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1.
Brief Bioinform ; 23(2)2022 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-35037026

RESUMEN

There is a lack of robust generalizable predictive biomarkers of response to immune checkpoint blockade in multiple types of cancer. We develop hDirect-MAP, an algorithm that maps T cells into a shared high-dimensional (HD) expression space of diverse T cell functional signatures in which cells group by the common T cell phenotypes rather than dimensional reduced features or a distorted view of these features. Using projection-free single-cell modeling, hDirect-MAP first removed a large group of cells that did not contribute to response and then clearly distinguished T cells into response-specific subpopulations that were defined by critical T cell functional markers of strong differential expression patterns. We found that these grouped cells cannot be distinguished by dimensional-reduction algorithms but are blended by diluted expression patterns. Moreover, these identified response-specific T cell subpopulations enabled a generalizable prediction by their HD metrics. Tested using five single-cell RNA-seq or mass cytometry datasets from basal cell carcinoma, squamous cell carcinoma and melanoma, hDirect-MAP demonstrated common response-specific T cell phenotypes that defined a generalizable and accurate predictive biomarker.


Asunto(s)
Inmunoterapia , Melanoma , Biomarcadores , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Linfocitos T
2.
J Transl Med ; 22(1): 292, 2024 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-38504345

RESUMEN

BACKGROUND: Naturally occurring colorectal cancers (CRC) in rhesus macaques share many features with their human counterparts and are useful models for cancer immunotherapy; but mechanistic data are lacking regarding the comparative molecular pathogenesis of these cancers. METHODS: We conducted state-of-the-art imaging including CT and PET, clinical assessments, and pathological review of 24 rhesus macaques with naturally occurring CRC. Additionally, we molecularly characterized these tumors utilizing immunohistochemistry (IHC), microsatellite instability assays, DNAseq, transcriptomics, and developed a DNA methylation-specific qPCR assay for MLH1, CACNA1G, CDKN2A, CRABP1, and NEUROG1, human markers for CpG island methylator phenotype (CIMP). We furthermore employed Monte-Carlo simulations to in-silico model alterations in DNA topology in transcription-factor binding site-rich promoter regions upon experimentally demonstrated DNA methylation. RESULTS: Similar cancer histology, progression patterns, and co-morbidities could be observed in rhesus as reported for human CRC patients. IHC identified loss of MLH1 and PMS2 in all cases, with functional microsatellite instability. DNA sequencing revealed the close genetic relatedness to human CRCs, including a similar mutational signature, chromosomal instability, and functionally-relevant mutations affecting KRAS (G12D), TP53 (R175H, R273*), APC, AMER1, ALK, and ARID1A. Interestingly, MLH1 mutations were rarely identified on a somatic or germline level. Transcriptomics not only corroborated the similarities of rhesus and human CRCs, but also demonstrated the significant downregulation of MLH1 but not MSH2, MSH6, or PMS2 in rhesus CRCs. Methylation-specific qPCR suggested CIMP-positivity in 9/16 rhesus CRCs, but all 16/16 exhibited significant MLH1 promoter hypermethylation. DNA hypermethylation was modelled to affect DNA topology, particularly propeller twist and roll profiles. Modelling the DNA topology of a transcription factor binding motif (TFAP2A) in the MLH1 promoter that overlapped with a methylation-specific probe, we observed significant differences in DNA topology upon experimentally shown DNA methylation. This suggests a role of transcription factor binding interference in epigenetic silencing of MLH1 in rhesus CRCs. CONCLUSIONS: These data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. We consider this spontaneous, uninduced CRC in immunocompetent, treatment-naïve rhesus macaques to be a uniquely informative model for human CRC.


