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1.
Nature ; 464(7287): 405-8, 2010 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-20173735

RESUMEN

Chronic infection with the hepatitis C virus (HCV) affects 170 million people worldwide and is an important cause of liver-related morbidity and mortality. The standard of care therapy combines pegylated interferon (pegIFN) alpha and ribavirin (RBV), and is associated with a range of treatment-limiting adverse effects. One of the most important of these is RBV-induced haemolytic anaemia, which affects most patients and is severe enough to require dose modification in up to 15% of patients. Here we show that genetic variants leading to inosine triphosphatase deficiency, a condition not thought to be clinically important, protect against haemolytic anaemia in hepatitis-C-infected patients receiving RBV.


Asunto(s)
Anemia Hemolítica/inducido químicamente , Anemia Hemolítica/genética , Variación Genética/genética , Hepatitis C Crónica/tratamiento farmacológico , Pirofosfatasas/genética , Alelos , Anemia Hemolítica/complicaciones , Antivirales , Cromosomas Humanos Par 20 , Europa (Continente)/etnología , Estudio de Asociación del Genoma Completo , Hemoglobinas/deficiencia , Hemoglobinas/metabolismo , Hepatitis C Crónica/complicaciones , Humanos , Polimorfismo de Nucleótido Simple/genética , Pirofosfatasas/deficiencia , Pirofosfatasas/metabolismo , Grupos Raciales/genética , Ribavirina/uso terapéutico , Estados Unidos , Inosina Trifosfatasa
2.
J Exp Clin Cancer Res ; 41(1): 172, 2022 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-35546239

RESUMEN

BACKGROUND: Lung cancer is the leading cause of cancer death, partially owing to its extensive heterogeneity. The analysis of intertumor heterogeneity has been limited by an inability to concurrently obtain tissue from synchronous metastases unaltered by multiple prior lines of therapy. METHODS: In order to study the relationship between genomic, epigenomic and T cell repertoire heterogeneity in a rare autopsy case from a 32-year-old female never-smoker with left lung primary late-stage lung adenocarcinoma (LUAD), we did whole-exome sequencing (WES), DNA methylation and T cell receptor (TCR) sequencing to characterize the immunogenomic landscape of one primary and 19 synchronous metastatic tumors. RESULTS: We observed heterogeneous mutation, methylation, and T cell patterns across distinct metastases. Only TP53 mutation was detected in all tumors suggesting an early event while other cancer gene mutations were later events which may have followed subclonal diversification. A set of prevalent T cell clonotypes were completely excluded from left-side thoracic tumors indicating distinct T cell repertoire profiles between left-side and non left-side thoracic tumors. Though a limited number of predicted neoantigens were shared, these were associated with homology of the T cell repertoire across metastases. Lastly, ratio of methylated neoantigen coding mutations was negatively associated with T-cell density, richness and clonality, suggesting neoantigen methylation may partially drive immunosuppression. CONCLUSIONS: Our study demonstrates heterogeneous genomic and T cell profiles across synchronous metastases and how restriction of unique T cell clonotypes within an individual may differentially shape the genomic and epigenomic landscapes of synchronous lung metastases.


Asunto(s)
Adenocarcinoma del Pulmón , Adenocarcinoma , Neoplasias Pulmonares , Adenocarcinoma/genética , Adenocarcinoma del Pulmón/genética , Adulto , Femenino , Humanos , Neoplasias Pulmonares/patología , Mutación , Secuenciación del Exoma
3.
iScience ; 24(2): 102053, 2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33537658

RESUMEN

In patients with high-grade serous ovarian cancer (HGSC), it is unclear which genomic features are related to complete gross resection (R0), which is typically associated with better clinical outcomes, or response to neoadjuvant chemotherapy (NACT). In this study, we evaluated T cell receptor (TCR) repertoire diversity in primary and metastatic tumor samples (n = 90) from clinically well-annotated patients with HGSC who achieved R0 or received NACT with excellent or poor response based on a laparoscopic triage algorithm. TCR sequencing followed by an integrative analysis with comprehensive multi-omics data identified higher TCR diversity (e.g., higher number of unique productive sequences and less clonal relatedness) in the R0 than NACT groups. We found enrichment of specific TCRß genes usage, distinct mutual exclusiveness and co-occurrence pattern of TCRß genes among the groups. We also found significantly positive correlations between clonal relatedness and neoantigens, copy number variations, and mutation load in the groups.

