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1.
Cell ; 149(6): 1381-92, 2012 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-22682255

RESUMEN

Despite the explosive growth of genomic data, functional annotation of regulatory sequences remains difficult. Here, we introduce "comparative epigenomics"-interspecies comparison of DNA and histone modifications-as an approach for annotation of the regulatory genome. We measured in human, mouse, and pig pluripotent stem cells the genomic distributions of cytosine methylation, H2A.Z, H3K4me1/2/3, H3K9me3, H3K27me3, H3K27ac, H3K36me3, transcribed RNAs, and P300, TAF1, OCT4, and NANOG binding. We observed that epigenomic conservation was strong in both rapidly evolving and slowly evolving DNA sequences, but not in neutrally evolving sequences. In contrast, evolutionary changes of the epigenome and the transcriptome exhibited a linear correlation. We suggest that the conserved colocalization of different epigenomic marks can be used to discover regulatory sequences. Indeed, seven pairs of epigenomic marks identified exhibited regulatory functions during differentiation of embryonic stem cells into mesendoderm cells. Thus, comparative epigenomics reveals regulatory features of the genome that cannot be discerned from sequence comparisons alone.


Asunto(s)
Secuencia Conservada , Metilación de ADN , Epigenómica/métodos , Código de Histonas , Elementos Reguladores de la Transcripción , Animales , Secuencia de Bases , Células Madre Embrionarias/metabolismo , Regulación de la Expresión Génica , Humanos , Ratones , Células Madre Pluripotentes/metabolismo , Porcinos , Factores de Transcripción/metabolismo , Transcripción Genética
2.
Mol Cancer ; 23(1): 115, 2024 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-38811992

RESUMEN

BACKGROUND: We explored potential predictive biomarkers of immunotherapy response in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with durvalumab (D) + tremelimumab (T) + etoposide-platinum (EP), D + EP, or EP in the randomized phase 3 CASPIAN trial. METHODS: 805 treatment-naïve patients with ES-SCLC were randomized (1:1:1) to receive D + T + EP, D + EP, or EP. The primary endpoint was overall survival (OS). Patients were required to provide an archived tumor tissue block (or ≥ 15 newly cut unstained slides) at screening, if these samples existed. After assessment for programmed cell death ligand-1 expression and tissue tumor mutational burden, residual tissue was used for additional molecular profiling including by RNA sequencing and immunohistochemistry. RESULTS: In 182 patients with transcriptional molecular subtyping, OS with D ± T + EP was numerically highest in the SCLC-inflamed subtype (n = 10, median 24.0 months). Patients derived benefit from immunotherapy across subtypes; thus, additional biomarkers were investigated. OS benefit with D ± T + EP versus EP was greater with high versus low CD8A expression/CD8 cell density by immunohistochemistry, but with no additional benefit with D + T + EP versus D + EP. OS benefit with D + T + EP versus D + EP was associated with high expression of CD4 (median 25.9 vs. 11.4 months) and antigen-presenting and processing machinery (25.9 vs. 14.6 months) and MHC I and II (23.6 vs. 17.3 months) gene signatures, and with higher MHC I expression by immunohistochemistry. CONCLUSIONS: These findings demonstrate the tumor microenvironment is important in mediating better outcomes with D ± T + EP in ES-SCLC, with canonical immune markers associated with hypothesized immunotherapy mechanisms of action defining patient subsets that respond to D ± T. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03043872.


Asunto(s)
Biomarcadores de Tumor , Inmunoterapia , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/inmunología , Carcinoma Pulmonar de Células Pequeñas/terapia , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/metabolismo , Femenino , Masculino , Inmunoterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Persona de Mediana Edad , Anciano , Anticuerpos Monoclonales/uso terapéutico , Resultado del Tratamiento , Estadificación de Neoplasias , Anticuerpos Monoclonales Humanizados/uso terapéutico , Pronóstico , Adulto
3.
BMC Cancer ; 22(1): 13, 2022 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-34979999

