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1.
Nature ; 569(7757): 503-508, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31068700

RESUMO

Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a rigorous framework with which to study genetic variants, candidate targets, and small-molecule and biological therapeutics and to identify new marker-driven cancer dependencies. To improve our understanding of the molecular features that contribute to cancer phenotypes, including drug responses, here we have expanded the characterizations of cancer cell lines to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression and reverse-phase protein array data for 1,072 cell lines from individuals of various lineages and ethnicities. Integration of these data with functional characterizations such as drug-sensitivity, short hairpin RNA knockdown and CRISPR-Cas9 knockout data reveals potential targets for cancer drugs and associated biomarkers. Together, this dataset and an accompanying public data portal provide a resource for the acceleration of cancer research using model cancer cell lines.


Assuntos
Linhagem Celular Tumoral , Neoplasias/genética , Neoplasias/patologia , Antineoplásicos/farmacologia , Biomarcadores Tumorais , Metilação de DNA , Resistencia a Medicamentos Antineoplásicos , Etnicidade/genética , Edição de Genes , Histonas/metabolismo , Humanos , MicroRNAs/genética , Terapia de Alvo Molecular , Neoplasias/metabolismo , Análise Serial de Proteínas , Splicing de RNA
2.
Genet Med ; 24(5): 986-998, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35101336

RESUMO

PURPOSE: Several professional societies have published guidelines for the clinical interpretation of somatic variants, which specifically address diagnostic, prognostic, and therapeutic implications. Although these guidelines for the clinical interpretation of variants include data types that may be used to determine the oncogenicity of a variant (eg, population frequency, functional, and in silico data or somatic frequency), they do not provide a direct, systematic, and comprehensive set of standards and rules to classify the oncogenicity of a somatic variant. This insufficient guidance leads to inconsistent classification of rare somatic variants in cancer, generates variability in their clinical interpretation, and, importantly, affects patient care. Therefore, it is essential to address this unmet need. METHODS: Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group and ClinGen Germline/Somatic Variant Subcommittee, the Cancer Genomics Consortium, and the Variant Interpretation for Cancer Consortium used a consensus approach to develop a standard operating procedure (SOP) for the classification of oncogenicity of somatic variants. RESULTS: This comprehensive SOP has been developed to improve consistency in somatic variant classification and has been validated on 94 somatic variants in 10 common cancer-related genes. CONCLUSION: The comprehensive SOP is now available for classification of oncogenicity of somatic variants.


Assuntos
Genoma Humano , Neoplasias , Testes Genéticos/métodos , Variação Genética/genética , Genoma Humano/genética , Genômica/métodos , Humanos , Neoplasias/genética , Virulência
3.
Hum Mutat ; 42(4): 342-345, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33600011

RESUMO

Splice site variants may lead to transcript alterations, causing exons inclusion, exclusion, truncation, or intron retention. Interpreting the consequences of a specific splice site variant is not straightforward, especially if the variant is located outside of the canonical splice sites. We developed MutSpliceDB: https://brb.nci.nih.gov/splicing, a public resource to facilitate the interpretation of splice sites variants effects on splicing based on manually reviewed RNA-seq BAM files from samples with splice site variants.


Assuntos
Sítios de Splice de RNA , Splicing de RNA , Processamento Alternativo , Éxons/genética , Humanos , Íntrons/genética , Sítios de Splice de RNA/genética , Splicing de RNA/genética , RNA-Seq
5.
Hum Mutat ; 39(11): 1542-1552, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30311369

RESUMO

In its landmark paper about Standards and Guidelines for the Interpretation of Sequence Variants, the American College of Medical Genetics and Genomics (ACMG), and Association for Molecular Pathology (AMP) did not address how to use tumor data when assessing the pathogenicity of germline variants. The Clinical Genome Resource (ClinGen) established a multidisciplinary working group, the Germline/Somatic Variant Subcommittee (GSVS) with this focus. The GSVS implemented a survey to determine current practices of integrating somatic data when classifying germline variants in cancer predisposition genes. The GSVS then reviewed and analyzed available resources of relevant somatic data, and performed integrative germline variant curation exercises. The committee determined that somatic hotspots could be systematically integrated into moderate evidence of pathogenicity (PM1). Tumor RNA sequencing data showing altered splicing may be considered as strong evidence in support of germline pathogenicity (PVS1) and tumor phenotypic features such as mutational signatures be considered supporting evidence of pathogenicity (PP4). However, at present, somatic data such as focal loss of heterozygosity and mutations occurring on the alternative allele are not recommended to be systematically integrated, instead, incorporation of this type of data should take place under the advisement of multidisciplinary cancer center tumor-normal sequencing boards.