Asunto(s)
Neoplasias Encefálicas , Neoplasias Colorrectales , Inestabilidad de Microsatélites , Síndromes Neoplásicos Hereditarios , Humanos , Animales , Macaca mulatta/genética , Macaca mulatta/metabolismo , Homólogo 1 de la Proteína MutL/genética , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/metabolismo , Neoplasias Colorrectales/patología , Metilación de ADN/genética , Epigénesis Genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , ADN/metabolismo , Reparación de la Incompatibilidad de ADN/genética
3.
J Transl Med ; 22(1): 190, 2024 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-38383458

RESUMEN

BACKGROUND: Predictive biomarkers of immune checkpoint inhibitor (ICI) efficacy are currently lacking for non-small cell lung cancer (NSCLC). Here, we describe the results from the Anti-PD-1 Response Prediction DREAM Challenge, a crowdsourced initiative that enabled the assessment of predictive models by using data from two randomized controlled clinical trials (RCTs) of ICIs in first-line metastatic NSCLC. METHODS: Participants developed and trained models using public resources. These were evaluated with data from the CheckMate 026 trial (NCT02041533), according to the model-to-data paradigm to maintain patient confidentiality. The generalizability of the models with the best predictive performance was assessed using data from the CheckMate 227 trial (NCT02477826). Both trials were phase III RCTs with a chemotherapy control arm, which supported the differentiation between predictive and prognostic models. Isolated model containers were evaluated using a bespoke strategy that considered the challenges of handling transcriptome data from clinical trials. RESULTS: A total of 59 teams participated, with 417 models submitted. Multiple predictive models, as opposed to a prognostic model, were generated for predicting overall survival, progression-free survival, and progressive disease status with ICIs. Variables within the models submitted by participants included tumor mutational burden (TMB), programmed death ligand 1 (PD-L1) expression, and gene-expression-based signatures. The best-performing models showed improved predictive power over reference variables, including TMB or PD-L1. CONCLUSIONS: This DREAM Challenge is the first successful attempt to use protected phase III clinical data for a crowdsourced effort towards generating predictive models for ICI clinical outcomes and could serve as a blueprint for similar efforts in other tumor types and disease states, setting a benchmark for future studies aiming to identify biomarkers predictive of ICI efficacy. TRIAL REGISTRATION: CheckMate 026; NCT02041533, registered January 22, 2014. CheckMate 227; NCT02477826, registered June 23, 2015.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/patología , Antígeno B7-H1 , Biomarcadores de Tumor
4.
Ann Surg Oncol ; 30(6): 3833-3844, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36864326

RESUMEN

BACKGROUND: Liquid biopsies have become an integral part of cancer management as minimally invasive options to detect molecular and genetic changes. However, current options show poor sensitivity in peritoneal carcinomatosis (PC). Novel exosome-based liquid biopsies may provide critical information on these challenging tumors. In this initial feasibility analysis, we identified an exosome gene signature of 445 genes (ExoSig445) from colon cancer patients, including those with PC, that is distinct from healthy controls. METHODS: Plasma exosomes from 42 patients with metastatic and non-metastatic colon cancer and 10 healthy controls were isolated and verified. RNAseq analysis of exosomal RNA was performed and differentially expressed genes (DEGs) were identified by the DESeq2 algorithm. The ability of RNA transcripts to discriminate control and cancer cases was assessed by principal component analysis (PCA) and Bayesian compound covariate predictor classification. An exosomal gene signature was compared with tumor expression profiles of The Cancer Genome Atlas. RESULTS: Unsupervised PCA using exosomal genes with greatest expression variance showed stark separation between controls and patient samples. Using separate training and test sets, gene classifiers were constructed capable of discriminating control and patient samples with 100% accuracy. Using a stringent statistical threshold, 445 DEGs fully delineated control from cancer samples. Furthermore, 58 of these exosomal DEGs were found to be overexpressed in colon tumors. CONCLUSIONS: Plasma exosomal RNAs can robustly discriminate colon cancer patients, including patients with PC, from healthy controls. ExoSig445 can potentially be developed as a highly sensitive liquid biopsy test in colon cancer.


Asunto(s)
Neoplasias del Colon , Exosomas , Humanos , Biomarcadores de Tumor/metabolismo , Exosomas/genética , Exosomas/metabolismo , Teorema de Bayes , Neoplasias del Colon/patología , ARN/metabolismo
5.
Cancer ; 128(17): 3254-3264, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-35767280