RESUMEN

BACKGROUND: DNA repair deficiencies are characteristic of cancer and homologous recombination deficiency (HRD) is the most common. HRD sensitizes tumour cells to PARP inhibitors so it is important to understand the landscape of HRD across different solid tumour types. METHODS: Germline and somatic BRCA mutations in breast and ovarian cancers were evaluated using sequencing data from The Cancer Genome Atlas (TCGA) database. Secondly, a larger independent genomic dataset was analysed to validate the TCGA results and determine the frequency of germline and somatic mutations across 15 different candidate homologous recombination repair (HRR) genes, and their relationship with the genetic events of bi-allelic loss, loss of heterozygosity (LOH) and tumour mutation burden (TMB). RESULTS: Approximately one-third of breast and ovarian cancer BRCA mutations were somatic. These showed a similar degree of bi-allelic loss and clinical outcomes to germline mutations, identifying potentially 50% more patients that may benefit from precision treatments. HRR mutations were present in sizable proportions in all tumour types analysed and were associated with high TMB and LOH scores. We also identified numerous BRCA reversion mutations across all tumour types. CONCLUSIONS: Our results will facilitate future research into the efficacy of precision oncology treatments, including PARP and immune checkpoint inhibitors.


Asunto(s)
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Recombinación Homóloga/genética , Neoplasias Ováricas/genética , Bases de Datos Genéticas , Conjuntos de Datos como Asunto , Femenino , Genómica , Mutación de Línea Germinal/genética , Humanos , Pérdida de Heterocigocidad/genética , Mutación/genética , Reparación del ADN por Recombinación/genética
4.
Nature ; 502(7471): 333-339, 2013 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-24132290

RESUMEN

The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects. Using the integrated data sets, we identified 127 significantly mutated genes from well-known (for example, mitogen-activated protein kinase, phosphatidylinositol-3-OH kinase, Wnt/ß-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the number of driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.


Asunto(s)
Carcinogénesis/genética , Mutación/genética , Neoplasias/clasificación , Neoplasias/genética , Ciclo Celular/genética , Células Clonales/metabolismo , Células Clonales/patología , Estudios de Cohortes , Reparación del ADN/genética , Humanos , Mutación INDEL/genética , Proteínas Quinasas Activadas por Mitógenos/genética , Modelos Genéticos , Neoplasias/metabolismo , Neoplasias/patología , Oncogenes/genética , Fosfatidilinositol 3-Quinasas/genética , Mutación Puntual/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Análisis de Supervivencia , Factores de Tiempo
5.
Bioinformatics ; 33(23): 3799-3801, 2017 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-28961932

RESUMEN

SUMMARY: MIRMMR predicts microsatellite instability status in cancer samples using methylation and mutation information, in contrast to existing methods that rely on observed microsatellites. Additionally, MIRMMR highlights those genetic alterations contributing to microsatellite instability. AVAILABILITY AND IMPLEMENTATION: Source code is freely available at https://github.com/ding-lab/MIRMMR under the MIT license, implemented in R and supported on Unix/OS X operating systems. CONTACT: smfoltz@wustl.edu or lding@wustl.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Metilación de ADN , Genómica/métodos , Inestabilidad de Microsatélites , Mutación , Neoplasias/genética , Programas Informáticos , Humanos , Neoplasias/metabolismo
6.
Genome Res ; 23(9): 1541-53, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23804401

