Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 25
Filtrar
1.
J Surg Oncol ; 127(3): 426-433, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36251352

RESUMO

BACKGROUND AND OBJECTIVES: Deep learning utilizing convolutional neural networks (CNNs) applied to hematoxylin & eosin (H&E)-stained slides numerically encodes histomorphological tumor features. Tumor heterogeneity is an emerging biomarker in colon cancer that is, captured by these features, whereas microsatellite instability (MSI) is an established biomarker traditionally assessed by immunohistochemistry or polymerase chain reaction. METHODS: H&E-stained slides from The Cancer Genome Atlas (TCGA) colon cohort are passed through the CNN. Resulting imaging features are used to cluster morphologically similar slide regions. Tile-level pairwise similarities are calculated and used to generate a tumor heterogeneity score (THS). Patient-level THS is then correlated with TCGA-reported biomarkers, including MSI-status. RESULTS: H&E-stained images from 313 patients generated 534 771 tiles. Deep learning automatically identified and annotated cells by type and clustered morphologically similar slide regions. MSI-high tumors demonstrated significantly higher THS than MSS/MSI-low (p < 0.001). THS was higher in MLH1-silent versus non-silent tumors (p < 0.001). The sequencing derived MSIsensor score also correlated with THS (r = 0.51, p < 0.0001). CONCLUSIONS: Deep learning provides spatially resolved visualization of imaging-derived biomarkers and automated quantification of tumor heterogeneity. Our novel THS correlates with MSI-status, indicating that with expanded training sets, translational tools could be developed that predict MSI-status using H&E-stained images alone.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Aprendizado Profundo , Humanos , Instabilidade de Microssatélites , Repetições de Microssatélites , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia
2.
Genes Chromosomes Cancer ; 59(1): 64-68, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31353684

RESUMO

Adenomatous polyposis coli (APC) mutations are causally associated with familial adenomatous polyposis (FAP) and are recurrent somatic events across numerous tumor types, including gastric adenocarcinoma. Severity of disease in FAP correlates with specific APC mutations, but the impact of given mutations on phenotype in gastric cancer is not well studied. Sequencing data from the Genomic Data Commons (GDC) demonstrate an APC mutational pattern in gastric cancer that differs dramatically from that seen in colon cancer. Exome sequencing data from APC-mutant colon and gastric adenocarcinomas in GDC was filtered for single nucleotide variants (SNVs) using MuTect2 Variant Aggregation and Masking pipeline, Somatic Aggregation Workflow. APC mutations were found in 57/441 gastric (12.9%) and 309/433 colon adenocarcinomas (71.4%). There was a significant difference in the proportion of stopgain, frameshift, and missense mutations between tumor types(P < .00001). Colon tumors were predominated by frameshift and stopgains, comprising 47.7% and 35.7%, respectively. In contrast, 47.1% of gastric mutations were missense. Gastric tumors harboring missense mutations showed decreased overall survival relative to other mutational subtypes(P = .008). In the gastric samples, 25.9% of frameshift and stopgain mutations are in the 3' portion of the gene, compared to 1.4% of colon samples. APC mutations demonstrate different distributions in gastric and colon adenocarcinoma, with a shift toward missense variants in gastric tumors and worse survival in gastric tumors harboring them. As different mutations confer variable degrees of protein dysfunction and resultant clinical manifestation, expanded investigation of specific mutational patterns will prove integral to future-risk stratification strategies.

