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Descubren un nuevo síndrome genético que predispone al cáncer

Fuente: UAB | Publicado: 09-10-2017
Una investigación liderada por Jordi Surrallés, ha identificado un nuevo síndrome genético causado por mutaciones en ambas copias del gen FANCM. Los resultados, publicados en Genetics in Medicine, sugieren que estas mutaciones predisponen a la aparición precoz de tumores y a la toxicidad de la quimioterapia.
Derechos: istockphoto/PanuRuangjan
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Una investigación liderada por Jordi Surrallés, Catedrático del Departamento de Genética y Microbiología de la UAB, Director del Servicio de Genética del Hospital de la Santa Creu i Sant Pau y jefe de grupo del Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), ha identificado un nuevo síndrome genético causado por mutaciones en ambas copias del gen FANCM –las denominadas mutaciones bialélicas-. Los resultados, publicados en Genetics in Medicine la revista oficial del American College of Medical Genetics, del grupo Nature, sugieren que estas mutaciones predisponen a la aparición precoz de tumores y a la toxicidad de la quimioterapia.

En el artículo, cuyo primer firmante es el investigador Massimo Bogliolo, contratado del CIBERER en el grupo de investigación liderado por el doctor Surrallés, se han analizado mutaciones bialélicas en FANCM en tres individuos.



Aunque el número de pacientes en este tipo de estudios es siempre bajo, al tratarse de enfermedades raras, se ha observado que desarrollaron cáncer de aparición precoz y toxicidad a la quimioterapia pero no presentaban ninguna malformación congénita o fenotipo hematológico que pudiera sugerir que estaban afectados por la anemia de Fanconi, enfermedad rara que afecta a uno de cada 100.000 niños. Hasta el momento se pensaba que el gen FANCM estaba relacionado con esta enfermedad, ya que en 2005 se observó la mutación bialélica en un paciente de anemia de Fanconi.


En otro artículo publicado en el mismo volumen de la revista, en el que han participado investigadores del grupo del doctor Surrallés y del grupo de investigación que lidera Javier Benítez en el CNIO y el CIBERER, se ha confirmado que mujeres con mutaciones bialélicas en el gen FANCM tampoco desarrollan anemia de Fanconi, pero sí que presentan un mayor riesgo de cáncer de mama, toxicidad a la quimioterapia y fragilidad cromosómica. Este último artículo ha sido coordinado por Paolo Peterlongo, del Instituto de Oncología Molecular de Milán (Italia) y participan varios hospitales y centros de investigación de Italia, Alemania, España y Suecia.

“Hasta ahora se pensaba que las mutaciones bialélicas en el gen FANCM causaban anemia de Fanconi, pero hemos demostrado que no es así, ya que entre los dos trabajos reportamos 8 pacientes con estas mutaciones y ninguno de ellos tiene anemia”, afirma Jordi Surrallés. Los pacientes, sin embargo, presentaban cáncer a edades muy tempranas y toxicidad a la quimioterapia. Por ello, ante el nuevo síndrome los autores recomiendan modificar el seguimiento clínico de los pacientes con mutaciones bialélicas enFANCM y tomar precauciones a la hora de utilizar quimioterapia y tratamientos de radiación por la toxicidad aguda que les pueden provocar.

Estudio genético de complementación

Para el trabajo, los investigadores han llevado a cabo estudios funcionales de complementación, un tipo de análisis muy importante en proyectos de secuenciación masiva en los que hay diversos genes con mutaciones y no está claro cuáles son las causantes de la enfermedad. Las células del paciente tienen un fenotipo claro de hipersensibilidad química al DEB, un agente que daña el ADN (las células del paciente no sobreviven bien a dosis altas de DEB). En cambio, cuando se transfiere una copia sana del gen FANCM dentro de las células del paciente con la ayuda de un virus (mediante transducción lentiviral) se observa cómo se revierte este fenotipo y las células se comportan como si fueran sanas (respuesta similar a las derivadas de un donante sano). Este estudio funcional es la demostración genética de que el gen causante de la enfermedad es FANCM y, por tanto, las mutaciones observadas en este gen son patogénicas.


Artículos de referencia: Massimo Bogliolo, Dominique Bluteau, James Lespinasse, Roser Pujol, Nadia Vasquez, Catherine Dubois d'Enghien, Dominique Stoppa-Lyonnet, Thierry Leblanc, Jean Soulier & Jordi Surrallés. Biallelic truncating FANCM mutations cause early-onset cancer but not Fanconi anemia. Genetics in Medicine. doi: 10.1038/gim.2017.124 http://www.nature.com/doifinder/10.1038/gim.2017.124

Irene Catucci et al. Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility. Genetics in Medicine. doi: 10.1038/gim.2017.123 http://www.nature.com/doifinder/10.1038/gim.2017.123
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