RESUMEN

Recent advancements in sequencing-based DNA methylation profiling methods provide an unprecedented opportunity to map complete DNA methylomes. These include whole-genome bisulfite sequencing (WGBS, MethylC-seq, or BS-seq), reduced-representation bisulfite sequencing (RRBS), and enrichment-based methods such as MeDIP-seq, MBD-seq, and MRE-seq. These methods yield largely comparable results but differ significantly in extent of genomic CpG coverage, resolution, quantitative accuracy, and cost, at least while using current algorithms to interrogate the data. None of these existing methods provides single-CpG resolution, comprehensive genome-wide coverage, and cost feasibility for a typical laboratory. We introduce methylCRF, a novel conditional random fields-based algorithm that integrates methylated DNA immunoprecipitation (MeDIP-seq) and methylation-sensitive restriction enzyme (MRE-seq) sequencing data to predict DNA methylation levels at single-CpG resolution. Our method is a combined computational and experimental strategy to produce DNA methylomes of all 28 million CpGs in the human genome for a fraction (<10%) of the cost of whole-genome bisulfite sequencing methods. methylCRF was benchmarked for accuracy against Infinium arrays, RRBS, WGBS sequencing, and locus-specific bisulfite sequencing performed on the same human embryonic stem cell line. methylCRF transformation of MeDIP-seq/MRE-seq was equivalent to a biological replicate of WGBS in quantification, coverage, and resolution. We used conventional bisulfite conversion, PCR, cloning, and sequencing to validate loci where our predictions do not agree with whole-genome bisulfite data, and in 11 out of 12 cases, methylCRF predictions of methylation level agree better with validated results than does whole-genome bisulfite sequencing. Therefore, methylCRF transformation of MeDIP-seq/MRE-seq data provides an accurate, inexpensive, and widely accessible strategy to create full DNA methylomes.


Asunto(s)
Algoritmos , Islas de CpG , Metilación de ADN , Genoma Humano , Análisis de Secuencia de ADN/métodos , Programas Informáticos , Enzimas de Restricción del ADN/química , Humanos
7.
Bioinformatics ; 30(7): 1015-6, 2014 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-24371154

RESUMEN

MOTIVATION: Microsatellite instability (MSI) is an important indicator of larger genome instability and has been linked to many genetic diseases, including Lynch syndrome. MSI status is also an independent prognostic factor for favorable survival in multiple cancer types, such as colorectal and endometrial. It also informs the choice of chemotherapeutic agents. However, the current PCR-electrophoresis-based detection procedure is laborious and time-consuming, often requiring visual inspection to categorize samples. We developed MSIsensor, a C++ program for automatically detecting somatic microsatellite changes. It computes length distributions of microsatellites per site in paired tumor and normal sequence data, subsequently using these to statistically compare observed distributions in both samples. Comprehensive testing indicates MSIsensor is an efficient and effective tool for deriving MSI status from standard tumor-normal paired sequence data. AVAILABILITY AND IMPLEMENTATION: https://github.com/ding-lab/msisensor


Asunto(s)
Inestabilidad de Microsatélites , Análisis de Secuencia de ADN/métodos , Automatización de Laboratorios , Genoma Humano , Humanos , Neoplasias/genética , Reacción en Cadena de la Polimerasa , Programas Informáticos
8.
Biol Pharm Bull ; 38(10): 1458-63, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26424010

RESUMEN

Spermatogenesis associated 4 (SPATA4) is a testis-specific gene first cloned by our laboratory, and plays an important role in maintaining the physiological function of germ cells. Accumulated evidence suggests that SPATA4 might be associated with apoptosis. Here we established HeLa cells that stably expressed SPATA4 to investigate the function of SPATA4 in apoptosis. SPATA4 protected HeLa cells from etoposide-induced apoptosis through the mitochondrial apoptotic pathway, in the way that SPATA4 suppressed decrease of the mitochondrial membrane potential, the release of cytochrome c, and subsequent activation of caspase-9 and -3. We further demonstrated that SPATA4 upregulated anti-apoptotic members of Bcl-2 family proteins, Bcl-2, and downregulated the pro-apoptotic member of Bcl-2 family proteins, Bax. Knockdown of SPATA4 in HeLa/SPATA4 cells could partially rescue expression levels of bcl-2 and bax. In conclusion, SPATA4 protects HeLa cells against etoposide-induced apoptosis through the mitochondrial apoptotic pathway. Our findings provide further evidence that SPATA4 plays a role in regulating apoptosis.