3.
J Surg Res ; 249: 58-66, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31923715

RESUMO

BACKGROUND: Treatment approaches for pediatric papillary thyroid cancer (PTC) are historically extrapolated from adult experience. However, pediatric PTC demonstrates a greater propensity for lymph node involvement, early metastases, and recurrence, highlighting the need for pediatric-specific treatment paradigms. MATERIALS AND METHODS: A retrospective review included patients with PTC aged ≤21 y, with ≥18 mo of follow-up, treated between 2002 and 2015. Fisher's exact test and Cox proportional hazard were used to estimate the effect of risk factors on disease recurrence. RESULTS: Seventy-two cases of PTC were identified with median age of 17.0 y and median follow-up of 64.1 mo. Disease recurred at a median of 24.6 mo (range 7.8-78.1) in 7 of 51 (13.7%) of patients with disease limited to the thyroid or central neck, 7 of 18 (39%) patients with lateral neck disease at presentation who underwent a compartment-based resection, and three of three patients (100%) with lateral neck disease who sought care after non-compartment-based resection. There were no deaths from disease. Univariate predictors of recurrence included tumor size >2 cm (P = 0.005), lateral neck disease (P = 0.004), lymphovascular invasion (P = 0.017), extracapsular invasion (P < 0.0001), multifocality (P = 0.03), and non-Caucasian race (P = 0.05). Multivariate analysis identified race (P = 0.05) as an independent predictor of recurrence. In patients without lateral neck disease, there was a trend toward lower recurrence in patients undergoing thyroidectomy with central neck dissection compared with thyroidectomy alone (P = 0.07). CONCLUSIONS: Pediatric PTC is associated with excellent survival, although recurrence is common in patients with lateral node involvement. Predictors of recurrence are multifactorial and may be influenced by extent of disease, patient or tumor biology, and aggressiveness of resection. LEVEL OF EVIDENCE: Prognosis study, level IV, retrospective case series.


Assuntos
Hospitais com Alto Volume de Atendimentos/estatística & dados numéricos , Recidiva Local de Neoplasia/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Câncer Papilífero da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia/efeitos adversos , Adolescente , Fatores Etários , Criança , Feminino , Seguimentos , Humanos , Linfonodos/patologia , Metástase Linfática/terapia , Masculino , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Complicações Pós-Operatórias/etiologia , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Análise de Sobrevida , Câncer Papilífero da Tireoide/mortalidade , Câncer Papilífero da Tireoide/patologia , Glândula Tireoide/patologia , Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Tireoidectomia/métodos , Tireoidectomia/estatística & dados numéricos , Resultado do Tratamento , Adulto Jovem
4.
Cell Commun Signal ; 16(1): 27, 2018 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-29884238

RESUMO

BACKGROUND: Altered expression of Solute Carrier Family 12 Member 7 (SLC12A7) is implicated to promote malignant behavior in multiple cancer types through an incompletely understood mechanism. Recent studies have shown recurrent gene amplifications and overexpression of SLC12A7 in adrenocortical carcinoma (ACC). The potential mechanistic effect(s) of SLC12A7 amplifications in portending an aggressive behavior in ACC has not been previously studied and is investigated here using two established ACC cell lines, SW-13 and NCI-H295R. METHODS: SW-13 cells, which express negligible amounts of SLC12A7, were enforced to express SLC12A7 constitutively, while RNAi gene silencing was performed in NCI-H295R cells, which have robust endogenous expression of SLC12A7. In vitro studies tested the outcomes of experimental alterations in SLC12A7 expression on malignant characteristics, including cell viability, growth, colony formation potential, motility, invasive capacity, adhesion and detachment kinetics, and cell membrane organization. Further, potential alterations in transcription regulation downstream to induced SLC12A7 overexpression was explored using targeted transcription factor expression arrays. RESULTS: Enforced SLC12A7 overexpression in SW-13 cells robustly promoted motility and invasive characteristics (p < 0.05) without significantly altering cell viability, growth, or colony formation potential. SLC12A7 overexpression also significantly increased rates of cellular attachment and detachment turnover (p < 0.05), potentially propelled by increased filopodia formation and/or Ezrin interaction. In contrast, RNAi gene silencing of SLC12A7 stymied cell attachment strength as well as migration and invasion capacity in NCI-H295R cells. Transcription factor expression analysis identified multiple signally pathways potentially affected by SLC12A7 overexpression, including osmotic stress, bone morphogenetic protein, and Hippo signaling pathways. CONCLUSIONS: Amplification of SLC12A7 observed in ACCs is shown here, in vitro, to exacerbate the malignant behavior of ACC cells by promoting invasive capacities, possibly mediated by alterations in multiple signaling pathways, including the osmotic stress pathway.


Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Adesão Celular , Simportadores/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Transdução de Sinais , Simportadores/genética
5.
Hum Mol Genet ; 24(8): 2318-29, 2015 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-25576899

RESUMO

Anaplastic thyroid carcinoma (ATC) is a frequently lethal malignancy that is often unresponsive to available therapeutic strategies. The tumorigenesis of ATC and its relationship to the widely prevalent well-differentiated thyroid carcinomas are unclear. We have analyzed 22 cases of ATC as well as 4 established ATC cell lines using whole-exome sequencing. A total of 2674 somatic mutations (121/sample) were detected. Ontology analysis revealed that the majority of variants aggregated in the MAPK, ErbB and RAS signaling pathways. Mutations in genes related to malignancy not previously associated with thyroid tumorigenesis were observed, including mTOR, NF1, NF2, MLH1, MLH3, MSH5, MSH6, ERBB2, EIF1AX and USH2A; some of which were recurrent and were investigated in 24 additional ATC cases and 8 ATC cell lines. Somatic mutations in established thyroid cancer genes were detected in 14 of 22 (64%) tumors and included recurrent mutations in BRAF, TP53 and RAS-family genes (6 cases each), as well as PIK3CA (2 cases) and single cases of CDKN1B, CDKN2C, CTNNB1 and RET mutations. BRAF V600E and RAS mutations were mutually exclusive; all ATC cell lines exhibited a combination of mutations in either BRAF and TP53 or NRAS and TP53. A hypermutator phenotype in two cases with >8 times higher mutational burden than the remaining mean was identified; both cases harbored unique somatic mutations in MLH mismatch-repair genes. This first comprehensive exome-wide analysis of the mutational landscape of ATC identifies novel genes potentially associated with ATC tumorigenesis, some of which may be targets for future therapeutic intervention.


Assuntos
Exoma , Mutação , Carcinoma Anaplásico da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteína Supressora de Tumor p53/genética
6.
BMC Cancer ; 16: 646, 2016 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-27538953

RESUMO

BACKGROUND: Cancer is increasingly understood to arise in the context of dynamically evolving genomes with continuously generated variants subject to selective pressures. Diverse mutations have been identified in papillary thyroid carcinoma (PTC), but unifying theories underlying genomic change are lacking. Applying a framework of somatic evolution, we sought to broaden understanding of the PTC genome through identification of global trends that help explain risk of tumorigenesis. METHODS: Exome sequencing was performed on 53 PTC and matched adjacent non-tumor thyroid tissues (ANT). Single nucleotide substitution (SNS) signatures from each sample pair were divided into three subsets based on their presence in tumor, non-tumor thyroid, or both. Nine matched blood samples were sequenced and SNS signatures intersected with these three subsets. The intersected genomic signatures were used to define branch-points in the evolution of the tumor genome, distinguishing variants present in the tissues' common ancestor cells from those unique to each tissue type and therefore acquired after genomic divergence of the tumor, non-tumor, and blood samples. RESULTS: Single nucleotide substitutions shared by the tumor and the non-tumor thyroid were dominated by C-to-T transitions, whereas those unique to either tissue type were enriched for C-to-A transversions encoding non-synonymous, predicted-deleterious variants. On average, SNSs of matched blood samples were 81 % identical to those shared by tumor and non-tumor thyroid, but only 12.5 % identical to those unique to either tissue. Older age and BRAF mutation were associated with increased SNS burden. CONCLUSIONS: The current study demonstrates novel patterns of genomic change in PTC, supporting a theory of somatic evolution in which the zygote's germline genome undergoes continuous remodeling to produce progressively differentiated, tissue-specific signatures. Late somatic events in thyroid tissue demonstrate shifted mutational spectra compared to earlier polymorphisms. These late events are enriched for predicted-deleterious variants, suggesting a mechanism of genomic instability in PTC tumorigenesis.


Assuntos
Carcinoma/genética , Redes Reguladoras de Genes , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos , Neoplasias da Glândula Tireoide/genética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carcinoma Papilar , Evolução Clonal , Exoma , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide , Adulto Jovem
7.
Genes Chromosomes Cancer ; 54(9): 542-54, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26032282