4.
Nat Commun ; 12(1): 2607, 2021 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-33972549

RESUMEN

Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RAS-RTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML.


Asunto(s)
Antineoplásicos/uso terapéutico , Metilación de ADN , Resistencia a Antineoplásicos/genética , Inhibidores Enzimáticos/uso terapéutico , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Células Madre/metabolismo , Anciano , Aminopiridinas/uso terapéutico , Proteínas Potenciadoras de Unión a CCAAT/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Metilación de ADN/efectos de los fármacos , Metilación de ADN/genética , Proteínas de Unión al ADN/genética , Dioxigenasas , Epigenómica , Evolución Molecular , Femenino , Glicina/análogos & derivados , Glicina/uso terapéutico , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Familia de Multigenes , Recurrencia Local de Neoplasia/tratamiento farmacológico , Proteínas Proto-Oncogénicas/genética , Piridinas/uso terapéutico , RNA-Seq , Proteínas Represoras/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Análisis de la Célula Individual , Triazinas/uso terapéutico , Proteínas ras/genética
5.
Nat Commun ; 12(1): 6655, 2021 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-34789716

RESUMEN

Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, using multi-region whole exome/T cell receptor (TCR) sequencing as well as immunohistochemistry, we reveal a rather homogeneous mutational landscape but extremely cold and heterogeneous TCR repertoire in limited-stage SCLC tumors (LS-SCLCs). Compared to localized non-small cell lung cancers, LS-SCLCs have similar predicted neoantigen burden and genomic ITH, but significantly colder and more heterogeneous TCR repertoire associated with higher chromosomal copy number aberration (CNA) burden. Furthermore, copy number loss of IFN-γ pathway genes is frequently observed and positively correlates with CNA burden. Higher mutational burden, higher T cell infiltration and positive PD-L1 expression are associated with longer overall survival (OS), while higher CNA burden is associated with shorter OS in patients with LS-SCLC.


Asunto(s)
Neoplasias Pulmonares/genética , Carcinoma Pulmonar de Células Pequeñas/genética , Linfocitos T/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Variaciones en el Número de Copia de ADN , Femenino , Heterogeneidad Genética , Antígenos HLA/genética , Humanos , Interferón gamma/inmunología , Pérdida de Heterocigocidad , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal/genética , Carcinoma Pulmonar de Células Pequeñas/inmunología , Carcinoma Pulmonar de Células Pequeñas/patología , Análisis de Supervivencia , Secuenciación del Exoma
6.
Clin Cancer Res ; 26(20): 5477-5486, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-32816946

RESUMEN

PURPOSE: Malignant pleural mesothelioma (MPM) is considered an orphan disease with few treatment options. Despite multimodality therapy, the majority of MPMs recur and eventually become refractory to any systemic treatment. One potential mechanism underlying therapeutic resistance may be intratumor heterogeneity (ITH), making MPM challenging to eradicate. However, the ITH architecture of MPM and its clinical impact have not been well studied. EXPERIMENTAL DESIGN: We delineated the immunogenomic ITH by multiregion whole-exome sequencing and T-cell receptor (TCR) sequencing of 69 longitudinal MPM specimens from nine patients with resectable MPM, who were treated with dasatinib. RESULTS: The median total mutation burden before dasatinib treatment was 0.65/Mb, similar with that of post-dasatinib treatment (0.62/Mb). The median proportion of mutations shared by any given pair of two tumor regions within the same tumors was 80% prior to and 83% post-dasatinib treatment indicating a relatively homogenous genomic landscape. T-cell clonality, a parameter indicating T-cell expansion and reactivity, was significantly increased in tumors after dasatinib treatment. Furthermore, on average, 82% of T-cell clones were restricted to individual tumor regions, with merely 6% of T-cell clones shared by all regions from the same tumors indicating profound TCR heterogeneity. Interestingly, patients with higher T-cell clonality and higher portion of T cells present across all tumor regions in post-dasatinib-treated tumors had significantly longer survival. CONCLUSIONS: Despite the homogeneous genomic landscape, the TCR repertoire is extremely heterogeneous in MPM. Dasatinib may potentially induce T-cell response leading to improved survival.