Asunto(s)
Apoptosis/fisiología , Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Citocromos c/metabolismo , Etopósido , Células HeLa , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/fisiología , Proteínas/genética , Inhibidores de Topoisomerasa II
9.
Hum Mutat ; 35(1): 63-5, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24130125

RESUMEN

Tumors with defective mismatch repair acquire large numbers of strand slippage mutations including frameshifts in coding sequence repeats. We identified a mutational hotspot, p.T204fs, in the insulator-binding protein (CTCF) in MSI-positive endometrial cancers. Although CTCF was described as a significantly mutated gene by the endometrial cancer TCGA, the A7 track variants leading to T204 frameshifts were not reported. Reanalysis of TCGA data using Pindel revealed frequent T204fs mutations, confirming CTCF is an MSI target gene and revealed the same frameshifts in tumors with intact mismatch repair. We show that T204fs transcripts are subject to nonsense-mediated decay and as such, T204fs mutations are unlikely to act as dominant negatives. The spectrum and pattern of mutations observed is consistent with CTCF acting as a haploinsufficient tumor suppressor.


Asunto(s)
Neoplasias Endometriales/genética , Mutación del Sistema de Lectura , Inestabilidad de Microsatélites , Proteínas Represoras/genética , Secuencia de Bases , Factor de Unión a CCCTC , Reparación de la Incompatibilidad de ADN , Neoplasias Endometriales/patología , Exoma , Femenino , Variación Genética , Haploinsuficiencia , Humanos , Repeticiones de Microsatélite , Tasa de Mutación , Degradación de ARNm Mediada por Codón sin Sentido , Análisis de Secuencia de ADN , Proteínas Supresoras de Tumor/genética
10.
Clin Cancer Res ; 2024 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-39017667

RESUMEN

PURPOSE: The phase II, multiarm, signal-searching BALTIC study (NCT02937818) assessed novel treatment combinations for platinum-refractory/resistant extensive-stage small-cell lung cancer (ES-SCLC). EXPERIMENTAL DESIGN: Patients with ES-SCLC with progressive disease during or within 90 days of completing first-line platinum-based chemotherapy received one of three regimens: durvalumab plus tremelimumab followed by durvalumab monotherapy (arm A), adavosertib plus carboplatin (arm B), or ceralasertib plus olaparib (arm C). The primary endpoint was objective response rate (ORR). Prespecified exploratory biomarker analyses were conducted in arms A and C. RESULTS: In arm A (n=41), arm B (n=10), and arm C (n=21), confirmed ORR was 7.3%, 0%, and 4.8%, respectively. Safety profiles in all arms were consistent with those of the individual drugs. In arm A, patients with PD-L1 expression (tumor cells [TC] or immune cells [IC]) ≥1% appeared to have a greater likelihood of achieving disease control with durvalumab plus tremelimumab than those with PD-L1 (TC and IC) <1%, and lower baseline circulating tumor DNA (ctDNA) and reduction in on-treatment ctDNA level were both associated with longer overall survival (OS). Among patients treated with ceralasertib plus olaparib in arm C, specific immune response-relevant circulating chemokines and cytokines were identified as early biomarkers of survival and pharmacodynamic biomarkers. CONCLUSIONS: In BALTIC, all combination regimens demonstrated tolerable safety profiles, but antitumor activity was limited in refractory/resistant ES-SCLC. Among patients treated with durvalumab plus tremelimumab, an association of on-treatment reduction in ctDNA with longer OS suggests the potential use of ctDNA as a surrogate of treatment response, warranting further investigation.