Assuntos
Variação Genética/genética , Genoma Humano/genética , Mutação/genética , Alelos , Biologia Computacional , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Genômica , Mutação em Linhagem Germinativa/genética , Humanos
6.
Hum Mutat ; 39(11): 1721-1732, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30311370

RESUMO

Harmonization of cancer variant representation, efficient communication, and free distribution of clinical variant-associated knowledge are central problems that arise with increased usage of clinical next-generation sequencing. The Clinical Genome Resource (ClinGen) Somatic Working Group (WG) developed a minimal variant level data (MVLD) representation of cancer variants, and has an ongoing collaboration with Clinical Interpretations of Variants in Cancer (CIViC), an open-source platform supporting crowdsourced and expert-moderated cancer variant curation. Harmonization between MVLD and CIViC variant formats was assessed by formal field-by-field analysis. Adjustments to the CIViC format were made to harmonize with MVLD and support ClinGen Somatic WG curation activities, including four new features in CIViC: (1) introduction of an assertions feature for clinical variant assessment following the Association of Molecular Pathologists (AMP) guidelines, (2) group-level curation tracking for organizations, enabling member transparency, and curation effort summaries, (3) introduction of ClinGen Allele Registry IDs to CIViC, and (4) mapping of CIViC assertions into ClinVar submission with automated submissions. A generalizable workflow utilizing MVLD and new CIViC features is outlined for use by ClinGen Somatic WG task teams for curation and submission to ClinVar, and provides a model for promoting harmonization of cancer variant representation and efficient distribution of this information.


Assuntos
Genoma Humano/genética , Neoplasias/genética , Bases de Dados Genéticas , Testes Genéticos , Variação Genética/genética , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Software
7.
Nature ; 483(7391): 603-7, 2012 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-22460905

RESUMO

The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.


Assuntos
Bases de Dados Factuais , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Enciclopédias como Assunto , Modelos Biológicos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Linhagem da Célula , Cromossomos Humanos/genética , Ensaios Clínicos como Assunto/métodos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes ras/genética , Genoma Humano/genética , Genômica , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Farmacogenética , Plasmócitos/citologia , Plasmócitos/efeitos dos fármacos , Plasmócitos/metabolismo , Medicina de Precisão/métodos , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Análise de Sequência de DNA , Inibidores da Topoisomerase/farmacologia
8.
Hum Mutat ; 38(11): 1449-1453, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28762582

RESUMO

Tumor-suppressor genes can be inactivated by several mechanisms and, in a majority of cases, both alleles need to be affected. One of the mechanisms of inactivation is due to deletions ranging from dozen to hundreds of nucleotides; such deletions are often missed by variant callers. HomDelDetect is a method to detect such homozygous deletions in cancer models, such as cancer cell lines and potentially patient tumor-derived xenografts. This method can be applied to partial exome, whole-exome sequencing, whole-genome sequencing, and RNA-seq data. We applied our method across a panel of CCLE cancer cell lines and observed good concordance with SNP array-based analysis and also detected deletions that have been missed by variant callers and by SNP arrays, demonstrating the ability of HomDelDetect to improve the annotations of tumor-suppressor genes in cancer models.


Assuntos
Genes Supressores , Homozigoto , Modelos Biológicos , Neoplasias/genética , Deleção de Sequência , Linhagem Celular Tumoral , Exoma , Expressão Gênica , Inativação Gênica , Genômica/métodos , Genótipo , Humanos , Neoplasias/diagnóstico , Análise de Sequência com Séries de Oligonucleotídeos , Sequenciamento do Exoma
9.
Genet Med ; 24(9): 1989-1990, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35796744
11.
Hum Mutat ; 37(9): 865-76, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27328919

RESUMO

TP53 gene mutations are one of the most frequent somatic events in cancer. The IARC TP53 Database (http://p53.iarc.fr) is a popular resource that compiles occurrence and phenotype data on TP53 germline and somatic variations linked to human cancer. The deluge of data coming from cancer genomic studies generates new data on TP53 variations and attracts a growing number of database users for the interpretation of TP53 variants. Here, we present the current contents and functionalities of the IARC TP53 Database and perform a systematic analysis of TP53 somatic mutation data extracted from this database and from genomic data repositories. This analysis showed that IARC has more TP53 somatic mutation data than genomic repositories (29,000 vs. 4,000). However, the more complete screening achieved by genomic studies highlighted some overlooked facts about TP53 mutations, such as the presence of a significant number of mutations occurring outside the DNA-binding domain in specific cancer types. We also provide an update on TP53 inherited variants including the ones that should be considered as neutral frequent variations. We thus provide an update of current knowledge on TP53 variations in human cancer as well as inform users on the efficient use of the IARC TP53 Database.


