RESUMEN
Recent advances in genomic sequencing technologies now allow results from deep next-generation sequencing to be obtained within clinically meaningful timeframes, making this an attractive approach to better guide personalized treatment strategies. No multiple myeloma-specific gene panel has been established so far; we therefore designed a 47-gene-targeting gene panel, containing 39 genes known to be mutated in ≥3 % of multiple myeloma cases and eight genes in pathways therapeutically targeted in multiple myeloma (MM). We performed targeted sequencing on tumor/germline DNA of 25 MM patients in which we also had a sequential sample post treatment. Mutation analysis revealed KRAS as the most commonly mutated gene (36 % in each time point), followed by NRAS (20 and 16 %), TP53 (16 and 16 %), DIS3 (16 and 16 %), FAM46C (12 and 16 %), and SP140 (12 and 12 %). We successfully tracked clonal evolution and identified mutation acquisition and/or loss in FAM46C, FAT1, KRAS, NRAS, SPEN, PRDM1, NEB, and TP53 as well as two mutations in XBP1, a gene associated with bortezomib resistance. Thus, we present the first longitudinal analysis of a MM-specific targeted sequencing gene panel that can be used for individual tumor characterization and for tracking clonal evolution over time.
Asunto(s)
Mieloma Múltiple/diagnóstico , Mieloma Múltiple/genética , Mutación/genética , Análisis de Secuencia de ADN/tendencias , Humanos , Estudios Longitudinales , Análisis de Secuencia de ADN/métodosRESUMEN
We employed a customized Multiple Myeloma (MM)-specific Mutation Panel (M(3)P) to screen a homogenous cohort of 142 untreated MM patients for relevant mutations in a selection of disease-specific genes. M(3)Pv2.0 includes 77 genes selected for being either actionable targets, potentially related to drug-response or part of known key pathways in MM biology. We identified mutations in potentially actionable genes in 49% of patients and provided prognostic evidence of STAT3 mutations. This panel may serve as a practical alternative to more comprehensive sequencing approaches, providing genomic information in a timely and cost-effective manner, thus allowing clinically oriented variant screening in MM.
Asunto(s)
Variaciones en el Número de Copia de ADN , Secuenciación de Nucleótidos de Alto Rendimiento , Mieloma Múltiple/genética , Mutación , Adulto , Anciano , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Evolución Clonal/genética , Análisis Mutacional de ADN , Estudios de Seguimiento , Heterogeneidad Genética , Humanos , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Mieloma Múltiple/mortalidad , Pronóstico , Transducción de Señal/efectos de los fármacosRESUMEN
Neurotensin and bombesin have been tested for their effects on body temperature and locomotor activity in an open field. Both peptides induce hypothermia and suppress ambulation and rearing. The time curves of the hypothermic effects of both peptides appear to be rather similar, although bombesin is a more potent hypothermic agent than neurotensin. The time curves of the effects on locomotor activity appear to be quite different. The suppressive effect of neurotensin on locomotor activity is relatively short lasting and reaches its maximum at approximately 32 minutes. The effect of bombesin follows a different time curve and shows two peaks, suggesting that two different mechanisms are involved in the suppressive action of bombesin on locomotor activity. Calculation of the correlation coefficients between the effects of neurotensin and of bombesin on body temperature and on locomotor activity (ambulation) suggest that a causal relationship between these two effects is not likely, in particular for neurotensin.