Descripción del proyecto
Nuevos genes de predisposición en el cáncer de mama hereditario
El cáncer de mama hereditario (FBC, por sus siglas en inglés) está relacionado con genes de cáncer de mama heredados genéticamente como BRCA1 y BRCA2. Con todo, se desconoce la predisposición genética de más del 60 % de los casos de FBC. El objetivo del proyecto financiado con fondos europeos FBC predisposition es identificar nuevas variantes genéticas en el FBC y utilizarlas para la evaluación y la supervisión de los pacientes. Un análisis de alto rendimiento en pacientes con inicio temprano de la enfermedad ha identificado 270 genes relacionados posiblemente con el cáncer de mama. La dilucidación de la función molecular de estos genes candidatos puede servir de base para la estratificación de los pacientes según el riesgo de FBC y para el desarrollo de intervenciones específicas.
Objetivo
Breast cancer is the most common cancer in women worldwide. Familial breast cancer (FBC) is expected to account for up to 15% of breast cancers. Although recent breakthroughs have resulted in the identification of distinct new groups of genetically inherent breast cancer genes, about 64% of the genetic predisposition to FBC remains unexplained. Therefore, new approaches are required to identify remaining genetic factors underlying FBC susceptibility. This is crucial because the elucidation of inherent cancer defects offers the ability to counsel and monitor patients. Importantly, it also provides firm ground for therapeutically targeting particular cancer pathways for example through Poly ADP-ribose polymerase inhibitors (PARPi) that exploit synthetic lethality with particular DNA repair deficiencies.
To advance the field, my host lab has performed High-Throughput phenotypic screen, based on gene variants recognized in a FBC cohort of 135 early-onset (age <35 years) breast cancer patients through whole exome sequencing. The 270 new genes with potential disease association were enrolled in screens, focusing on genome maintenance and PARPi sensitivity. These unique preliminary data form the basis for my project. I hypothesize that by performing following specific analyses I will be able to elucidate new FBC predisposition genes:
•Ranking of screen hits by performing FBC-associated variant analysis in an international and Danish FBC cohort.
•Elucidating molecular function of novel FBC predisposition genes in genome maintenance.
•Unraveling the molecular network of candidate proteins by unbiased Mass-spectrometry as well as follow-up analysis of interactors.
I anticipate that my work will provide novel FBC predisposition genes, which will markedly contribute to clinical risk assessment tools (such as targeted sequencing) by ensuring identification of individuals at elevated risk who benefit from advances in surveillance and targeted interventions.
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
1165 Kobenhavn
Dinamarca