Assuntos
Bases de Dados Genéticas , Mutação , Neoplasias/genética , Proteína Supressora de Tumor p53/genética , Curadoria de Dados , Predisposição Genética para Doença , Genômica , Humanos , Fenótipo , Domínios Proteicos , Software , Proteína Supressora de Tumor p53/química
12.
Cancer Genet ; 286-287: 18-24, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38909530

RESUMO

There is a rich history of cancer treatments which provides a number of important lessons for present and future cancer therapies. We outline this history by looking in the past, reviewing the current landscape of cancer treatments, and by glancing at the potential future cancer therapies.

13.
Mol Cancer Ther ; 22(11): 1270-1279, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37550087

RESUMO

The NCI-60 human tumor cell line panel has proved to be a useful tool for the global cancer research community in the search for novel chemotherapeutics. The publicly available cell line characterization and compound screening data from the NCI-60 assay have significantly contributed to the understanding of cellular mechanisms targeted by new oncology agents. Signature sensitivity/resistance patterns generated for a given chemotherapeutic agent against the NCI-60 panel have long served as fingerprint presentations that encompass target information and the mechanism of action associated with the tested agent. We report the establishment of a new public NCI-60 resource based on the cell line screening of a large and growing set of 175 FDA-approved oncology drugs (AOD) plus >825 clinical and investigational oncology agents (IOA), representing a diverse set (>250) of therapeutic targets and mechanisms. This data resource is available to the public (https://ioa.cancer.gov) and includes the raw data from the screening of the IOA and AOD collection along with an extensive set of visualization and analysis tools to allow for comparative study of individual test compounds and multiple compound sets.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico
14.
PLoS Genet ; 5(2): e1000367, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19197353

RESUMO

Many components of Wnt/beta-catenin signaling pathway also play critical roles in mammary tumor development, yet the role of the tumor suppressor gene APC (adenomatous polyposis coli) in breast oncongenesis is unclear. To better understand the role of Apc in mammary tumorigenesis, we introduced conditional Apc mutations specifically into two different mammary epithelial populations using K14-cre and WAP-cre transgenic mice that express Cre-recombinase in mammary progenitor cells and lactating luminal cells, respectively. Only the K14-cre-mediated Apc heterozygosity developed mammary adenocarcinomas demonstrating histological heterogeneity, suggesting the multilineage progenitor cell origin of these tumors. These tumors harbored truncation mutation in a defined region in the remaining wild-type allele of Apc that would retain some down-regulating activity of beta-catenin signaling. Activating mutations at codons 12 and 61 of either H-Ras or K-Ras were also found in a subset of these tumors. Expression profiles of acinar-type mammary tumors from K14-cre; Apc(CKO/+) mice showed luminal epithelial gene expression pattern, and clustering analysis demonstrated more correlation to MMTV-neu model than to MMTV-Wnt1. In contrast, neither WAP-cre-induced Apc heterozygous nor homozygous mutations resulted in predisposition to mammary tumorigenesis, although WAP-cre-mediated Apc deficiency resulted in severe squamous metaplasia of mammary glands. Collectively, our results suggest that not only the epithelial origin but also a certain Apc mutations are selected to achieve a specific level of beta-catenin signaling optimal for mammary tumor development and explain partially the colon- but not mammary-specific tumor development in patients that carry germline mutations in APC.


Assuntos
Polipose Adenomatosa do Colo/genética , Genes APC , Neoplasias Mamárias Animais/genética , Animais , Feminino , Regulação Neoplásica da Expressão Gênica , Mutação em Linhagem Germinativa , Integrases/genética , Integrases/metabolismo , Queratina-14/genética , Queratina-14/metabolismo , Glândulas Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas do Leite/genética , Proteínas do Leite/metabolismo , Neoplasias/genética , Transdução de Sinais , beta Catenina/genética , beta Catenina/metabolismo
15.
Proc Natl Acad Sci U S A ; 105(40): 15493-8, 2008 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-18832169

