bottlenecks lead to a modified genetic landscape and subclonal heterogeneity for driver gene alterations in part due to intermetastatic seeding. In 1 patient what was believed to be recurrent disease was an independent (second) primary tumor. These findings suggest routine post-treatment sampling may have value in the management of recurrent pancreatic cancer. SIGNIFICANCE: The biological features or clinical vulnerabilities of recurrent pancreatic cancer after pancreaticoduodenectomy are unknown. Using whole-exome sequencing we find that recurrent disease has a distinct genomic landscape, intermetastatic genetic heterogeneity, diverse clonal origins, and higher mutational burden than found for treatment-naïve disease.See related commentary by Bednar and Pasca di Magliano, p. 762.This article is highlighted in the In This Issue feature, p. 747.
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Carcinoma Ductal Pancreático/genética , Metástasis de la Neoplasia/genética , Recurrencia Local de Neoplasia/genética , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/secundario , Evolución Molecular , Humanos , Recurrencia Local de Neoplasia/patología , Neoplasias Pancreáticas/patología , Secuenciación del ExomaRESUMEN
IMPORTANCE: Diagnosing the site of origin for cancer is a pillar of disease classification that has directed clinical care for more than a century. Even in an era of precision oncologic practice, in which treatment is increasingly informed by the presence or absence of mutant genes responsible for cancer growth and progression, tumor origin remains a critical factor in tumor biologic characteristics and therapeutic sensitivity. OBJECTIVE: To evaluate whether data derived from routine clinical DNA sequencing of tumors could complement conventional approaches to enable improved diagnostic accuracy. DESIGN, SETTING, AND PARTICIPANTS: A machine learning approach was developed to predict tumor type from targeted panel DNA sequence data obtained at the point of care, incorporating both discrete molecular alterations and inferred features such as mutational signatures. This algorithm was trained on 7791 tumors representing 22 cancer types selected from a prospectively sequenced cohort of patients with advanced cancer. RESULTS: The correct tumor type was predicted for 5748 of the 7791 patients (73.8%) in the training set as well as 8623 of 11â¯644 patients (74.1%) in an independent cohort. Predictions were assigned probabilities that reflected empirical accuracy, with 3388 cases (43.5%) representing high-confidence predictions (>95% probability). Informative molecular features and feature categories varied widely by tumor type. Genomic analysis of plasma cell-free DNA yielded accurate predictions in 45 of 60 cases (75.0%), suggesting that this approach may be applied in diverse clinical settings including as an adjunct to cancer screening. Likely tissues of origin were predicted from targeted tumor sequencing in 95 of 141 patients (67.4%) with cancers of unknown primary site. Applying this method prospectively to patients under active care enabled genome-directed reassessment of diagnosis in 2 patients initially presumed to have metastatic breast cancer, leading to the selection of more appropriate treatments, which elicited clinical responses. CONCLUSIONS AND RELEVANCE: These results suggest that the application of artificial intelligence to predict tissue of origin in oncologic practice can act as a useful complement to conventional histologic review to provide integrated pathologic diagnoses, often with important therapeutic implications.
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Inteligencia Artificial , Neoplasias de la Mama , Femenino , Genómica/métodos , Humanos , Aprendizaje Automático , Análisis de Secuencia de ADNRESUMEN
INTRODUCTION: EGFR-mutant lung cancers are clinically and genomically heterogeneous with concurrent RB transcriptional corepressor 1 (RB1)/tumor protein p53 (TP53) alterations identifying a subset at increased risk for small cell transformation. The genomic alterations that induce lineage plasticity are unknown. METHODS: Patients with EGFR/RB1/TP53-mutant lung cancers, identified by next-generation sequencing from 2014 to 2018, were compared to patients with untreated, metastatic EGFR-mutant lung cancers without both RB1 and TP53 alterations. Time to EGFR-tyrosine kinase inhibitor discontinuation, overall survival, SCLC transformation rate, and genomic alterations were evaluated. RESULTS: Patients with EGFR/RB1/TP53-mutant lung cancers represented 5% (43 of 863) of EGFR-mutant lung cancers but were uniquely at risk for transformation (7 of 39, 18%), with no transformations in EGFR-mutant lung cancers without baseline TP53 and RB1 alterations. Irrespective of transformation, patients with EGFR/TP53/RB1-mutant lung cancers had a shorter time to discontinuation than EGFR/TP53- and EGFR-mutant -only cancers (9.5 versus 12.3 versus 36.6 months, respectively, p = 2 × 10-9). The triple-mutant population had a higher incidence of whole-genome doubling compared to NSCLC and SCLC at large (80% versus 34%, p < 5 × 10-9 versus 51%, p < 0.002, respectively) and further enrichment in triple-mutant cancers with eventual small cell histology (seven of seven pre-transformed plus four of four baseline SCLC versus 23 of 32 never transformed, respectively, p = 0.05). Activation-induced cytidine deaminase/apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like mutation signature was also enriched in triple-mutant lung cancers that transformed (false discovery rate = 0.03). CONCLUSIONS: EGFR/TP53/RB1-mutant lung cancers are at unique risk of histologic transformation, with 25% presenting with de novo SCLC or eventual small cell transformation. Triple-mutant lung cancers are enriched in whole-genome doubling and Activation-induced cytidine deaminase/apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like hypermutation which may represent early genomic determinants of lineage plasticity.
