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1.
Genome Res ; 27(4): 613-625, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28179366

RESUMO

Drug resistance is an almost inevitable consequence of cancer therapy and ultimately proves fatal for the majority of patients. In many cases, this is the consequence of specific gene mutations that have the potential to be targeted to resensitize the tumor. The ability to uniformly saturate the genome with point mutations without chromosome or nucleotide sequence context bias would open the door to identify all putative drug resistance mutations in cancer models. Here, we describe such a method for elucidating drug resistance mechanisms using genome-wide chemical mutagenesis allied to next-generation sequencing. We show that chemically mutagenizing the genome of cancer cells dramatically increases the number of drug-resistant clones and allows the detection of both known and novel drug resistance mutations. We used an efficient computational process that allows for the rapid identification of involved pathways and druggable targets. Such a priori knowledge would greatly empower serial monitoring strategies for drug resistance in the clinic as well as the development of trials for drug-resistant patients.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Genoma Humano , Acúmulo de Mutações , Taxa de Mutação , Linhagem Celular Tumoral , Humanos , Modelos Genéticos , Mutação Puntual
2.
Nat Commun ; 10(1): 2198, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097696

RESUMO

Many gene fusions are reported in tumours and for most their role remains unknown. As fusions are used for diagnostic and prognostic purposes, and are targets for treatment, it is crucial to assess their function in cancer. To systematically investigate the role of fusions in tumour cell fitness, we utilized RNA-sequencing data from 1011 human cancer cell lines to functionally link 8354 fusion events with genomic data, sensitivity to >350 anti-cancer drugs and CRISPR-Cas9 loss-of-fitness effects. Established clinically-relevant fusions were identified. Overall, detection of functional fusions was rare, including those involving cancer driver genes, suggesting that many fusions are dispensable for tumour fitness. Therapeutically actionable fusions involving RAF1, BRD4 and ROS1 were verified in new histologies. In addition, recurrent YAP1-MAML2 fusions were identified as activators of Hippo-pathway signaling in multiple cancer types. Our approach discriminates functional fusions, identifying new drivers of carcinogenesis and fusions that could have clinical implications.


Assuntos
Biomarcadores Tumorais/genética , Sistemas CRISPR-Cas/genética , Fusão Gênica/genética , Neoplasias/genética , Antineoplásicos/farmacologia , Carcinogênese/genética , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Detecção Precoce de Câncer/métodos , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias/diagnóstico , Análise de Sequência de RNA
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