RESUMO

To examine the role of Rb1 in gastrointestinal (GI) tumors, we generated mice with an Apc(1638N) allele, Rb(tm2brn) floxed alleles, and a villin-cre transgene (RBVCA). These animals had exon 19 deleted from Rb1 throughout the GI tract. We have shown previously that Rb1 deficiency is insufficient for GI tumor initiation, with inactivation of an Apc allele capable of overcoming the insufficiency. In this study we demonstrate that RBVCA mice have reduced median survival because of an increase in tumor incidence and multiplicity in the cecum and the proximal colon. Large intestinal tumors are predominantly adenomas, whereas the tumors of the small intestine are a mixture of adenomas and adenocarcinomas. We find truncation mutations to the second Apc allele in tumors of both the large and small intestine. Expression profiles of duodenal and cecal tumors relative to each other show unique gene subsets up and down regulated. Substantial expression patterns compare to human colorectal cancer, including recapitulation of embryonic genes. Our results indicate that Rb1 has significant influence over tumor location in the GI tract, and that both cecal and duodenal tumors initiate through inactivation of Apc. Expression profile analysis indicates the two tumor types differentially regulate distinct sets of genes that are over-expressed in a majority of human colorectal carcinomas.


Assuntos
Neoplasias do Ceco/genética , Neoplasias do Colo/genética , Trato Gastrointestinal/metabolismo , Genes APC , Proteína do Retinoblastoma/fisiologia , Alelos , Animais , Neoplasias do Ceco/metabolismo , Ceco/metabolismo , Ceco/patologia , Colo/metabolismo , Colo/patologia , Neoplasias do Colo/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Trato Gastrointestinal/patologia , Perfilação da Expressão Gênica , Camundongos , Camundongos Transgênicos , Mutação , Proteína do Retinoblastoma/genética
16.
Sci Rep ; 11(1): 17275, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446762

RESUMO

TP53 is one of the most frequently altered genes in cancer; it can be inactivated by a number of different mechanisms. NM_000546.6 (ENST00000269305.9) is by far the predominant TP53 isoform, however a few other alternative isoforms have been described to be expressed at much lower levels. To better understand patterns of TP53 alternative isoforms expression in cancer and normal samples we performed exon-exon junction reads based analysis of TP53 isoforms using RNA-seq data from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), and Genotype-Tissue Expression (GTEx) project. TP53 C-terminal alternative isoforms have abolished or severely decreased tumor suppressor activity, and therefore, an increase in fraction of TP53 C-terminal alternative isoforms may be expected in tumors with wild type TP53. Despite our expectation that there would be increase of fraction of TP53 C-terminal alternative isoforms, we observed no substantial increase in fraction of TP53 C-terminal alternative isoforms in TCGA tumors and CCLE cancer cell lines with wild type TP53, likely indicating that TP53 C-terminal alternative isoforms expression cannot be reliably selected for during tumor progression.


Assuntos
Processamento Alternativo , Éxons/genética , Regulação Neoplásica da Expressão Gênica , Mutação , Neoplasias/genética , Proteína Supressora de Tumor p53/genética , Linhagem Celular Tumoral , Progressão da Doença , Genes Supressores de Tumor , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA-Seq/métodos , Proteína Supressora de Tumor p53/metabolismo
17.
Methods Mol Biol ; 2055: 649-678, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31502173

RESUMO

In recent years, cancer immunotherapy has emerged as a highly promising approach to treat patients with cancer, as the patient's own immune system is harnessed to attack cancer cells. However, the application of these approaches is still limited to a minority of patients with cancer and it is difficult to predict which patients will derive the greatest clinical benefit.One of the challenges faced by the biomedical community in the search of more effective biomarkers is the fact that translational research efforts involve collecting and accessing data at many different levels: from the type of material examined (e.g., cell line, animal models, clinical samples) to multiple data type (e.g., pharmacodynamic markers, genetic sequencing data) to the scale of a study (e.g., small preclinical study, moderate retrospective study on stored specimen sets, clinical trials with large cohorts).This chapter reviews several publicly available bioinformatics tools and data resources for high throughput molecular analyses applied to a range of data types, including those generated from microarray, whole-exome sequencing (WES), RNA-seq, DNA copy number, and DNA methylation assays, that are extensively used for integrative multidimensional data analysis and visualization.


