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MUTACIONES DEL GEN <I>NOTCH1</I> EN LA LEUCEMIA LINFOCITICA CRONICA

MUTACIONES DEL GEN NOTCH1 EN LA LEUCEMIA LINFOCITICA CRONICA

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La leucemia linfocítica crónica es la leucemia más frecuente en adultos de Occidente. Presenta un curso clínico altamente variable, con pacientes que requieren tratamiento inmediato y otros con un curso indolente de la enfermedad. Nuestro objetivo fue evaluar mutaciones de NOTCH1 en nuestros pacientes mediante ASO-PCR y secuenciación.
Autor:
Camila Galvano
Columnista Experta de SIIC

Institución:
Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina


Artículos publicados por Camila Galvano
Coautores
Patricia Dos Santos* Carmen Stanganelli** Irma Slavutsky*** 
Licenciada en Genética, Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina, CABA, Argentina*
Bioquímica, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, CABA, Argentina**
Médica, Instituto de Medicina Experimental, CONICET-Academia Nacional de Medicina, CABA, Argentina***
Recepción del artículo
3 de Junio, 2019
Aprobación
3 de Junio, 2019
Primera edición
29 de Julio, 2019
Segunda edición, ampliada y corregida
7 de Junio, 2021

Resumen
La leucemia linfocítica crónica (LLC) es la leucemia más frecuente en adultos de Occidente. Presenta un curso clínico altamente variable, con pacientes que requieren tratamiento inmediato y otros con un curso indolente de la enfermedad. Los estudios genéticos constituyen herramientas de suma utilidad en esta enfermedad, encontrándose incorporados a las clasificaciones de riesgo internacionales. El análisis de los rearreglos genómicos y del estado mutacional de los genes IGHV (immunoglobulin heavy chain variable region) ha hecho factible establecer grupos de riesgo de alto valor pronóstico. Más recientemente, estudios de secuenciación de última generación permitieron la detección de mutaciones somáticas previamente desconocidas en esta afección, que podrían explicar la amplia variabilidad clínica observada en la LLC. Entre ellas, resultan de interés las observadas en el gen NOTCH1 (neurogenic locus notch homolog protein 1), cuya desregulación se asocia con el desarrollo tumoral. Estas mutaciones se acumulan en mayor medida en el exón 34 (80% de los casos) y en la región 3´UTR (untraslated region), lo que genera codones de terminación prematuros que originan una proteína NOTCH1 constitutivamente activa y más estable, los cuales se asocian con pronóstico adverso y refractariedad al tratamiento. Nuestro objetivo fue evaluar mutaciones de NOTCH1 en nuestros pacientes mediante ASO-PCR y secuenciación. Se detectaron mutaciones en el 4.4% de los casos, valor concordante con los datos internacionales (5% a 10%). Su inclusión en la caracterización genética de los pacientes con LLC permitirá refinar la categorización de los grupos de riesgo, aspecto de suma importancia tanto en el seguimiento clínico como en la toma de decisiones terapéuticas.

Palabras clave
gen NOTCH1, mutaciones, leucemia linfocítica crónica, citogenética, FISH, IgH


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Abstract
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. The disease has a highly variable clinical course, ranging from very indolent cases to patients with aggressive and rapidly progressing outcome. Genetic studies are useful tools in analyzing this pathology, and have been incorporated in international risk classifications. The analysis of genomic rearrangements and the mutational status of immunoglobulin heavy chain variable have allowed risk groups of high prognostic value to be established. More recently, next generation sequencing studies have identified novel somatic mutations that could explain the wide clinical variability of this pathology. Among them, the analysis of NOTCH1 (neurogenic locus notch homolog protein 1) gene mutations are of interest, as deregulation is associated with tumorigenesis.
NOTCH1 mutations are mostly located at exon 34 (80% of cases) and 3´UTR (untranslated region). They produce premature stop codons that produce a constitutively active and stable NOTCH1 protein. NOTCH1 mutations are associated with adverse prognosis and refractoriness to treatment. The aim of this study was to analyze NOTCH1 mutations in CLL patients by ASO-PCR and sequencing. Our results found 4.4% of cases with NOTCH1 mutated values concordant with international observations (5%-10%). Including them in the genetic status of CLL patients allows the characterization of risk groups, an aspect of great importance in clinical practice and therapeutic decisions, to be refined.

Key words
NOTCH1 gene, mutations, chronic lymphocytic leukemia, cytogenetics, FISH, IgH


Clasificación en siicsalud
Artículos originales > Expertos de Iberoamérica >
página   www.siicsalud.com/des/expertocompleto.php/

Especialidades
Principal: Genética Humana, Hematología
Relacionadas: Diagnóstico por Laboratorio, Oncología



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Enviar correspondencia a:
Irma Slavutsky, 1425, Pacheco de Melo 3081, CABA, Argentina
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