Publication: Estudio de splicing alternativo y variantes sin clasificar en genes de susceptibilidad al cáncer de mama y ovario: implicaciones clínicas
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2018-11-08
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Universidad Complutense de Madrid
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Abstract
Durante casi 20 años, BRCA1 y BRCA2 han sido los únicos genes que han proporcionado información útil para el asesoramiento de las familias con sospecha de padecer un síndrome hereditario de cáncer de mama y ovario (HBOC), a pesar de que los defectos germinales en estos genes no explican más de un 40% de estos síndromes. La detección de una mutación patogénica en estos dos genes ha permitido individualizar el asesoramiento genético y proponer estrategias reductoras de riesgo más agresivas, como las cirugías profilácticas. Sin embargo, no siempre el resultado de los test genéticos es de carácter informativo, sino que en muchas ocasiones nos encontramos con mutaciones de significado clínico desconocido. Estas variantes son un problema importante, ya que no se puede concluir la relevancia clínica de la variante, y por tanto resulta complicada su clasificación clínica. Hoy en día está bien establecido que los defectos genéticos en PALB2 (cáncer de mama), y RAD51C o RAD51D (cáncer de ovario), tienen una contribución significativa al exceso de riesgo familiar (aunque las estimaciones de riesgo asociadas a cada uno de estos genes son imprecisas), lo que justifica su inclusión junto a BRCA1 y BRCA2 en paneles multigénicos con finalidad diagnóstica. Por ello, esperamos que el número de variantes genéticas de significado clínicamente desconocido en estos genes aumente de forma drástica en un futuro próximo, causando un serio problema en el asesoramiento genético. En la presente tesis doctoral defendemos que la incorporación de los estudios in vitro de splicing a la rutina diagnóstica pueden aportar información importante para la clasificación clínica de variantes genéticas no sólo demostrando que ciertas variantes son patogénicas al alterar el splicing, sino también identificando variantes (en particular variantes sinónimas e intrónicas) que muy probablemente no lo sean al demostrarse que no afectan al splicing. Además, en esta tesis doctoral defendemos la relevancia clínica de estudiar potenciales alteraciones de splicing asociadas a variantes genéticas inequívocamente no patogénicas (clasificación multifactorial), como es el caso de BRCA1 c.594-2A>C (IVS9-2A>C) y BRCA2 c.687T>A (IVS2-7T>A)...
For almost 20 years, only BRCA1 and BRCA2 genes have provided useful information in the genetic counseling of families with a suspected hereditary Breast and Ovarian cancer syndrome (HBOC), allthough germ-defects in these genes do not explain more than 40% of these syndromes. The detection of a pathogenic mutation in these genes, allows the individualization of the genetic counseling and suggests more aggresive reducing-risk strategies, such as prophylactic surgeries. However, the result of the genetic test is not always informative, because often variants of unknown clinical significance are found. These variants represent an important problem, since the clinical relevance of these variants cannot be concluded; and therefore, their clinical classification is complicated. Nowadays, it is well established that genetic defects in PALB2 (Breast Cancer), and RAD51C or RAD51D (ovarian cancer), have a significant contribution to the familial risk excess (althoguh the estimation risks for each gene are imprecise), which justifies their inclusion together with BRCA1 and BRCA2 genes in a multigenic panel for diagnostic. Therefore, we expect a dramatic increase in the number of unclassified variants in these genes, causing a serious problem in the genetic counseling. In the present thesis project, we argue that the incorporation of in vitro splicing studies into the diagnostic routine may provide important information in the classification of genetic variants, not only demonstrating that certain pathogenic mutations altered the splicing, but also identifying variants (particularly synonymous and intronic variants) that probable are not pathogenic because they do not affect the splicing. Also, in this thesis we defend the clinical relevance of studying potencial splicing alterations associated with non-pathogenic variants (multifactorial classification), such as BRCA1 c.594-2A>C (IVS9-2A>C) and BRCA2 c.68-7T>A (IVS2-7T>A)...
For almost 20 years, only BRCA1 and BRCA2 genes have provided useful information in the genetic counseling of families with a suspected hereditary Breast and Ovarian cancer syndrome (HBOC), allthough germ-defects in these genes do not explain more than 40% of these syndromes. The detection of a pathogenic mutation in these genes, allows the individualization of the genetic counseling and suggests more aggresive reducing-risk strategies, such as prophylactic surgeries. However, the result of the genetic test is not always informative, because often variants of unknown clinical significance are found. These variants represent an important problem, since the clinical relevance of these variants cannot be concluded; and therefore, their clinical classification is complicated. Nowadays, it is well established that genetic defects in PALB2 (Breast Cancer), and RAD51C or RAD51D (ovarian cancer), have a significant contribution to the familial risk excess (althoguh the estimation risks for each gene are imprecise), which justifies their inclusion together with BRCA1 and BRCA2 genes in a multigenic panel for diagnostic. Therefore, we expect a dramatic increase in the number of unclassified variants in these genes, causing a serious problem in the genetic counseling. In the present thesis project, we argue that the incorporation of in vitro splicing studies into the diagnostic routine may provide important information in the classification of genetic variants, not only demonstrating that certain pathogenic mutations altered the splicing, but also identifying variants (particularly synonymous and intronic variants) that probable are not pathogenic because they do not affect the splicing. Also, in this thesis we defend the clinical relevance of studying potencial splicing alterations associated with non-pathogenic variants (multifactorial classification), such as BRCA1 c.594-2A>C (IVS9-2A>C) and BRCA2 c.68-7T>A (IVS2-7T>A)...
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Tesis de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, Departamento de Bioquímica y Biología Molecular, leída el 15/02/2018