RESUMO

As subsets of pheochromocytomas (PCCs) lack a defined molecular etiology, we sought to characterize the mutational landscape of PCCs to identify novel gene candidates involved in disease development. A discovery cohort of 15 PCCs wild type for mutations in PCC susceptibility genes underwent whole-exome sequencing, and an additional 83 PCCs served as a verification cohort for targeted sequencing of candidate mutations. A low rate of nonsilent single nucleotide variants (SNVs) was detected (6.1/sample). Somatic HRAS and EPAS1 mutations were observed in one case each, whereas the remaining 13 cases did not exhibit variants in established PCC genes. SNVs aggregated in apoptosis-related pathways, and mutations in COSMIC genes not previously reported in PCCs included ZAN, MITF, WDTC1, and CAMTA1. Two somatic mutations and one constitutional variant in the well-established cancer gene lysine (K)-specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome-sequencing in the verification cohort. An additional 11 PCCs displayed KMT2D variants, of which two were recurrent. In total, missense KMT2D variants were found in 14 (11 somatic, two constitutional, one undetermined) of 99 PCCs (14%). Five cases displayed somatic mutations in the functional FYR/SET domains of KMT2D, constituting 36% of all KMT2D-mutated PCCs. KMT2D expression was upregulated in PCCs compared to normal adrenals, and KMT2D overexpression positively affected cell migration in a PCC cell line. We conclude that KMT2D represents a recurrently mutated gene with potential implication for PCC development.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Proteínas de Ligação a DNA/genética , Exoma , Mutação , Proteínas de Neoplasias/genética , Feocromocitoma/genética , Neoplasias das Glândulas Suprarrenais/etiologia , Linhagem Celular Tumoral , Estudos de Coortes , Proteínas de Ligação a DNA/metabolismo , Feminino , Dosagem de Genes , Humanos , Masculino , Proteínas de Neoplasias/metabolismo , Feocromocitoma/etiologia , Feocromocitoma/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Análise de Sequência de Proteína , Transcriptoma
9.
Cell Rep Methods ; 4(5): 100759, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38626768

RESUMO

We designed a Nextflow DSL2-based pipeline, Spatial Transcriptomics Quantification (STQ), for simultaneous processing of 10x Genomics Visium spatial transcriptomics data and a matched hematoxylin and eosin (H&E)-stained whole-slide image (WSI), optimized for patient-derived xenograft (PDX) cancer specimens. Our pipeline enables the classification of sequenced transcripts for deconvolving the mouse and human species and mapping the transcripts to reference transcriptomes. We align the H&E WSI with the spatial layout of the Visium slide and generate imaging and quantitative morphology features for each Visium spot. The pipeline design enables multiple analysis workflows, including single or dual reference genome input and stand-alone image analysis. We show the utility of our pipeline on a dataset from Visium profiling of four melanoma PDX samples. The clustering of Visium spots and clustering of H&E imaging features reveal similar patterns arising from the two data modalities.


Assuntos
Xenoenxertos , Humanos , Animais , Camundongos , Perfilação da Expressão Gênica/métodos , Amarelo de Eosina-(YS) , Hematoxilina , Transcriptoma , Processamento de Imagem Assistida por Computador/métodos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
bioRxiv ; 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38370717

RESUMO

Resistance of BRAF-mutant melanomas to targeted therapy arises from the ability of cells to enter a persister state, evade treatment with relative dormancy, and repopulate the tumor when reactivated. Using spatial transcriptomics in patient derived xenograft models, we capture clonal lineage evolution during treatment, finding the persister state to show increased oxidative phosphorylation, decreased proliferation, and increased invasive capacity, with central-to-peripheral gradients. Phylogenetic tracing identifies intrinsic- and acquired-resistance mechanisms (e.g. dual specific phosphatases, Reticulon-4, CDK2) and suggests specific temporal windows of potential therapeutic efficacy. Using deep learning to analyze histopathological slides, we find morphological features of specific cell states, demonstrating that juxtaposition of transcriptomics and histology data enables identification of phenotypically-distinct populations using imaging data alone. In summary, we define state change and lineage selection during melanoma treatment with spatiotemporal resolution, elucidating how choice and timing of therapeutic agents will impact the ability to eradicate resistant clones. Statement of Significance: Tumor evolution is accelerated by application of anti-cancer therapy, resulting in clonal expansions leading to dormancy and subsequently resistance, but the dynamics of this process are incompletely understood. Tracking clonal progression during treatment, we identify conserved, global transcriptional changes and local clone-clone and spatial patterns underlying the emergence of resistance.