11.
Clin Cancer Res ; 30(4): 824-835, 2024 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-37801329

RESUMEN

PURPOSE: In the CASPIAN trial, first-line durvalumab plus platinum-etoposide (EP) significantly improved overall survival (OS) versus EP alone in extensive-stage small cell lung cancer (ES-SCLC). We report exploratory analyses of CASPIAN outcomes by programmed cell death ligand-1 (PD-L1) expression and tissue tumor mutational burden (tTMB). EXPERIMENTAL DESIGN: Patients were randomized (1:1:1) to durvalumab (1,500 mg) plus EP, durvalumab plus tremelimumab (75 mg) plus EP, or EP alone. Treatment effects in PD-L1 and tTMB subgroups were estimated using an unstratified Cox proportional hazards model. RESULTS: The PD-L1 and tTMB biomarker-evaluable populations (BEP) comprised 54.4% (438/805) and 35.2% (283/805) of the intention-to-treat population, respectively. PD-L1 prevalence was low: 5.7%, 25.8%, and 28.3% had PD-L1 expression on ≥1% tumor cells (TC), ≥1% immune cells (IC), and ≥1% TCs or ICs, respectively. OS benefit with durvalumab plus EP versus EP was similar across PD-L1 subgroups, with HRs all falling within the 95% confidence interval (CI) for the PD-L1 BEP (0.47‒0.79). OS benefit with durvalumab plus tremelimumab plus EP versus EP was greater in PD-L1 ≥1% versus <1% subgroups, although CIs overlapped. There was no evidence of an interaction between tTMB and treatment effect on OS (durvalumab plus EP vs. EP, P = 0.916; durvalumab plus tremelimumab plus EP vs. EP, P = 0.672). CONCLUSIONS: OS benefit with first-line durvalumab plus EP in patients with ES-SCLC was observed regardless of PD-L1 or tTMB status. PD-L1 expression may prove to be a useful biomarker for combined treatment with PD-(L)1 and CTLA-4 inhibition, although this requires confirmation with an independent dataset. See related commentary by Rolfo and Russo, p. 652.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/genética , Antígeno B7-H1/genética , Etopósido , Platino (Metal) , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
12.
J Clin Invest ; 131(15)2021 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-34156976

RESUMEN

Clear cell sarcoma (CCS) is a deadly malignancy affecting adolescents and young adults. It is characterized by reciprocal translocations resulting in expression of the chimeric EWSR1-ATF1 or EWSR1-CREB1 fusion proteins, driving sarcomagenesis. Besides these characteristics, CCS has remained genomically uncharacterized. Copy number analysis of human CCSs showed frequent amplifications of the MITF locus and chromosomes 7 and 8. Few alterations were shared with Ewing sarcoma or desmoplastic, small round cell tumors, which are other EWSR1-rearranged tumors. Exome sequencing in mouse tumors generated by expression of EWSR1-ATF1 from the Rosa26 locus demonstrated no other repeated pathogenic variants. Additionally, we generated a new CCS mouse by Cre-loxP-induced chromosomal translocation between Ewsr1 and Atf1, resulting in copy number loss of chromosome 6 and chromosome 15 instability, including amplification of a portion syntenic to human chromosome 8, surrounding Myc. Additional experiments in the Rosa26 conditional model demonstrated that Mitf or Myc can contribute to sarcomagenesis. Copy number observations in human tumors and genetic experiments in mice rendered, for the first time to our knowledge, a functional landscape of the CCS genome. These data advance efforts to understand the biology of CCS using innovative models that will eventually allow us to validate preclinical therapies necessary to achieve longer and better survival for young patients with this disease.


Asunto(s)
Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 8/genética , Amplificación de Genes , Factor de Transcripción Asociado a Microftalmía/genética , Proteínas de Fusión Oncogénica/genética , Sarcoma de Células Claras/genética , Animales , Línea Celular Tumoral , Humanos , Ratones , Sarcoma de Células Claras/metabolismo
13.
Clin Cancer Res ; 26(23): 6335-6349, 2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-32943458

