Publication: Determinación de las mutaciones "BRAF" en melanomas primarios y metastásicos
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2017-09-18
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Universidad Complutense de Madrid
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Abstract
El melanoma es un cáncer cuya incidencia se ha incrementado en los últimos años, con una respuesta clínica decepcionante a los tratamientos convencionales con dacarbazina, interferón alfa-‐2b e interleucina-‐2, por lo que su supervivencia global no se ha modificado en absoluto. El desarrollo de nuevas técnicas de biología molecular y análisis genómicos, ha permitido la identificación de mutaciones y otras alteraciones genéticas y epigenéticas implicadas en el inicio y en la progresión del melanoma. El principal oncogén relacionado con la iniciación del melanoma es el v-‐raf sarcoma murino viral B1 homólogo (BRAF). La mutación puntual en el gen BRAF (predominantemente la V600E, donde la valina es sustituida por ácido glutámico en el aminoácido 600) se detecta en 40-‐60% de los pacientes con melanoma. Esta mutación es responsable de la activación constitutiva de la vía de la proteína quinasa activadora de mitógenos (MAPK) y la consecuente inducción de programas de proliferación y supervivencia celulares. La aparición de los inhibidores de BRAFV600E ha generado un importante avance en el manejo de esta enfermedad. La justificación del uso de inhibidores selectivos contra estas proteínas oncogénicas, como BRAFV600E, depende de que los tumores sean clonales con respecto al oncogén mutado (homogeneidad intratumoral) y que la mutación se mantenga en las metástasis originadas (homogeneidad intertumoral). Sin embargo, en la práctica clínica se ha detectado un alto porcentaje de recidiva tras el tratamiento. Por tanto, la identificación de nuevos mecanismos de resistencia tumoral es una cuestión que sigue sin respuesta, y la existencia de heterogeneidad de la mutación BRAFV600E en melanomas cutáneos, podría suponer un importante mecanismo de resistencia tumoral a los nuevos inhibidores de BRAFV600E...
Melanoma is a cancer whose incidence has increased in the last years, with a disappointing clinical response to conventional treatments (dacarbazine, interferon alfa-‐2b and interleukin-‐2). The development of new molecular and genomic analysis techniques has allowed the identification of mutations and other genetic and epigenetic alterations involved in the initiation and progression of melanoma. The main oncogene associated with the initiation of melanoma is the v-‐raf murine sarcoma viral oncogene homolog B1 (BRAF). A point mutation in the BRAF gene (predominantly the V600E, in which valine is substituted for glutamic acid at amino acid 600) is detected in 40-‐60% of patients with melanoma. This mutation is responsible for constitutive activation of the protein mitogen activating kinase (MAPK) protein and the consequent induction of cell proliferation programs and survival. The appearance of BRAFV600E inhibitors has generated a significant advance in the management of this disease. The justification for the use of selective inhibitors against these oncogenic proteins, such as BRAFV600E depends on whether tumors are clonal with respect to the mutated oncogene (intratumoral homogeneity) and whether the mutation is maintained in originating metastases (intertumoral homogeneity). However, in clinical practice a high rate of recurrence after treatment has been detected. Thus, the identification of new mechanisms of tumor resistance is a question that remains unanswered. The existence of heterogeneity in BRAFV600E mutation in cutaneous melanomas, could be a major mechanism of tumor resistance to new BRAFV600E inhibitors...
Melanoma is a cancer whose incidence has increased in the last years, with a disappointing clinical response to conventional treatments (dacarbazine, interferon alfa-‐2b and interleukin-‐2). The development of new molecular and genomic analysis techniques has allowed the identification of mutations and other genetic and epigenetic alterations involved in the initiation and progression of melanoma. The main oncogene associated with the initiation of melanoma is the v-‐raf murine sarcoma viral oncogene homolog B1 (BRAF). A point mutation in the BRAF gene (predominantly the V600E, in which valine is substituted for glutamic acid at amino acid 600) is detected in 40-‐60% of patients with melanoma. This mutation is responsible for constitutive activation of the protein mitogen activating kinase (MAPK) protein and the consequent induction of cell proliferation programs and survival. The appearance of BRAFV600E inhibitors has generated a significant advance in the management of this disease. The justification for the use of selective inhibitors against these oncogenic proteins, such as BRAFV600E depends on whether tumors are clonal with respect to the mutated oncogene (intratumoral homogeneity) and whether the mutation is maintained in originating metastases (intertumoral homogeneity). However, in clinical practice a high rate of recurrence after treatment has been detected. Thus, the identification of new mechanisms of tumor resistance is a question that remains unanswered. The existence of heterogeneity in BRAFV600E mutation in cutaneous melanomas, could be a major mechanism of tumor resistance to new BRAFV600E inhibitors...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Anatomía Patológica, leída el 05-04-2016