11.
Cancer Res ; 84(13): 2060-2072, 2024 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-39082680

RESUMO

Patient-derived xenografts (PDX) model human intra- and intertumoral heterogeneity in the context of the intact tissue of immunocompromised mice. Histologic imaging via hematoxylin and eosin (H&E) staining is routinely performed on PDX samples, which could be harnessed for computational analysis. Prior studies of large clinical H&E image repositories have shown that deep learning analysis can identify intercellular and morphologic signals correlated with disease phenotype and therapeutic response. In this study, we developed an extensive, pan-cancer repository of >1,000 PDX and paired parental tumor H&E images. These images, curated from the PDX Development and Trial Centers Research Network Consortium, had a range of associated genomic and transcriptomic data, clinical metadata, pathologic assessments of cell composition, and, in several cases, detailed pathologic annotations of neoplastic, stromal, and necrotic regions. The amenability of these images to deep learning was highlighted through three applications: (i) development of a classifier for neoplastic, stromal, and necrotic regions; (ii) development of a predictor of xenograft-transplant lymphoproliferative disorder; and (iii) application of a published predictor of microsatellite instability. Together, this PDX Development and Trial Centers Research Network image repository provides a valuable resource for controlled digital pathology analysis, both for the evaluation of technical issues and for the development of computational image-based methods that make clinical predictions based on PDX treatment studies. Significance: A pan-cancer repository of >1,000 patient-derived xenograft hematoxylin and eosin-stained images will facilitate cancer biology investigations through histopathologic analysis and contributes important model system data that expand existing human histology repositories.


Assuntos
Aprendizado Profundo , Neoplasias , Humanos , Animais , Camundongos , Neoplasias/genética , Neoplasias/patologia , Neoplasias/diagnóstico por imagem , Genômica/métodos , Xenoenxertos , Ensaios Antitumorais Modelo de Xenoenxerto , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/patologia , Processamento de Imagem Assistida por Computador/métodos
12.
bioRxiv ; 2023 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-37546876

RESUMO

Highlights: We have developed an automated data processing pipeline to quantify mouse and human data from patient-derived xenograft samples assayed by Visium spatial transcriptomics with matched hematoxylin and eosin (H&E) stained image. We enable deconvolution of reads with Xenome, quantification of spatial gene expression from host and graft species with Space Ranger, extraction of B-allele frequencies, and splicing quantification with Velocyto. In the H&E image processing sub-workflow, we generate morphometric and deep learning-derived feature quantifications complementary to the Visium spots, enabling multi-modal H&E/expression comparisons. We have wrapped the pipeline into Nextflow DSL2 in a scalable, portable, and easy-to-use framework. Summary: We designed a Nextflow DSL2-based pipeline, Spatial Transcriptomics Quantification (STQ), for simultaneous processing of 10x Genomics Visium spatial transcriptomics data and a matched hematoxylin and eosin (H&E)-stained whole slide image (WSI), optimized for Patient-Derived Xenograft (PDX) cancer specimens. Our pipeline enables the classification of sequenced transcripts for deconvolving the mouse and human species and mapping the transcripts to reference transcriptomes. We align the H&E WSI with the spatial layout of the Visium slide and generate imaging and quantitative morphology features for each Visium spot. The pipeline design enables multiple analysis workflows, including single or dual reference genomes input and stand-alone image analysis. We showed the utility of our pipeline on a dataset from Visium profiling of four melanoma PDX samples. The clustering of Visium spots and clustering of imaging features of H&E data reveal similar patterns arising from the two data modalities.

13.
Yale J Biol Med ; 85(3): 331-7, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23012581

RESUMO

The mainstream application of massively parallel, high-throughput assays in biomedical research has created a demand for scientists educated in Computational Biology and Bioinformatics (CBB). In response, formalized graduate programs have rapidly evolved over the past decade. Concurrently, there is increasing need for clinicians trained to oversee the responsible translation of CBB research into clinical tools. Physician-scientists with dedicated CBB training can facilitate such translation, positioning themselves at the intersection between computational biomedical research and medicine. This perspective explores key elements of the educational path to such a position, specifically addressing: 1) evolving perceptions of the role of the computational biologist and the impact on training and career opportunities; 2) challenges in and strategies for obtaining the core skill set required of a biomedical researcher in a computational world; and 3) how the combination of CBB with medical training provides a logical foundation for a career in academic medicine and/or biomedical research.