RESUMEN

PURPOSE: Danvatirsen is a therapeutic antisense oligonucleotide (ASO) that selectively targets STAT3 and has shown clinical activity in two phase I clinical studies. We interrogated the clinical mechanism of action using danvatirsen-treated patient samples and conducted back-translational studies to further elucidate its immunomodulatory mechanism of action. EXPERIMENTAL DESIGN: Paired biopsies and blood samples from danvatirsen-treated patients were evaluated using immunohistochemistry and gene-expression analysis. To gain mechanistic insight, we used mass cytometry, flow cytometry, and immunofluorescence analysis of CT26 tumors treated with a mouse surrogate STAT3 ASO, and human immune cells were treated in vitro with danvatirsen. RESULTS: Within the tumors of treated patients, danvatirsen uptake was observed mainly in cells of the tumor microenvironment (TME). Gene expression analysis comparing baseline and on-treatment tumor samples showed increased expression of proinflammatory genes. In mouse models, STAT3 ASO demonstrated partial tumor growth inhibition and enhanced the antitumor activity when combined with anti-PD-L1. Immune profiling revealed reduced STAT3 protein in immune and stromal cells, and decreased suppressive cytokines correlating with increased proinflammatory macrophages and cytokine production. These changes led to enhanced T-cell abundance and function in combination with anti-PD-L1. CONCLUSIONS: STAT3 ASO treatment reverses a suppressive TME and promotes proinflammatory gene expression changes in patients' tumors and mouse models. Preclinical data provide evidence that ASO-mediated inhibition of STAT3 in the immune compartment is sufficient to remodel the TME and enhance the activity of checkpoint blockade without direct STAT3 inhibition in tumor cells. Collectively, these data provide a rationale for testing this combination in the clinic.


Asunto(s)
Antineoplásicos Inmunológicos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Neoplasias del Colon/terapia , Neoplasias/terapia , Oligonucleótidos/farmacología , Factor de Transcripción STAT3/antagonistas & inhibidores , Microambiente Tumoral/inmunología , Ensayos Clínicos Fase I como Asunto , Neoplasias del Colon/inmunología , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Quimioterapia Combinada , Humanos , Inmunomodulación , Macrófagos/inmunología , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/patología , Pronóstico , Factor de Transcripción STAT3/genética , Linfocitos T/inmunología , Células Tumorales Cultivadas
14.
J Immunother Cancer ; 8(1)2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32217756

RESUMEN

BACKGROUND: Tumor mutational burden (TMB), defined as the number of somatic mutations per megabase of interrogated genomic sequence, demonstrates predictive biomarker potential for the identification of patients with cancer most likely to respond to immune checkpoint inhibitors. TMB is optimally calculated by whole exome sequencing (WES), but next-generation sequencing targeted panels provide TMB estimates in a time-effective and cost-effective manner. However, differences in panel size and gene coverage, in addition to the underlying bioinformatics pipelines, are known drivers of variability in TMB estimates across laboratories. By directly comparing panel-based TMB estimates from participating laboratories, this study aims to characterize the theoretical variability of panel-based TMB estimates, and provides guidelines on TMB reporting, analytic validation requirements and reference standard alignment in order to maintain consistency of TMB estimation across platforms. METHODS: Eleven laboratories used WES data from The Cancer Genome Atlas Multi-Center Mutation calling in Multiple Cancers (MC3) samples and calculated TMB from the subset of the exome restricted to the genes covered by their targeted panel using their own bioinformatics pipeline (panel TMB). A reference TMB value was calculated from the entire exome using a uniform bioinformatics pipeline all members agreed on (WES TMB). Linear regression analyses were performed to investigate the relationship between WES and panel TMB for all 32 cancer types combined and separately. Variability in panel TMB values at various WES TMB values was also quantified using 95% prediction limits. RESULTS: Study results demonstrated that variability within and between panel TMB values increases as the WES TMB values increase. For each panel, prediction limits based on linear regression analyses that modeled panel TMB as a function of WES TMB were calculated and found to approximately capture the intended 95% of observed panel TMB values. Certain cancer types, such as uterine, bladder and colon cancers exhibited greater variability in panel TMB values, compared with lung and head and neck cancers. CONCLUSIONS: Increasing uptake of TMB as a predictive biomarker in the clinic creates an urgent need to bring stakeholders together to agree on the harmonization of key aspects of panel-based TMB estimation, such as the standardization of TMB reporting, standardization of analytical validation studies and the alignment of panel-based TMB values with a reference standard. These harmonization efforts should improve consistency and reliability of panel TMB estimates and aid in clinical decision-making.


