Genetic studies have a central role in the study of multiple myeloma (MM), as they become a critical component in the risk-based stratification of the disease. Significant efforts have been made to identify genetic changes and signatures that can predict clinical outcome and include them in the routine clinical care. Fluorescence in situ hybridization (FISH) still remains the most used genetic technique in clinical practice, mostly due to its very straightforward implementation and the simplicity of data analysis. The advent of high-resolution genomics (i.e. array CGH, exome and whole genome sequencing) and transcriptomics tests (i.e. gene expression profiling - GEP, and mRNA sequencing) provide a comprehensive analysis of the already defined genetic prognostic factors and are helpful tools for the identification of potential novel disease markers on the MM tumor clone. Indeed, GEP has been successfully implemented in MM as a risk-stratification tool, holding the greatest power in outcome discrimination. Nevertheless, some technical and logistic intricacies (need of a highly purified tumor clone, cost of the assay and complexity of data analysis) need to be considered before the definitive incorporation of high-throughput technologies in routine clinical tests. Until then, FISH remains the standard tool for genomic abnormality detection and disease prognostication.

Los estudios genéticos han alcanzado un papel central en el estudio del mieloma múltiple (MM), al convertirse en un componente crítico en la estratificación basada en el riesgo de la enfermedad. Se han hecho grandes esfuerzos para identificar cambios genéticos que puedan predecir el resultado clínico e incluirlos en la práctica clínica diaria. La hibridización in situ fluorescente (FISH) es todavía la técnica genética más utilizada en la práctica clínica, mayormente debido a su sencilla implementación y su simplicidad para el análisis de datos. El advenimiento de la genómica (hibridización genómica comparativa, secuenciación exónica o genómica completa) y del transcriptoma de alta resolución (perfiles de expresión de genes - GEP y secuenciación de ARNm) proveen un análisis exhaustivo de los ya definidos factores pronósticos genéticos y son herramientas útiles para la identificación de potenciales nuevos marcadores pronósticos de enfermedad en el clon tumoral de MM. Más aún, GEP ha sido exitosamente implementado en MM como una herramienta de estratificación de riesgo, siendo la de mayor poder de discriminación de resultados. De todas maneras, algunos aspectos técnicos y logísticos complejos (necesidad de una elevada purificación del clon tumoral, costo de los ensayos y complejidad en los análisis de los datos) deben ser considerados antes de la incorporación definitiva de estas tecnologías de alto rendimiento dentro de los ensayos clínicos de rutina. Hasta entonces, FISH continúa siendo la herramienta estándar para la detección de anormalidades genéticas y de valoración pronóstico de enfermedad.

The search for prognostic factors in multiple myeloma has identified the genetic profile of the tumor as the main determinant of patient survival and response to treatment. There is an association between a dismal prognosis and the presence of t(4:14) translocations or 17p deletion, determined by fluorescent in situ hybridization (FISH) or the detection of chromosome 13 deletion using conventional cytogenetic techniques. These alterations define a subpopulation that comprises 25% of patients with a bad prognosis even if they are treated with high dose chemotherapy These patients should be early derived to more specific therapies. In the other hand, the other 75% of patients without a genetic risk factor, have a higher probability of success with conventional treatment.

Nos últimos anos tem acontecido uma revolução no conhecimento dos mecanismos moleculares envolvidos na patogênese do mieloma múltiplo, principalmente devido à incorporação de técnicas de citogenética molecular (hibridização in situ fluorescente - FISH) e biologia molecular (Reação em cadeia da polimerase - PCR, hibridização genômica comparativa baseada em microarranjos - aCGH e microarranjos de RNA). Estas técnicas permitem estudar as células em interfase e detectar alterações cromossômicas crípticas, superando assim problemas metodológicos relacionados à análise por citogenética convencional. Por outro lado, a complexidade metodológica relacionada com a realização das técnicas de FISH e biologia molecular tem impossibilitado que sejam amplamente utilizadas na rotina laboratorial. Este trabalho tem como objetivo fazer uma revisão das principais vias moleculares alteradas no mieloma múltiplo, o seu valor prognóstico e a sua utilização na estratificação dos pacientes em diferentes grupos de risco. São detalhadas diferentes abordagens metodológicas e uma ênfase especial é dada em relação à importância da análise se restringir exclusivamente às células plasmocitárias. Por último, discutimos uma série de prioridades e estratégias de estudo na rotina laboratorial.

In recent years, we have seen an explosion in knowledge on genetic and cytogenetic mechanisms involved in the pathogenesis of multiple myeloma, mainly due to the incorporation of molecular tools in its study (fluorescence in situ hybridization - FISH, Real time PCR and RNA microarrays). These tools have enabled the study of cells in interphase and to detect cryptic chromosomal abnormalities, replacing cytogenetic techniques. The technical complexities associated with the performance of these tests, however, have limited their widespread applicability in routine clinical practice. The aim of this work is to review the present status of our knowledge of the pathogenetic pathways of the disease, the prognostic value of the main chromosomal abnormalities and its role in risk stratification of multiple myeloma patients. We detail technical aspects, emphasizing the importance to restrict analysis to myeloma cells. Finally, we discuss different strategies and recommendations for the adoption of routine molecular genetic testing.