RESUMEN

BACKGROUND: Cellular and intrinsic markers of sarcoma immunogenicity are poorly understood. To gain insight into whether tumor-immune interactions correlate with clinical aggressiveness, the authors examined the prognostic significance of immune gene signatures in combination with tumor mutational burden (TMB) and cancer-testis antigen (CTA) expression. METHODS: RNA sequencing and clinical data of 259 soft tissue sarcomas from The Cancer Genome Atlas project were used to investigate associations between published immune gene signatures and patient overall survival (OS) in the contexts of TMB, as computed from whole-exome sequencing data, and CTA gene expression. Multivariate Cox proportional hazards regression models and log-rank tests were used to assess survival associations. RESULTS: Immune signature scores that reflected in part the intratumoral abundance of cytotoxic T cells showed significant positive associations with OS. However, the prognostic power of the T-cell signatures was highly dependent on TMB-high status, consistent with protective effects of tumor-infiltrating T cells in tumors with elevated antigenicity. In TMB-low tumors, a signature of infiltrating plasma B cells was significantly and positively associated with OS, independent of T-cell signature status. Although tumor subtypes based on differential expression patterns of CTA genes showed different survival associations within leiomyosarcoma and myxofibrosarcoma histologies, neither CTA nor histologic subtype interacted with the T-cell-survival association. CONCLUSIONS: Signatures of T-cell and plasma B-cell infiltrates were associated with a survival benefit in soft tissue sarcomas. TMB, but not CTA expression, influenced the prognostic power of T-cell-associated, but not plasma B-cell-associated, survival. LAY SUMMARY: Clinical data and RNA analysis of 259 soft tissue sarcomas from The Cancer Genome Atlas project were used to investigate associations between five published gene immune cell expression signatures and survival in the context of tumor mutations. Activated T cells had a significant positive association with patient survival. Although high tumor mutation burden was associated with good survival, the prognostic power of T-cell signatures was highly dependent on tumor mutational status, consistent with protective effects of tumor-infiltrating T cells in tumors with high levels of antigens. In low tumor mutation-bearing tumors, plasma B cells were positively associated with survival.


Asunto(s)
Sarcoma , Neoplasias de los Tejidos Blandos , Adulto , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Mutación , Pronóstico , Sarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Secuenciación del Exoma
6.
Nucleic Acids Res ; 47(6): 2703-2715, 2019 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-30812030

RESUMEN

P53-binding protein 1 (53BP1) mediates DNA repair pathway choice and promotes checkpoint activation. Chromatin marks induced by DNA double-strand breaks and recognized by 53BP1 enable focal accumulation of this multifunctional repair factor at damaged chromatin. Here, we unveil an additional level of regulation of 53BP1 outside repair foci. 53BP1 movements are constrained throughout the nucleoplasm and increase in response to DNA damage. 53BP1 interacts with the structural protein NuMA, which controls 53BP1 diffusion. This interaction, and colocalization between the two proteins in vitro and in breast tissues, is reduced after DNA damage. In cell lines and breast carcinoma NuMA prevents 53BP1 accumulation at DNA breaks, and high NuMA expression predicts better patient outcomes. Manipulating NuMA expression alters PARP inhibitor sensitivity of BRCA1-null cells, end-joining activity, and immunoglobulin class switching that rely on 53BP1. We propose a mechanism involving the sequestration of 53BP1 by NuMA in the absence of DNA damage. Such a mechanism may have evolved to disable repair functions and may be a decisive factor for tumor responses to genotoxic treatments.


Asunto(s)
Antígenos Nucleares/fisiología , Roturas del ADN de Doble Cadena , Reparación del ADN/genética , Proteínas Asociadas a Matriz Nuclear/fisiología , Proteína 1 de Unión al Supresor Tumoral P53/metabolismo , Proteínas de Ciclo Celular , Células Cultivadas , Reparación del ADN por Unión de Extremidades/genética , Regulación hacia Abajo , Femenino , Células HEK293 , Humanos , Unión Proteica
7.
Ann Surg Oncol ; 27(13): 5016-5023, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32705511