Asunto(s)
Guías como Asunto/normas , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Carga Tumoral/genética , Simulación por Computador , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Mutación
15.
Clin Cancer Res ; 26(12): 2908-2920, 2020 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-31911545

RESUMEN

PURPOSE: Tumor genomic features have been of particular interest because of their potential impact on the tumor immune microenvironment and response to immunotherapy. Due to the substantial heterogeneity, an integrative approach incorporating diverse molecular features is needed to characterize immunologic features underlying primary resistance to immunotherapy and for the establishment of novel predictive biomarkers. EXPERIMENTAL DESIGN: We developed a pan-cancer deep machine learning model integrating tumor mutation burden, microsatellite instability, and somatic copy-number alterations to classify tumors of different types into different genomic clusters, and assessed the immune microenvironment in each genomic cluster and the association of each genomic cluster with response to immunotherapy. RESULTS: Our model grouped 8,646 tumors of 29 cancer types from The Cancer Genome Atlas into four genomic clusters. Analysis of RNA-sequencing data revealed distinct immune microenvironment in tumors of each genomic class. Furthermore, applying this model to tumors from two melanoma immunotherapy clinical cohorts demonstrated that patients with melanoma of different genomic classes achieved different benefit from immunotherapy. Interestingly, tumors in cluster 4 demonstrated a cold immune microenvironment and lack of benefit from immunotherapy despite high microsatellite instability burden. CONCLUSIONS: Our study provides a proof for principle that deep learning modeling may have the potential to discover intrinsic statistical cross-modality correlations of multifactorial input data to dissect the molecular mechanisms underlying primary resistance to immunotherapy, which likely involves multiple factors from both the tumor and host at different molecular levels.


Asunto(s)
Biomarcadores de Tumor/genética , Aprendizaje Profundo , Regulación Neoplásica de la Expresión Génica , Genómica/métodos , Inmunoterapia/mortalidad , Neoplasias/patología , Microambiente Tumoral/inmunología , Variaciones en el Número de Copia de ADN , Estudios de Seguimiento , Humanos , Inestabilidad de Microsatélites , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/inmunología , Pronóstico , Tasa de Supervivencia
17.
Nat Med ; 22(1): 97-104, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26657142

RESUMEN

Complex insertions and deletions (indels) are formed by simultaneously deleting and inserting DNA fragments of different sizes at a common genomic location. Here we present a systematic analysis of somatic complex indels in the coding sequences of samples from over 8,000 cancer cases using Pindel-C. We discovered 285 complex indels in cancer-associated genes (such as PIK3R1, TP53, ARID1A, GATA3 and KMT2D) in approximately 3.5% of cases analyzed; nearly all instances of complex indels were overlooked (81.1%) or misannotated (17.6%) in previous reports of 2,199 samples. In-frame complex indels are enriched in PIK3R1 and EGFR, whereas frameshifts are prevalent in VHL, GATA3, TP53, ARID1A, PTEN and ATRX. Furthermore, complex indels display strong tissue specificity (such as VHL in kidney cancer samples and GATA3 in breast cancer samples). Finally, structural analyses support findings of previously missed, but potentially druggable, mutations in the EGFR, MET and KIT oncogenes. This study indicates the critical importance of improving complex indel discovery and interpretation in medical research.


Asunto(s)
Minería de Datos/métodos , Genómica/métodos , Mutación INDEL/genética , Neoplasias/genética , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase Ia , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Receptores ErbB/genética , Factor de Transcripción GATA3/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-met/genética , Factores de Transcripción/genética , Proteína p53 Supresora de Tumor/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Proteína Nuclear Ligada al Cromosoma X
18.
Sci Rep ; 6: 28294, 2016 06 24.
Artículo en Inglés | MEDLINE | ID: mdl-27339696