Asunto(s)
Dasatinib/administración & dosificación , Mesotelioma Maligno/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Linfocitos T/efectos de los fármacos , Adulto , Anciano , Evolución Clonal/genética , Dasatinib/efectos adversos , Evolución Molecular , Femenino , Heterogeneidad Genética , Genoma Humano/efectos de los fármacos , Genómica , Humanos , Masculino , Mesotelioma Maligno/genética , Mesotelioma Maligno/patología , Persona de Mediana Edad , Mutación/genética , Proteínas de Neoplasias/genética , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Supervivencia sin Progresión , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T/patología , Secuenciación del Exoma
7.
J Invest Dermatol ; 140(11): 2146-2156.e4, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32304704

RESUMEN

The integrity of the immune system represents a pivotal risk factor and prognostic biomarker for Merkel cell carcinoma. A higher density of tumor-associated T cells correlates with improved Merkel cell carcinoma-specific survival, but the prognostic importance of the T-cell infiltrate reactivity is unknown. We evaluated the T-cell receptor repertoire associated with 72 primary Merkel cell carcinomas and correlated metrics of the T-cell receptor repertoire with clinicopathologic characteristics and patient outcomes. We showed that a high Simpson's Dominance index (SDom) was significantly associated with fewer metastases (P = 0.01), lower stage at presentation (P = 0.02), lower final stage at last follow-up (P = 0.05), and longer time to first lymph node metastasis (P = 0.04). These correlations were mostly preserved in the Merkel cell polyomavirus-negative subgroup. Combining SDom with CD3+ or CD8+ T-cell density revealed three distinct prognostic groups with respect to disease-specific survival. Patients with both high SDom and high CD3+ or CD8+ T-cell density had markedly improved disease-specific survival compared with patients with low SDom and low CD3+ or CD8+ T-cell density (P = 0.002 and P = 0.03, respectively). Patients with either high SDom or high CD3+ or CD8+ had intermediate disease-specific survival. Our findings demonstrate that the quality of the tumor-associated T-cell infiltrate informs patient prognosis in primary Merkel cell carcinoma beyond the T-cell density.


Asunto(s)
Carcinoma de Células de Merkel/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Neoplasias Cutáneas/inmunología , Linfocitos T/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células de Merkel/mortalidad , Carcinoma de Células de Merkel/patología , Femenino , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología
8.
Nat Commun ; 11(1): 1839, 2020 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-32296058

RESUMEN

Complex tumor microenvironmental (TME) features influence the outcome of cancer immunotherapy (IO). Here we perform immunogenomic analyses on 67 intratumor sub-regions of a PD-1 inhibitor-resistant melanoma tumor and 2 additional metastases arising over 8 years, to characterize TME interactions. We identify spatially distinct evolution of copy number alterations influencing local immune composition. Sub-regions with chromosome 7 gain display a relative lack of leukocyte infiltrate but evidence of neutrophil activation, recapitulated in The Cancer Genome Atlas (TCGA) samples, and associated with lack of response to IO across three clinical cohorts. Whether neutrophil activation represents cause or consequence of local tumor necrosis requires further study. Analyses of T-cell clonotypes reveal the presence of recurrent priming events manifesting in a dominant T-cell clonotype over many years. Our findings highlight the links between marked levels of genomic and immune heterogeneity within the physical space of a tumor, with implications for biomarker evaluation and immunotherapy response.


Asunto(s)
Genómica/métodos , Melanoma/metabolismo , Biomarcadores de Tumor/genética , Variaciones en el Número de Copia de ADN/genética , Humanos , Melanoma/genética , Mutación/genética , Activación Neutrófila/genética , Activación Neutrófila/fisiología , Microambiente Tumoral/genética , Microambiente Tumoral/fisiología
9.
Nat Commun ; 11(1): 603, 2020 01 30.
Artículo en Inglés | MEDLINE | ID: mdl-32001676

RESUMEN

Immunotherapy targeting T cells is increasingly utilized to treat solid tumors including non-small cell lung cancer (NSCLC). This requires a better understanding of the T cells in the lungs of patients with NSCLC. Here, we report T cell repertoire analysis in a cohort of 236 early-stage NSCLC patients. T cell repertoire attributes are associated with clinicopathologic features, mutational and immune landscape. A considerable proportion of the most prevalent T cells in tumors are also prevalent in the uninvolved tumor-adjacent lungs and appear specific to shared background mutations or viral infections. Patients with higher T cell repertoire homology between the tumor and uninvolved tumor-adjacent lung, suggesting a less tumor-focused T cell response, exhibit inferior survival. These findings indicate that a concise understanding of antigens and T cells in NSCLC is needed to improve therapeutic efficacy and reduce toxicity with immunotherapy, particularly adoptive T cell therapy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/inmunología , Neoplasias Pulmonares/inmunología , Linfocitos T/inmunología , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Células Clonales , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Humanos , Pulmón/patología , Neoplasias Pulmonares/patología , Activación de Linfocitos/inmunología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Mutación/genética , Análisis de Supervivencia
10.
Nat Commun ; 10(1): 2978, 2019 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-31278276