RESUMEN

INTRODUCTION: Clinical decision-making is challenging in patients who undergo cytoreductive surgery/hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) when complete cytoreduction is not feasible. Nevertheless, some patients still benefit with long-term survival after incomplete CRS/HIPEC. There is currently no robust predictive tool that can assist clinical decision-making in this setting. METHODS: We quantified gene expression of 79 appendiceal mucinous neoplasms (AMN) from patients with incomplete CRS/HIPEC (R2 resection) using a custom NanoString gene panel. Using our previously defined, prognostic subtype classification algorithm based on signed nonnegative matrix factorization, we classified AMN cases into three molecular subtypes termed: immune enriched (IE), mixed (M), and oncogene enriched (OE). Kaplan-Meier and Cox proportional hazards analyses were used to associate subtypes and individual genes with overall survival (OS). RESULTS: Median overall survival (OS) was 7.7 years for IE, 3.6 years for M, and 1.4 years for OE. Compared with IE, OE was associated with significantly lower survival [hazard ratio (HR) 3.64, 95% confidence interval (CI) 1.63-8.13; p = 0.0017]. The differences were observed in both low-grade and high-grade tumors. While only two genes were identified to be associated with OS in low-grade tumors, multiple genes were identified to be associated with OS in high-grade tumors, particularly genes with functions in cell cycle/proliferation, mucin production, immune pathways, and cell adhesion/migration. CONCLUSION: Genetic signatures have prognostic value in patients with incomplete cytoreduction and provide valuable information to assist clinical and operative decision-making. Unraveling genetic alterations and involved pathways can direct efforts to design novel therapeutic modalities.


Asunto(s)
Neoplasias del Apéndice , Neoplasias Peritoneales , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Apéndice/tratamiento farmacológico , Neoplasias del Apéndice/terapia , Quimioterapia del Cáncer por Perfusión Regional , Terapia Combinada , Procedimientos Quirúrgicos de Citorreducción , Femenino , Humanos , Quimioterapia Intraperitoneal Hipertérmica , Masculino , Persona de Mediana Edad , Intervención Coronaria Percutánea , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/terapia , Estudios Retrospectivos , Tasa de Supervivencia
8.
Ann Surg Oncol ; 27(5): 1439-1447, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-31980985

RESUMEN

BACKGROUND: Appendiceal mucinous neoplasm (AMN) with peritoneal metastasis is a rare but deadly disease with few prognostic or therapy-predictive biomarkers to guide treatment decisions. Here, we investigated the prognostic and biological attributes of gene expression-based AMN molecular subtypes. METHODS: AMN specimens (n = 138) derived from a population-based subseries of patients treated at our institution with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) between 05/2000 and 05/2013 were analyzed for gene expression using a custom-designed NanoString 148-gene panel. Signed non-negative matrix factorization (sNMF) was used to define a gene signature capable of delineating robustly-classified AMN molecular subtypes. The sNMF class assignments were evaluated by topology learning, reverse-graph embedding and cross-cohort performance analysis. RESULTS: Three molecular subtypes of AMN were discerned by the expression patterns of 17 genes with roles in cancer progression or anti-tumor immunity. Tumor subtype assignments were confirmed by topology learning. AMN subtypes were termed immune-enriched (IE), oncogene-enriched (OE) and mixed (M) as evidenced by their gene expression patterns, and exhibited significantly different post-treatment survival outcomes. Genes with specialized immune functions, including markers of T-cells, natural killer cells, B-cells, and cytolytic activity showed increased expression in the low-risk IE subtype, while genes implicated in the promotion of cancer growth and progression were more highly expressed in the high-risk OE subtype. In multivariate analysis, the subtypes demonstrated independent prediction power for post-treatment survival. CONCLUSIONS: Our findings suggest a greater role for the immune system in AMN than previously recognized. AMN subtypes may have clinical utility for predicting CRS/HIPEC treatment outcomes.


Asunto(s)
Adenocarcinoma Mucinoso/genética , Neoplasias del Apéndice/genética , Procedimientos Quirúrgicos de Citorreducción , Quimioterapia Intraperitoneal Hipertérmica , Neoplasias Peritoneales/genética , Transcriptoma , Adenocarcinoma Mucinoso/secundario , Adenocarcinoma Mucinoso/terapia , Adulto , Anciano , Neoplasias del Apéndice/patología , Neoplasias del Apéndice/terapia , Femenino , Perfilación de la Expresión Génica , Humanos , Fenómenos del Sistema Inmunológico/genética , Masculino , Márgenes de Escisión , Persona de Mediana Edad , Clasificación del Tumor , Oncogenes/genética , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/terapia , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Tasa de Supervivencia
9.
Oncologist ; 23(4): 481-488, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29330212