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Transformación Celular Neoplásica/patología , Mutación , Proteínas de Unión a Retinoblastoma/genética , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Carcinoma Pulmonar de Células Pequeñas/patología , Proteína p53 Supresora de Tumor/genética , Ubiquitina-Proteína Ligasas/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/genética , Receptores ErbB/genética , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Inhibidores de Proteínas Quinasas , Factores de Riesgo , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/genética , Tasa de SupervivenciaRESUMEN
Altered expression of XPO1, the main nuclear export receptor in eukaryotic cells, has been observed in cancer, and XPO1 has been a focus of anticancer drug development. However, mechanistic evidence for cancer-specific alterations in XPO1 function is lacking. Here, genomic analysis of 42,793 cancers identified recurrent and previously unrecognized mutational hotspots in XPO1. XPO1 mutations exhibited striking lineage specificity, with enrichment in a variety of B-cell malignancies, and introduction of single amino acid substitutions in XPO1 initiated clonal, B-cell malignancy in vivo. Proteomic characterization identified that mutant XPO1 altered the nucleocytoplasmic distribution of hundreds of proteins in a sequence-specific manner that promoted oncogenesis. XPO1 mutations preferentially sensitized cells to inhibitors of nuclear export, providing a biomarker of response to this family of drugs. These data reveal a new class of oncogenic alteration based on change-of-function mutations in nuclear export signal recognition and identify therapeutic targets based on altered nucleocytoplasmic trafficking. SIGNIFICANCE: Here, we identify that heterozygous mutations in the main nuclear exporter in eukaryotic cells, XPO1, are positively selected in cancer and promote the initiation of clonal B-cell malignancies. XPO1 mutations alter nuclear export signal recognition in a sequence-specific manner and sensitize cells to compounds in clinical development inhibiting XPO1 function.This article is highlighted in the In This Issue feature, p. 1325.
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Transformación Celular Neoplásica , Señales de Exportación Nuclear , Transporte Activo de Núcleo Celular , Animales , Proliferación Celular , Modelos Animales de Enfermedad , Expresión Génica , Genes bcl-2 , Genes myc , Humanos , Carioferinas/química , Carioferinas/genética , Carioferinas/metabolismo , Leucemia de Células B/genética , Leucemia de Células B/metabolismo , Leucemia de Células B/mortalidad , Leucemia de Células B/patología , Ratones , Mutación , Especificidad de Órganos/genética , Unión Proteica , Receptores Citoplasmáticos y Nucleares/química , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Relación Estructura-Actividad , Proteína Exportina 1RESUMEN
PURPOSE: Microsatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) testing has traditionally been performed in patients with colorectal (CRC) and endometrial cancer (EC) to screen for Lynch syndrome (LS)-associated cancer predisposition. The recent success of immunotherapy in high-frequency MSI (MSI-H) and/or MMR-D tumors now supports testing for MSI in all advanced solid tumors. The extent to which LS accounts for MSI-H across heterogeneous tumor types is unknown. Here, we establish the prevalence of LS across solid tumors according to MSI status. METHODS: MSI status was determined using targeted next-generation sequencing, with tumors classified as MSI-H, MSI-indeterminate, or microsatellite-stable. Matched germline DNA was analyzed for mutations in LS-associated mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, EPCAM). In patients with LS with MSI-H/I tumors, immunohistochemical staining for MMR-D was assessed. RESULTS: Among 15,045 unique patients (more than 50 cancer types), LS was identified in 16.3% (53 of 326), 1.9% (13 of 699), and 0.3% (37 of 14,020) of patients with MSI-H, MSI-indeterminate, and microsatellite-stable tumors, respectively ( P < .001). Among patients with LS with MSI-H/I tumors, 50% (33 of 66) had tumors other than CRC/EC, including urothelial, prostate, pancreas, adrenocortical, small bowel, sarcoma, mesothelioma, melanoma, gastric, and germ cell tumors. In these patients with non-CRC/EC tumors, 45% (15 of 33) did not meet LS genetic testing criteria on the basis of personal/family history. Immunohistochemical staining of LS-positive MSI-H/I tumors demonstrated MMR-D in 98.2% (56 of 57) of available cases. CONCLUSION: MSI-H/MMR-D is predictive of LS across a much broader tumor spectrum than currently appreciated. Given implications for cancer surveillance and prevention measures in affected families, these data support germline genetic assessment for LS for patients with an MSI-H/MMR-D tumor, regardless of cancer type or family cancer history.