Assuntos
Pesquisa Biomédica/educação , Medicina Clínica/educação , Biologia Computacional/educação , Escolha da Profissão , Currículo , Bases de Dados Factuais , Educação de Pós-Graduação/métodos , Humanos , Comunicação Interdisciplinar , Pessoal de Laboratório Médico/educação , Estudantes de Medicina , Recursos Humanos
14.
J Transl Med ; 8: 67, 2010 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-20630094

RESUMO

Activating mutations in BRAF kinase are common in melanomas. Clinical trials with PLX4032, the mutant-BRAF inhibitor, show promising preliminary results in patients selected for the presence of V600E mutation. However, activating V600K mutation is the other most common mutation, yet patients with this variant are currently excluded from the PLX4032 trials. Here we present evidence that a patient bearing the BRAF V600K mutation responded remarkably to PLX4032, suggesting that clinical trials should include all patients with activating BRAF V600E/K mutations.


Assuntos
Indóis/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Sulfonamidas/uso terapêutico , Substituição de Aminoácidos/genética , Sequência de Bases , Análise Mutacional de DNA , Humanos , Melanoma/enzimologia , Dados de Sequência Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Cutâneas/enzimologia , Vemurafenib
15.
J Immunother Cancer ; 8(1)2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32209601

RESUMO

BACKGROUND: Checkpoint inhibitors (CPIs) are thought to be effective against cutaneous melanoma in part because of the large burden of somatic mutations (neoantigens) generated from exposure to ultraviolet radiation. However, rare melanoma subtypes arising from acral skin, mucosal surfaces, and the uveal tract are largely sun-shielded. Genomic studies show these sun-shielded melanomas have a paucity of neoantigens and unique biology; they are thought to be largely resistant to immunotherapy. It has not been definitively shown that CPI improves survival in metastatic sun-shielded melanoma. METHODS: We reviewed a single institutional experience using antibodies against CTLA-4, PD-1 and/or PD-L1 to treat patients with metastatic melanoma. Primary tumor histology was categorized as cutaneous, unknown, acral, mucosal, or uveal. We studied demographic data, treatment characteristics, and overall survival (OS) after CPI. RESULTS: We treated 428 patients with metastatic melanoma from 2007 to 2019. Primary tumors were cutaneous in 283 (66%), unknown in 55 (13%), acral in 22 (5%), mucosal in 38 (9%), and uveal in 30 (7%). Patients with metastatic disease from cutaneous primary tumors had median OS after CPI of 45 months compared with 17 months for acral (p=0.047), 18 months for mucosal (p=0.003), and 12 months for uveal (p<0.001). For all patients with sun-shielded melanoma (n=90), first treatment with anti-PD-1 or anti-PD-L1 was followed by a median OS of 9 months compared with 18 months after anti-CTLA-4 (p=0.010) and 20 months after combination therapy (p=0.003). There were 21 patients who achieved actual 3-year survival; 20 received both anti-CTLA-4 and anti-PD-1, either sequentially or in combination. Over 80% of 3-year survivors with progressive disease were treated with local therapy after CPI. CONCLUSIONS: Long survival in patients with metastatic melanoma from acral, mucosal, and uveal primary tumors was associated with receipt of both anti-CTLA-4 and anti-PD-1 antibodies. Complete responses were rare, and local therapy was frequently employed to control disease progression. While sun-shielded melanomas exhibit worse outcomes after CPI than cutaneous melanomas, with an aggressive multidisciplinary approach, 5-year survival is still possible for 25%-32% of these patients.


Assuntos
Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Uveais/tratamento farmacológico , Idoso , Feminino , Humanos , Masculino , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Neoplasias Uveais/mortalidade , Neoplasias Uveais/patologia , Melanoma Maligno Cutâneo
16.
Surg Clin North Am ; 99(3): 511-527, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31047039

RESUMO

Next-generation sequencing has enabled genome-wide molecular profiling of gastric and esophageal malignancies at single-nucleotide resolution. The resultant genomic profiles provide information about the specific oncogenic pathways that are the likely driving forces behind tumorigenesis and progression. The abundance of available genomic data has immense potential to redefine management paradigms for these difficult disease processes. The ability to capitalize on the information provided through high-throughput sequencing technologies will define cancer care in the coming decades and could shift the paradigm from current stage-based, organ-specific treatments toward tailored regimens that target the specific culprit pathways driving individual tumors.


