RESUMO
5-Fluorouracil (5-FU) is a chemotherapeutic drug commonly used for the treatment of solid cancers. It is proposed that 5-FU interferes with nucleotide synthesis and incorporates into DNA, which may have a mutational impact on both surviving tumor and healthy cells. Here, we treat intestinal organoids with 5-FU and find a highly characteristic mutational pattern that is dominated by T>G substitutions in a CTT context. Tumor whole genome sequencing data confirms that this signature is also identified in vivo in colorectal and breast cancer patients who have received 5-FU treatment. Taken together, our results demonstrate that 5-FU is mutagenic and may drive tumor evolution and increase the risk of secondary malignancies. Furthermore, the identified signature shows a strong resemblance to COSMIC signature 17, the hallmark signature of treatment-naive esophageal and gastric tumors, which indicates that distinct endogenous and exogenous triggers can converge onto highly similar mutational signatures.
Assuntos
Carcinogênese/efeitos dos fármacos , Fluoruracila/efeitos adversos , Neoplasias/genética , Mutação Puntual/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Adulto , Idade de Início , Idoso , Biópsia , Carcinogênese/genética , Técnicas de Cultura de Células , Linhagem Celular , Ensaios Clínicos como Assunto , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Intestinos/citologia , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Taxa de Mutação , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Organoides , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Células-Tronco , Transcriptoma/genética , Sequenciamento Completo do Genoma , Adulto JovemRESUMO
In collaboration with the department of Quality and Operations Improvement, Clinical Applications and the Information Warehouse, we have leveraged available Information Warehouse data to build a Best Practice Compliance Measurement Dashboard. This tool combines information from our operating room charting system, our order entry system and coding information from the patient billing and management system to provide 'previous day', data on a patients current course of treatment.