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Biomarcadores de Tumor/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN , Inestabilidad de Microsatélites , Mutación , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Ciudad de Nueva York/epidemiología , Fenotipo , Prevalencia , Estudios Prospectivos , TranscriptomaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Driven by the recent advances of next generation sequencing (NGS) technologies and an urgent need to decode complex human diseases, a multitude of large-scale studies were conducted recently that have resulted in an unprecedented volume of whole transcriptome sequencing (RNA-seq) data, such as the Genotype Tissue Expression project (GTEx) and The Cancer Genome Atlas (TCGA). While these data offer new opportunities to identify the mechanisms underlying disease, the comparison of data from different sources remains challenging, due to differences in sample and data processing. Here, we developed a pipeline that processes and unifies RNA-seq data from different studies, which includes uniform realignment, gene expression quantification, and batch effect removal. We find that uniform alignment and quantification is not sufficient when combining RNA-seq data from different sources and that the removal of other batch effects is essential to facilitate data comparison. We have processed data from GTEx and TCGA and successfully corrected for study-specific biases, enabling comparative analysis between TCGA and GTEx. The normalized datasets are available for download on figshare.
Asunto(s)
Neoplasias/genética , ARN Neoplásico , ARN , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Análisis de Secuencia de ARNRESUMEN
Ploidy abnormalities are a hallmark of cancer, but their impact on the evolution and outcomes of cancers is unknown. Here, we identified whole-genome doubling (WGD) in the tumors of nearly 30% of 9,692 prospectively sequenced advanced cancer patients. WGD varied by tumor lineage and molecular subtype, and arose early in carcinogenesis after an antecedent transforming driver mutation. While associated with TP53 mutations, 46% of all WGD arose in TP53-wild-type tumors and in such cases was associated with an E2F-mediated G1 arrest defect, although neither aberration was obligate in WGD tumors. The variability of WGD across cancer types can be explained in part by cancer cell proliferation rates. WGD predicted for increased morbidity across cancer types, including KRAS-mutant colorectal cancers and estrogen receptor-positive breast cancers, independently of established clinical prognostic factors. We conclude that WGD is highly common in cancer and is a macro-evolutionary event associated with poor prognosis across cancer types.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias Colorrectales/genética , Mutación , Proliferación Celular/genética , Femenino , Genoma Humano , Estudio de Asociación del Genoma Completo/métodos , Humanos , Pronóstico , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Driver mutations in oncogenes encode proteins with gain-of-function properties that enhance fitness. Heterozygous mutations are thus viewed as sufficient for tumorigenesis. We describe widespread oncogenic mutant allele imbalance in 13,448 prospectively characterized cancers. Imbalance was selected for through modest dosage increases of gain-of-fitness mutations. Negative selection targeted haplo-essential effectors of the spliceosome. Loss of the normal allele comprised a distinct class of imbalance driven by competitive fitness, which correlated with enhanced response to targeted therapies. In many cancers, an antecedent oncogenic mutation drove evolutionarily dependent allele-specific imbalance. In other instances, oncogenic mutations co-opted independent copy-number changes via the evolutionary process of exaptation. Oncogenic allele imbalance is a pervasive evolutionary innovation that enhances fitness and modulates sensitivity to targeted therapy.
Asunto(s)
Carcinogénesis/genética , Dosificación de Gen/genética , Regulación Neoplásica de la Expresión Génica/genética , Mutación/genética , Neoplasias/genética , Línea Celular Tumoral , Células HEK293 , Humanos , Neoplasias/patologíaRESUMEN
Purpose: Small-cell carcinoma of the bladder (SCCB) is a rare and aggressive neuroendocrine tumor with a dismal prognosis and limited treatment options. As SCCB is histologically indistinguishable from small-cell lung cancer, a shared pathogenesis and cell of origin has been proposed. The aim of this study is to determine whether SCCBs arise from a preexisting urothelial carcinoma or share a molecular pathogenesis in common with small-cell lung cancer.Experimental Design: We performed an integrative analysis of 61 SCCB tumors to identify histology- and organ-specific similarities and differences.Results: SCCB has a high somatic mutational burden driven predominantly by an APOBEC-mediated mutational process. TP53, RB1, and TERT promoter mutations were present in nearly all samples. Although these events appeared to arise early in all affected tumors and likely reflect an evolutionary branch point that may have driven small-cell lineage differentiation, they were unlikely the founding transforming event, as they were often preceded by diverse and less common driver mutations, many of which are common in bladder urothelial cancers, but not small-cell lung tumors. Most patient tumors (72%) also underwent genome doubling (GD). Although arising at different chronologic points in the evolution of the disease, GD was often preceded by biallelic mutations in TP53 with retention of two intact copies.Conclusions: Our findings indicate that small-cell cancers of the bladder and lung have a convergent but distinct pathogenesis, with SCCBs arising from a cell of origin shared with urothelial bladder cancer. Clin Cancer Res; 24(8); 1965-73. ©2017 AACRSee related commentary by Oser and Jänne, p. 1775.