Assuntos
Adenocarcinoma/genética , Neoplasias Esofágicas/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Gástricas/genética , Adenocarcinoma/classificação , Adenocarcinoma/terapia , Neoplasias Esofágicas/classificação , Neoplasias Esofágicas/terapia , Genômica , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Humanos , Instabilidade de Microssatélites , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Neoplasias Gástricas/classificação , Neoplasias Gástricas/terapia , Terminologia como Assunto
17.
J Pediatr Surg ; 54(1): 129-132, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30361076

RESUMO

BACKGROUND: Regional lymph node (LN) metastasis at the time of presentation plays a significant role in predicting recurrence in patients with papillary thyroid cancer (PTC). Multiple studies in the adult population have demonstrated that the lymph node ratio (LNR) in both the central and lateral neck can improve the accuracy of recurrence prediction, but this ratio has not been studied in the pediatric population. In this study, we sought to investigate the LNR in the central and lateral compartments as a prognostic predictor for recurrence in pediatric patients with PTC. METHODS: A retrospective analysis of pediatric patients (≤21 years old) at a single institution between 2002 and 2014 who underwent total thyroidectomy with prophylactic central neck dissection (TTpCND) with at least 3 sampled nodes or total thyroidectomy with unilateral modified radical neck dissection (TTMRND) with at least 10 sampled nodes, and on whom at least 24 months of follow up data were available was performed. The LNR was defined as the ratio of metastatic LNs to total number of investigated LNs. Recurrence after TTpCND and TTMRND was examined separately as a function of LNR, using the value of 0.45 as a cutoff. RESULTS: Forty-eight patients met inclusion criteria. Thirty-two underwent TTpCND, and sixteen underwent TTMRND. Median age at time of operation was 17 years (range 6-20), and median duration of follow-up was 53.5 months (range 24-183). In the TTpCND, LNR ranged from 0 to 1.0. There were two recurrences among the eight patients (25%) undergoing TTpCND in patients with LNRs >0.45 and a single recurrence among the 24 patients (4.2%) undergoing TTpCND with an LNR ≤0.45. In the TTMRND, LNR ranged from 0.1 to 1.0. There were 3 recurrences in 12 patients with LNR ≤0.45 (30.8%%) and 4 recurrences in 4 patients with LNR >0.45 (100%) (p = 0.03). CONCLUSIONS: Although limited by small sample size, LNR may be a useful predictor to stratify the likelihood of recurrence in pediatric patients undergoing TTpCND or TTMRND for pathologic N1a or N1b PTC. TYPE OF STUDY: Prognosis study / retrospective case series. LEVEL OF EVIDENCE: Level IV.


Assuntos
Metástase Linfática/patologia , Recidiva Local de Neoplasia/patologia , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Adolescente , Adulto , Criança , Feminino , Humanos , Linfonodos/patologia , Masculino , Esvaziamento Cervical/métodos , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Câncer Papilífero da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia/métodos , Adulto Jovem
18.
J Endocr Soc ; 1(7): 926-930, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29264543

RESUMO

Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a rare autosomal dominant cause of familial hyperparathyroidism associated with benign, ossifying fibromas of the maxillofacial bones and increased risk of parathyroid carcinoma. The putative tumor suppressor gene CDC73 has been implicated in the syndrome, with a multitude of inactivating mutations identified; however, HPT-JT due to large-scale deletion of the chromosomal region containing the gene is exceedingly rare, and the clinical significance of this variant remains unclear. We report the case of a 32-year-old woman with a history of mandibular ossifying fibroma who presented with primary hyperparathyroidism and was found to harbor a large-scale, germline deletion on chromosome 1q31, including the CDC73 locus. HPT-JT is associated with loss of function of the putative tumor suppressor gene CDC73. Over 100 mutations and small insertions/deletions have been identified within the gene, the majority of which result in premature truncation of the parafibromin protein product. We report a case of HPT-JT associated with a large chromosomal deletion (4.1 Mb) encompassing the CDC73 gene locus. In the future, molecular testing in this autosomal dominant disorder should use techniques that allow for the detection of large-scale deletions in addition to the more commonly observed mutations and smaller-scale copy number alterations. Further investigation is needed to determine whether HPT-JT associated with a large-scale deletion carries increased risk of malignancy relative to the more common truncating mutations and what the implications are for genetic counseling.