RESUMEN

BACKGROUND: Metaplastic breast cancer (MBC) is a rare disease subtype characterized by an aggressive clinical course. MBC is commonly triple negative (TN), although hormone receptor (HR) positive and human epidermal growth receptor 2 (HER2) positive cases do occur. Previous studies have reported similar outcomes for MBC with regard to HR status. Less is known about outcomes for HER2 positive MBC. MATERIALS AND METHODS: Surveillance, Epidemiology, and End Results Program data were used to identify women diagnosed 2010-2014 with MBC or invasive ductal carcinoma (IDC). Kaplan-Meier curves estimated overall survival (OS) and multivariate Cox models were fitted. For survival analyses, only first cancers were included, and 2014 diagnoses were excluded to allow for sufficient follow-up. RESULTS: Our MBC sample included 1,516 women. Relative to women with IDC, women with MBC were more likely to be older (63 vs. 61 years), black (16.0% vs. 11.1%), and present with stage III disease (15.6% vs. 10.8%). HER2 positive and HER2 negative/HR positive MBC tumors represented 5.2% and 23.0% of cases. For MBC overall, 3-year OS was greatest for women with HER2 positive MBC (91.8%), relative to women with TN (75.4%) and HER2 negative/HR positive MBC (77.1%). This difference was more pronounced for stage III MBC, for which 3-year OS was 92.9%, 47.1%, and 42.2% for women with HER2 positive, TN, and HER2 negative/HR positive MBC, respectively. A multivariate Cox model of MBC demonstrated that HER2 positive tumors (relative to TN) were associated with improved survival (hazard ratio = 0.32, 95% confidence interval [CI] 0.13-0.79). In a second Cox model of exclusively HER2 positive tumors, OS did not differ between MBC and IDC disease subtypes (hazard ratio = 1.16, 95% CI 0.48-2.81). CONCLUSION: In this contemporary, population-based study of women with MBC, HER2 but not HR status was associated with improved survival. Survival was similar between HER2 positive MBC and HER2 positive IDC. This suggests HER2 positive MBC is responsive to HER2-directed therapy, a finding that may offer insights for additional therapeutic approaches to MBC. IMPLICATIONS FOR PRACTICE: This population-based study reports recent outcomes, by receptor status, for women with metaplastic breast cancer. Survival in metaplastic breast cancer is not impacted by hormone receptor status. To the authors' knowledge, this is the first report indicating that women with human epidermal growth receptor 2 (HER2) positive metaplastic breast cancer have survival superior to women with HER2 negative metaplastic breast cancer and survival similar to women with HER2 positive invasive ductal carcinoma. This information can be used for counseling patients diagnosed with metaplastic breast cancer. Further understanding of HER2 positive metaplastic breast cancer could offer insights for the development of therapeutic approaches to metaplastic breast cancer more broadly.


Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Receptor ErbB-2/metabolismo , Programa de VERF/estadística & datos numéricos , Anciano , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/mortalidad , Carcinoma Ductal de Mama/epidemiología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/patología , Femenino , Humanos , Metaplasia , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Análisis de Supervivencia
12.
Neuroradiology ; 60(10): 1043-1051, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30094640

RESUMEN

PURPOSE: For glioblastoma (GBM), imaging response (IR) or pseudoprogression (PSP) is frequently observed after chemoradiation and may connote a favorable prognosis. With tumors categorized by the Cancer Genome Atlas Project (mesenchymal, classical, neural, and proneural) and by methylguanine-methyltransferase (MGMT) methylation status, we attempted to determine if certain genomic or molecular subtypes of GBM were specifically associated with IR or PSP. METHODS: Patients with GBM treated at two institutions were reviewed. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Mantel-cox test determined effect of IR and PSP on OS and PFS. Fisher's exact test was utilized to correlate IR and PSP with genomic subtypes and MGMT status. RESULTS: Eighty-two patients with GBM were reviewed. The median OS and PFS were 17.9 months and 8.9 months. IR was observed in 28 (40%) and was associated with improved OS (median 29.4 vs 14.5 months p < 0.01) and PFS (median 17.7 vs 5.5 months, p < 0.01). PSP was observed in 14 (19.2%) and trended towards improved PFS (15.0 vs 7.7 months p = 0.08). Tumors with a proneural component had a higher rate of IR compared to those without a proneural component (IR 60% vs 28%; p = 0.03). MGMT methylation was associated with IR (58% vs 24%, p = 0.032), but not PSP (34%, p = 0.10). CONCLUSION: IR is associated with improved OS and PFS. The proneural subtype and MGMT methylated tumors had higher rates of IR.


Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Genómica , Glioblastoma/diagnóstico por imagen , Glioblastoma/genética , Glioblastoma/terapia , Anciano , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia
13.
J Am Soc Nephrol ; 28(4): 1093-1105, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27821631

RESUMEN

APOL1 G1 and G2 variants facilitate kidney disease in blacks. To elucidate the pathways whereby these variants contribute to disease pathogenesis, we established HEK293 cell lines stably expressing doxycycline-inducible (Tet-on) reference APOL1 G0 or the G1 and G2 renal-risk variants, and used Illumina human HT-12 v4 arrays and Affymetrix HTA 2.0 arrays to generate global gene expression data with doxycycline induction. Significantly altered pathways identified through bioinformatics analyses involved mitochondrial function; results from immunoblotting, immunofluorescence, and functional assays validated these findings. Overexpression of APOL1 by doxycycline induction in HEK293 Tet-on G1 and G2 cells led to impaired mitochondrial function, with markedly reduced maximum respiration rate, reserve respiration capacity, and mitochondrial membrane potential. Impaired mitochondrial function occurred before intracellular potassium depletion or reduced cell viability occurred. Analysis of global gene expression profiles in nondiseased primary proximal tubule cells from black patients revealed that the nicotinate phosphoribosyltransferase gene, responsible for NAD biosynthesis, was among the top downregulated transcripts in cells with two APOL1 renal-risk variants compared with those without renal-risk variants; nicotinate phosphoribosyltransferase also displayed gene expression patterns linked to mitochondrial dysfunction in HEK293 Tet-on APOL1 cell pathway analyses. These results suggest a pivotal role for mitochondrial dysfunction in APOL1-associated kidney disease.


Asunto(s)
Apolipoproteínas/genética , Enfermedades Renales/genética , Lipoproteínas HDL/genética , Enfermedades Mitocondriales/genética , Apolipoproteína L1 , Población Negra , Células Cultivadas , Femenino , Regulación de la Expresión Génica , Células HEK293 , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo
14.
BMC Cancer ; 16(1): 911, 2016 11 22.
Artículo en Inglés | MEDLINE | ID: mdl-27871313

RESUMEN

BACKGROUND: Tumor-infiltrating leukocytes can either limit cancer growth or facilitate its spread. Diagnostic strategies that comprehensively assess the functional complexity of tumor immune infiltrates could have wide-reaching clinical value. In previous work we identified distinct immune gene signatures in breast tumors that reflect the relative abundance of infiltrating immune cells and exhibited significant associations with patient outcomes. Here we hypothesized that immune gene signatures agnostic to tumor type can be identified by de novo discovery of gene clusters enriched for immunological functions and possessing internal correlation structure conserved across solid tumors from different anatomic sites. METHODS: We assembled microarray expression datasets encompassing 5,295 tumors of the breast, colon, lung, ovarian and prostate. Unsupervised clustering methods were used to determine number and composition of gene clusters within each dataset. Immune-enriched gene clusters (signatures) identified by gene ontology enrichment were analyzed for internal correlation structure and conservation across tumors then compared against expression profiles of: 1) flow-sorted leukocytes from peripheral blood and 2) >300 cancer cell lines from solid and hematologic cancers. Cox regression analysis was used to identify signatures with significant associations with clinical outcome. RESULTS: We identified nine distinct immune-enriched gene signatures conserved across all five tumor types. The signatures differentiated specific leukocyte lineages with moderate discernment overall, and naturally organized into six discrete groups indicative of admixed lineages. Moreover, seven of the signatures exhibit minimal and uncorrelated expression in cancer cell lines, suggesting that these signatures derive predominantly from infiltrating immune cells. All nine immune signatures achieved statistically significant associations with patient prognosis (p<0.05) in one or more tumor types with greatest significance observed in breast and skin cancers. Several signatures indicative of myeloid lineages exhibited poor outcome associations that were most apparent in brain and colon cancers. CONCLUSIONS: These findings suggest that tumor infiltrating immune cells can be differentiated by immune-specific gene expression patterns that quantify the relative abundance of multiple immune infiltrates across a range of solid tumor types. That these markers of immune involvement are significantly associated with patient prognosis in diverse cancers suggests their clinical utility as pan-cancer markers of tumor behavior and immune responsiveness.


Asunto(s)
Evolución Molecular , Regulación Neoplásica de la Expresión Génica , Inmunidad/genética , Neoplasias/genética , Neoplasias/mortalidad , Transcriptoma , Biomarcadores , Análisis por Conglomerados , Biología Computacional/métodos , Conjuntos de Datos como Asunto , Perfilación de la Expresión Génica , Humanos , Leucocitos/metabolismo , Anotación de Secuencia Molecular , Neoplasias/inmunología , Pronóstico
16.
Curr Opin Oncol ; 27(6): 433-44, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26418235

RESUMEN

PURPOSE OF REVIEW: Here, we focus on molecular biomarkers derived from transcriptomic studies to summarize the recent advances in our understanding of the mechanisms associated with differential prognosis and treatment outcome in breast cancer. RECENT FINDINGS: Breast cancer is certainly immunogenic; yet it has been historically resistant to immunotherapy. In the past few years, refined immunotherapeutic manipulations have been shown to be effective in a significant proportion of cancer patients. For example, drugs targeting the PD-1 immune checkpoint have been proven to be an effective therapeutic approach in several solid tumors including melanoma and lung cancer. Very recently, the activity of such therapeutics has also been demonstrated in breast cancer patients. Pari passu with the development of novel immune modulators, the transcriptomic analysis of human tumors unveiled unexpected and paradoxical relationships between cancer cells and immune cells. SUMMARY: This review examines our understanding of the molecular pathways associated with intratumoral immune response, which represents a critical step for the implementation of stratification strategies toward the development of personalized immunotherapy of breast cancer.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Vacunas contra el Cáncer/uso terapéutico , Inmunoterapia , Microambiente Tumoral/inmunología , Anticuerpos Monoclonales/uso terapéutico , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/genética , Femenino , Perfilación de la Expresión Génica , Marcadores Genéticos , Humanos , Inmunoterapia/métodos , Melanoma/tratamiento farmacológico , Pronóstico , Transcriptoma
18.
J Neurooncol ; 124(3): 447-53, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26186902

RESUMEN

We present a retrospective investigation of the role of genomics in the prediction of central versus marginal disease progression patterns for glioblastoma (GBM). Between August 2000 and May 2010, 41 patients with GBM and gene expression and methylation data available were treated with radiotherapy with or without concurrent temozolomide. Location of disease progression was categorized as within the high dose (60 Gy) or low dose (46 Gy) volume. Samples were grouped into previously described TCGA genomic groupings: Mesenchymal (m), classical (c), proneural (pn), and neural (n); and were also classified by MGMT-Methylation status and G-Cimp methylation phenotype. Genomic groupings and methylation status were investigated as a possible predictor of disease progression in the high dose region, progression in the low dose region, and time to progression. Based on TCGA category there was no difference in OS (p = 0.26), 60 Gy progression (PN: 71 %, N: 60 %, M: 89 %, C: 83 %, p = 0.19), 46 Gy progression (PN: 57 %, N: 40 %, M: 61 %,C: 50 %, p = 0.8) or time to progression (PN: 9 months, N:15 months, M: 9 months, C: 7 months, p = 0.58). MGMT methylation predicted for improved OS (median 25 vs. 13 months, p = 0.01), improved DFS (median 13 vs. 8 months, p = 0.007) and decreased 60 Gy (p = 0.003) and 46 Gy (p = 0.006) progression. There was a cohort of MGMT methylated patients with late marginal disease progression (4/22 patients, 18 %). TCGA groups demonstrated no difference in survival or progression patterns. MGMT methylation predicted for a statistically significant decrease in in-field and marginal disease progression. There was a cohort of MGMT methylated patients with late marginal progression. Validations of these findings would have implications that could affect radiation field size.


Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Glioblastoma/genética , Glioblastoma/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Metilación de ADN/efectos de la radiación , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Progresión de la Enfermedad , Relación Dosis-Respuesta en la Radiación , Femenino , Estudios de Seguimiento , Genómica , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Radioterapia/métodos , Estudios Retrospectivos , Terapia Recuperativa , Proteínas Supresoras de Tumor/metabolismo
19.
Am J Pathol ; 183(5): 1645-1653, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24012678

RESUMEN

Both epigenetic silencing and genetic deletion of tumor suppressors contribute to the development and progression of breast cancer. SOX7 is a transcription factor important to development, and its down-regulation has been reported in tumor tissues and cell lines of prostate, colon, and lung cancers. However, the regulation of SOX7 expression and its functional role in breast cancer have not been reported. The current study demonstrates that SOX7 mRNA and protein expression are down-regulated in breast cancer tissues and cell lines compared with adjacent normal tissues and nontumorigenic cells, respectively. The SOX7 promoter is hypermethylated in breast cancer cell lines compared with nontumorigenic cells, and the inhibition of DNA methylation increases SOX7 mRNA levels. With shRNA-mediated SOX7 silencing, nontumorigenic immortal breast cells display increased proliferation, migration, and invasion and form structures that resemble that of breast cancer cells in a three-dimensional culture system. Conversely, ectopic SOX7 expression inhibits proliferation, migration, and invasion of breast cancer cells in vitro and tumor growth in vivo. Importantly, we discovered that SOX7 transcript levels positively correlated with clinical outcome of 674 breast cancer patients. Overall, our data suggest that SOX7 acts as a tumor suppressor in breast cancer. SOX7 expression is likely regulated by multiple mechanisms and potentially serves as a prognostic marker for breast cancer patients.


Asunto(s)
Neoplasias de la Mama/genética , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción SOXF/genética , Proteínas Supresoras de Tumor/genética , Animales , Línea Celular Tumoral , Metilación de ADN/genética , Regulación hacia Abajo/genética , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Ratones Desnudos , Regiones Promotoras Genéticas , Factores de Transcripción SOXF/metabolismo , Resultado del Tratamiento , Proteínas Supresoras de Tumor/metabolismo
20.
Hepatology ; 57(4): 1469-83, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23175232

RESUMEN

UNLABELLED: Liver cancers, including hepatocellular carcinomas (HCCs), cholangiocarcinomas (CCs), and fibrolamellar HCCs (FL-HCCs) are among the most common cancers worldwide and are associated with a poor prognosis. Investigations of genes important in liver cancers have focused on Sal-like protein 4 (SALL4), a member of a family of zinc finger transcription factors. It is a regulator of embryogenesis, organogenesis, pluripotency, can elicit reprogramming of somatic cells, and is a marker of stem cells. We found it expressed in normal murine hepatoblasts, normal human hepatic stem cells, hepatoblasts and biliary tree stem cells, but not in mature parenchymal cells of liver or biliary tree. It was strongly expressed in surgical specimens of human HCCs, CCs, a combined hepatocellular and cholangiocarcinoma, a FL-HCC, and in derivative, transplantable tumor lines in immune-compromised hosts. Bioinformatics analyses indicated that elevated expression of SALL4 in tumors is associated with poor survival of HCC patients. Experimental manipulation of SALL4's expression results in changes in proliferation versus differentiation in human HCC cell lines in vitro and in vivo in immune-compromised hosts. Virus-mediated gene transfer of SALL4 was used for gain- and loss-of-function analyses in the cell lines. Significant growth inhibition in vitro and in vivo, accompanied by an increase in differentiation occurred with down-regulation of SALL4. Overexpression of SALL4 resulted in increased cell proliferation in vitro, correlating with an increase in expression of cytokeratin19 (CK19), epithelial cell adhesion molecules (EpCAM), and adenosine triphosphate (ATP)-binding cassette-G2 (ABCG2). CONCLUSION: SALL4's expression is an indicator of stem cells, a prognostic marker in liver cancers, correlates with cell and tumor growth, with resistance to 5-FU, and its suppression results in differentiation and slowed tumor growth. SALL4 is a novel therapeutic target for liver cancers.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/metabolismo , Proteínas de Unión al ADN/metabolismo , Neoplasias Hepáticas/metabolismo , Factores de Transcripción/metabolismo , Animales , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Proliferación Celular , Ciclina D1/metabolismo , Ciclina D2/metabolismo , Humanos , Técnicas In Vitro , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones SCID , Pronóstico , Trasplante Heterólogo
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