Assuntos
Biomarcadores Tumorais/genética , Biologia Computacional/métodos , Neoplasias/genética , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Regulação Neoplásica da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Estudos Retrospectivos , Software , Sequenciamento do Exoma
18.
Clin Epigenetics ; 12(1): 93, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32586373

RESUMO

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive neuroendocrine lung cancer. SCLC progression and treatment resistance involve epigenetic processes. However, links between SCLC DNA methylation and drug response remain unclear. We performed an epigenome-wide study of 66 human SCLC cell lines using the Illumina Infinium MethylationEPIC BeadChip array. Correlations of SCLC DNA methylation and gene expression with in vitro response to 526 antitumor agents were examined. RESULTS: We found multiple significant correlations between DNA methylation and chemosensitivity. A potentially important association was observed for TREX1, which encodes the 3' exonuclease I that serves as a STING antagonist in the regulation of a cytosolic DNA-sensing pathway. Increased methylation and low expression of TREX1 were associated with the sensitivity to Aurora kinase inhibitors AZD-1152, SCH-1473759, SNS-314, and TAK-901; the CDK inhibitor R-547; the Vertex ATR inhibitor Cpd 45; and the mitotic spindle disruptor vinorelbine. Compared with cell lines of other cancer types, TREX1 had low mRNA expression and increased upstream region methylation in SCLC, suggesting a possible relationship with SCLC sensitivity to Aurora kinase inhibitors. We also identified multiple additional correlations indicative of potential mechanisms of chemosensitivity. Methylation of the 3'UTR of CEP350 and MLPH, involved in centrosome machinery and microtubule tracking, respectively, was associated with response to Aurora kinase inhibitors and other agents. EPAS1 methylation was associated with response to Aurora kinase inhibitors, a PLK-1 inhibitor and a Bcl-2 inhibitor. KDM1A methylation was associated with PLK-1 inhibitors and a KSP inhibitor. Increased promoter methylation of SLFN11 was correlated with resistance to DNA damaging agents, as a result of low or no SLFN11 expression. The 5' UTR of the epigenetic modifier EZH2 was associated with response to Aurora kinase inhibitors and a FGFR inhibitor. Methylation and expression of YAP1 were correlated with response to an mTOR inhibitor. Among non-neuroendocrine markers, EPHA2 was associated with response to Aurora kinase inhibitors and a PLK-1 inhibitor and CD151 with Bcl-2 inhibitors. CONCLUSIONS: Multiple associations indicate potential epigenetic mechanisms affecting SCLC response to chemotherapy and suggest targets for combination therapies. While many correlations were not specific to SCLC lineages, several lineage markers were associated with specific agents.


Assuntos
Linhagem Celular Tumoral/efeitos dos fármacos , Metilação de DNA/genética , Epigenoma/genética , Carcinoma de Pequenas Células do Pulmão/genética , Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Aurora Quinases/antagonistas & inibidores , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas Inibidoras de Quinase Dependente de Ciclina/farmacologia , Metilação de DNA/efeitos dos fármacos , Quimioterapia Combinada/estatística & dados numéricos , Exodesoxirribonucleases/genética , Exodesoxirribonucleases/metabolismo , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Histona Desmetilases/efeitos dos fármacos , Histona Desmetilases/genética , Humanos , Neoplasias Pulmonares/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas Nucleares/efeitos dos fármacos , Proteínas Nucleares/genética , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Quinase 1 Polo-Like
19.
Nat Genet ; 52(4): 448-457, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32246132

RESUMO

Precision oncology relies on accurate discovery and interpretation of genomic variants, enabling individualized diagnosis, prognosis and therapy selection. We found that six prominent somatic cancer variant knowledgebases were highly disparate in content, structure and supporting primary literature, impeding consensus when evaluating variants and their relevance in a clinical setting. We developed a framework for harmonizing variant interpretations to produce a meta-knowledgebase of 12,856 aggregate interpretations. We demonstrated large gains in overlap between resources across variants, diseases and drugs as a result of this harmonization. We subsequently demonstrated improved matching between a patient cohort and harmonized interpretations of potential clinical significance, observing an increase from an average of 33% per individual knowledgebase to 57% in aggregate. Our analyses illuminate the need for open, interoperable sharing of variant interpretation data. We also provide a freely available web interface (search.cancervariants.org) for exploring the harmonized interpretations from these six knowledgebases.


Assuntos
Variação Genética/genética , Neoplasias/genética , Bases de Dados Genéticas , Diploide , Genômica/métodos , Humanos , Bases de Conhecimento , Medicina de Precisão/métodos
20.
Lung Cancer Manag ; 8(2): LMT13, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31645891

RESUMO

Until recently, small cell lung cancer (SCLC) was described as SCLC and SCLC variant, based upon cellular morphology and loss of neuroendocrine markers in the SCLC variant. However, based on recent research advances, driven in part by the increase in comprehensive genomic data, it has become clear that there are multiple SCLC subtypes including an ASCL1 and NEUROD1 low, YAP1 high (SCLC-Y) subtype enriched for WT RB1. Comparing morphological and other features of this SCLC subtype to neuroendocrine negative RB1, KEAP1, STK11 WT LCNEC raises a number of important questions with diagnostic and therapeutic implications.

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