19.
Surgery ; 161(6): 1667-1674, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28073588

RESUMO

BACKGROUND: Cytochrome P450-mediated metabolism of chemotherapeutic agents contributes to chemotherapy resistance in multiple malignancies. Adrenocortical carcinoma is known to have a poor response to adjuvant therapies; however, the mechanism remains unknown. Recent comprehensive genetic analyses of adrenocortical carcinomas demonstrated recurrent copy number gains in multiple cytochrome P450 genes prompting investigation into whether cytochrome P450 overexpression potentiates adrenocortical carcinoma chemoresistance. METHODS: We determined the expression patterns of 6 cytochrome P450 genes (CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2S1, and CYP4F2) predicted to be amplified in adrenocortical carcinoma (n = 29) relative to normal adrenal cortex (n = 10). Gene copy numbers were determined with the TaqMan copy number assay. Gene silencing was performed via small interfering RNA (siRNA) in the adrenocortical carcinoma cell line NCI-H295R and treated with mitotane and cisplatin. RESULTS: Of the 6 cytochrome P450 genes tested, CYP2A6 was overexpressed with a 55-fold mean increase compared to normal adrenal samples (P < .05). Immunohistochemical analysis confirmed protein overexpression. Copy gains of CYP2A6 were found in 26% (7/27) of adrenocortical carcinoma specimens. Silencing of CYP2A6 in NCI-H295R cells resulted in decreased cell viability and increased chemosensitivity (P < .05). CONCLUSION: Frequent upregulation in adrenocortical carcinomas and the reversal of chemoresistance in adrenocortical carcinoma cells via enforced silencing suggest a role for CYP2A6 in adrenocortical malignancy.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Citocromo P-450 CYP2A6/genética , Sistema Enzimático do Citocromo P-450/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/patologia , Idoso , Análise de Variância , Antineoplásicos/uso terapêutico , Biópsia por Agulha , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Prognóstico , Medição de Risco , Estatísticas não Paramétricas , Regulação para Cima
20.
Surgery ; 159(1): 296-301, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26453132

RESUMO

BACKGROUND: Familial syndromes with specific genetic drivers account for a subset of adrenocortical carcinomas (ACCs), but the genomic underpinnings of sporadic cases remain poorly understood. Recent advances in copy number variation (CNV) prediction from exome sequencing are facilitating exploration of genomic rearrangements common to these carcinomas. METHODS: ACC and matched, nontumor samples underwent exome sequencing. CNVs were predicted using coverage-depth comparison. Clinicopathologic characteristics of amplification- and deletion-dominant samples were compared and pathway enrichment analysis performed for regions with significant variation. RESULTS: CNVs are distributed broadly across the ACC genome. Individual signatures demonstrate amplification or deletion dominance. Areas of recurrent amplification include chromosomes 5, 12, 19, and 20, whereas chromosomes 1, 10, 18, and 22 are deletion prone. Large-scale amplification of chromosome 19 occurred in 12 of 19 cases (63%), including 6 of 8 amplification-dominant samples (75%) and was associated with stage III/IV disease (P = .002). Genes within this amplified region are overrepresented among the adrenal hyperplasia and steroid biosynthesis pathways (P = 4.2(-5) and 2.5(-5), respectively). CONCLUSION: CNV detection via exome sequencing allows high-resolution cataloging of structural variations in ACC. Large-scale, recurrent amplifications encompassing known adrenal-specific gene pathways correlate with tumor stage. Further functional analysis of individual genes within these regions could provide mechanistic insight into specific drivers underlying pathogenesis and progression of ACC.


Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Cromossomos Humanos Par 19/genética , Variações do Número de Cópias de DNA , Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Exoma , Feminino , Amplificação de Genes , Humanos , Masculino , Pessoa de Meia-Idade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA