RESUMEN
Recent studies have provided direct evidence for genetic variegation in subclones for various cancer types. However, little is known about subclonal evolutionary processes according to treatment and subsequent relapse in multiple myeloma (MM). This issue was addressed in a cohort of 24 MM patients treated either with conventional chemotherapy or with the proteasome inhibitor, bortezomib. As MM is a highly heterogeneous disease associated with a large number of chromosomal abnormalities, a subset of secondary genetic events that seem to reflect progression, 1q21 gain, NF-κB-activating mutations, RB1 and TP53 deletions, was examined. By using high-resolution single-nucleotide polymorphism arrays, subclones were identified with nonlinear complex evolutionary histories. Such reordering of the spectrum of genetic lesions, identified in a third of MM patients during therapy, is likely to reflect the selection of genetically distinct subclones, not initially competitive against the dominant population but which survived chemotherapy, thrived and acquired new anomalies. In addition, the emergence of minor subclones at relapse appeared to be significantly associated with bortezomib treatment. These data support the idea that new strategies for future clinical trials in MM should combine targeted therapy and subpopulations' control to eradicate all myeloma subclones in order to obtain long-term remission.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/genética , Aberraciones Cromosómicas , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/inducido químicamente , Adulto , Anciano , Secuencia de Bases , Ácidos Borónicos/administración & dosificación , Bortezomib , Células Clonales , Dexametasona/administración & dosificación , Progresión de la Enfermedad , Evolución Molecular , Femenino , Estudios de Seguimiento , Eliminación de Gen , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mieloma Múltiple/complicaciones , Mieloma Múltiple/genética , Mutación , FN-kappa B/genética , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple/genética , Pirazinas/administración & dosificación , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteína de Retinoblastoma/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de Ácido Nucleico , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: We recently identified and validated UBE2C RNA as a prognostic marker in 252 node-positive (N+) breast cancers by means of a microarray study. The aim of this study was to validate UBE2C protein as a prognostic marker in N+ breast cancer by immunohistochemistry (IHC). METHODS: To this end, 92 paraffin-embedded blocks were used. The impact of UBE2C IHC value on metastasis-free survival (MFS) and overall survival (OS) was evaluated and compared with Ki-67 and Nottingham prognostic index (NPI) performances. RESULTS: In accordance with genomic data, UBE2C IHC had a significant impact both on MFS and OS (hazard ratio=6.79 - P=0.002; hazard ratio=7.14 - P=0.009, respectively). Akaike information criterion proved that the prognostic power of UBE2C IHC was stronger than that of Ki-67 (and close to that of NPI). Furthermore, multivariate analyses with NPI showed that, contrary to Ki-67 IHC, UBE2C IHC remained an independent factor, both for MFS (adjusted P=0.02) and OS (adjusted P=0.04). CONCLUSION: We confirmed that UBE2C protein measured by IHC could be used as a prognostic marker in N+ breast cancer. The potential predictive interest of UBE2C as a marker of proteasome activity needs further investigations.