RESUMEN

We applied a newly developed bioinformatics system called VirusScan to investigate the viral basis of 6,813 human tumors and 559 adjacent normal samples across 23 cancer types and identified 505 virus positive samples with distinctive, organ system- and cancer type-specific distributions. We found that herpes viruses (e.g., subtypes HHV4, HHV5, and HHV6) that are highly prevalent across cancers of the digestive tract showed significantly higher abundances in tumor versus adjacent normal samples, supporting their association with these cancers. We also found three HPV16-positive samples in brain lower grade glioma (LGG). Further, recurrent HBV integration at the KMT2B locus is present in three liver tumors, but absent in their matched adjacent normal samples, indicating that viral integration induced host driver genetic alterations are required on top of viral oncogene expression for initiation and progression of liver hepatocellular carcinoma. Notably, viral integrations were found in many genes, including novel recurrent HPV integrations at PTPN13 in cervical cancer. Finally, we observed a set of HHV4 and HBV variants strongly associated with ethnic groups, likely due to viral sequence evolution under environmental influences. These findings provide important new insights into viral roles of tumor initiation and progression and potential new therapeutic targets.


Asunto(s)
Neoplasias/virología , Neoplasias del Sistema Nervioso Central/virología , Biología Computacional , Femenino , Neoplasias Gastrointestinales/virología , Variación Genética , Neoplasias de Cabeza y Cuello/virología , Virus de Hepatitis/genética , Virus de Hepatitis/aislamiento & purificación , Herpesviridae/genética , Herpesviridae/aislamiento & purificación , Humanos , Masculino , Neoplasias/genética , Especificidad de Órganos , Papillomaviridae/genética , Papillomaviridae/aislamiento & purificación , ARN Viral/genética , ARN Viral/aislamiento & purificación , Análisis de Secuencia de ARN , Transcriptoma , Integración Viral , Virus/genética , Virus/aislamiento & purificación , Virus/patogenicidad
19.
J Biochem Mol Biol ; 38(6): 709-16, 2005 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-16336787

RESUMEN

Apoptosis and necrosis are distinguished by modality primarily. Here we show an apoptosis occurred instantly, induced by 300 muM W-7 ((N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride), inhibitor of calmodulin), which demonstrated necrotic modality. As early as 30 min after W-7 addition, apoptotic (sub-diploid) peak could be detected by fluorescence-activated cell sorter (FACS), "DNA ladders" began to emerge also at this time point, activity of caspase-3 elevated obviously within this period. Absence of mitochondrial membrane potential (MMP) reduction and cytochrome c, AIF (apoptosis inducing factor) release, verified that this rapid apoptosis did not proceed through mitochondria pathway. Activation of caspase-12 and changes of other endoplasmic reticulum (ER) located proteins ascertained that ER pathway mediated this necrosis-like apoptosis. Our findings suggest that it is not credible to judge apoptosis by modality. Elucidation of ER pathway is helpful to comprehend the pathology of diseases associated with ER stress, and may offer a new approach to the therapy of cancer and neurodegenerative diseases.


Asunto(s)
Apoptosis , Calcio/metabolismo , Necrosis , Factor Inductor de la Apoptosis/metabolismo , Caspasa 12/metabolismo , Separación Celular , Citocromos c/metabolismo , ADN/química , ADN/metabolismo , Retículo Endoplásmico/metabolismo , Activación Enzimática , Citometría de Flujo , Células HeLa , Humanos , Mitocondrias/metabolismo , Oscilometría
20.
Nat Commun ; 6: 10086, 2015 Dec 22.
Artículo en Inglés | MEDLINE | ID: mdl-26689913

RESUMEN

Large-scale cancer sequencing data enable discovery of rare germline cancer susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer. Burden testing identifies 13 cancer genes with significant enrichment of rare truncations, some associated with specific cancers (for example, RAD51C, PALB2 and MSH6 in AML, stomach and endometrial cancers, respectively). Significant, tumour-specific loss of heterozygosity occurs in nine genes (ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2 and RAD51C/D). Moreover, our homology-directed repair assay of 68 BRCA1 rare missense variants supports the utility of allelic enrichment analysis for characterizing variants of unknown significance. The scale of this analysis and the somatic-germline integration enable the detection of rare variants that may affect individual susceptibility to tumour development, a critical step toward precision medicine.


Asunto(s)
Variación Genética , Neoplasias/genética , Neoplasias/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Mutación , Neoplasias/clasificación , Neoplasias/epidemiología , Estados Unidos/epidemiología , Adulto Joven
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