RESUMEN

There has been a dramatic increase in the detection of lung nodules, many of which are preneoplasia atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) or invasive adenocarcinoma (ADC). The molecular landscape and the evolutionary trajectory of lung preneoplasia have not been well defined. Here, we perform multi-region exome sequencing of 116 resected lung nodules including AAH (n = 22), AIS (n = 27), MIA (n = 54) and synchronous ADC (n = 13). Comparing AAH to AIS, MIA and ADC, we observe progressive genomic evolution at the single nucleotide level and demarcated evolution at the chromosomal level supporting the early lung carcinogenesis model from AAH to AIS, MIA and ADC. Subclonal analyses reveal a higher proportion of clonal mutations in AIS/MIA/ADC than AAH suggesting neoplastic transformation of lung preneoplasia is predominantly associated with a selective sweep of unfit subclones. Analysis of multifocal pulmonary nodules from the same patients reveal evidence of convergent evolution.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Evolución Molecular , Neoplasias Pulmonares/genética , Pulmón/patología , Lesiones Precancerosas/genética , Adenocarcinoma del Pulmón/patología , Anciano , Anciano de 80 o más Años , Carcinogénesis/genética , Femenino , Humanos , Hiperplasia/genética , Hiperplasia/patología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Lesiones Precancerosas/patología , Secuenciación del Exoma
11.
Cancer Discov ; 7(10): 1088-1097, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28733428

RESUMEN

Genomic intratumor heterogeneity (ITH) may be associated with postsurgical relapse of localized lung adenocarcinomas. Recently, mutations, through generation of neoantigens, were shown to alter tumor immunogenicity through T-cell responses. Here, we performed sequencing of the T-cell receptor (TCR) in 45 tumor regions from 11 localized lung adenocarcinomas and observed substantial intratumor differences in T-cell density and clonality with the majority of T-cell clones restricted to individual tumor regions. TCR ITH positively correlated with predicted neoantigen ITH, suggesting that spatial differences in the T-cell repertoire may be driven by distinct neoantigens in different tumor regions. Finally, a higher degree of TCR ITH was associated with an increased risk of postsurgical relapse and shorter disease-free survival, suggesting a potential clinical significance of T-cell repertoire heterogeneity.Significance: The present study provides insights into the ITH of the T-cell repertoire in localized lung adenocarcinomas and its potential biological and clinical impact. The results suggest that T-cell repertoire ITH may be tightly associated to genomic ITH and disease relapse. Cancer Discov; 7(10); 1088-97. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1047.


Asunto(s)
Adenocarcinoma/cirugía , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Secuenciación del Exoma/métodos , Neoplasias Pulmonares/cirugía , Recurrencia Local de Neoplasia/genética , Receptores de Antígenos de Linfocitos T/genética , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Supervivencia sin Enfermedad , Regulación Neoplásica de la Expresión Génica , Heterogeneidad Genética , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Mutación , Recurrencia Local de Neoplasia/inmunología
12.
Artículo en Inglés | MEDLINE | ID: mdl-28819565

RESUMEN

Appreciation for genomic and immune heterogeneity in cancer has grown though the relationship of these factors to treatment response has not been thoroughly elucidated. To better understand this, we studied a large cohort of melanoma patients treated with targeted therapy or immune checkpoint blockade (n = 60). Heterogeneity in therapeutic responses via radiologic assessment was observed in the majority of patients. Synchronous melanoma metastases were analyzed via deep genomic and immune profiling, and revealed substantial genomic and immune heterogeneity in all patients studied, with considerable diversity in T cell frequency, and few shared T cell clones (<8% on average) across the cohort. Variables related to treatment response were identified via these approaches and through novel radiomic assessment. These data yield insight into differential therapeutic responses to targeted therapy and immune checkpoint blockade in melanoma, and have key translational implications in the age of precision medicine.

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