A compendium of mutational cancer driver genes

A fundamental goal in cancer research is to understand the mechanisms of cell transformation. This is key to developing more efficient cancer detection methods and therapeutic approaches. One milestone towards this objective is the identification of all the genes with mutations capable of driving tumours. Since the 1970s, the list of cancer genes has been growing steadily. Because cancer driver genes are under positive selection in tumorigenesis, their observed patterns of somatic mutations across tumours in a cohort deviate from those expected from neutral mutagenesis. These deviations, which constitute signals of positive selection, may be detected by carefully designed bioinformatics methods, which have become the state of the art in the identification of driver genes. A systematic approach combining several of these signals could lead to a compendium of mutational cancer genes. In this Review, we present the Integrative OncoGenomics (IntOGen) pipeline, an implementation of such an approach to obtain the compendium of mutational cancer drivers. Its application to somatic mutations of more than 28,000 tumours of 66 cancer types reveals 568 cancer genes and points towards their mechanisms of tumorigenesis. The application of this approach to the ever-growing datasets of somatic tumour mutations will support the continuous refinement of our knowledge of the genetic basis of cancer

Computational studies of DNA damage and repair of alkylating agents and UV light

Living cells are exposed to naturally occurring DNA-damaging agents that promote the loss of genome integrity, threatening the proper functioning of the cell. To counteract the toxic accumulation of DNA damage, organisms have acquired mechanisms of DNA repair, comprising multiple pathways charged with correcting the different types of damage a genome can accumulate. The aim of this thesis is the study of DNA damage caused by alkylating agents and UV light and their repair. First, we describe the first nucleotide-resolution alkylating damage maps in humans. Second, we present a novel approach to partition the genome by UV DNA damage repair activity aimed at studying the determinants of the UV mutagenic process that is unbiased by genomic features. Both projects contribute to expanding our knowledge of how different parts of DNA damage response interact with chromatin architecture and basic cell processes, like DNA replication or transcription.Les cèl·lules estan exposades a agents naturals que danyen l’ADN, posant en risc el seu funcionament. Per tal de contrarestar la toxicitat del dany genòmic, els éssers vius han adquirit mecanismes de reparació de l’ADN dedicats a corregir els diferents tipus de dany. L’objectiu d’aquesta tesi és estudiar l’acumulació i reparació del dany genòmic causat pels agents alquilants i la radiació ultraviolada. Primer, descrivim els primers mapes de dany genòmic induït per agents alquilants en humans. A continuació, presentem una nova aproximació per a dividir el genoma en base a la reparació del dany genòmic causat per la radiació ultraviolada amb l’objectiu d’estudiar, de manera no esbiaixada, els determinants mutacionals associats. Tots dos estudis contribueixen a ampliar el coneixement de com l’acumulació de dany genòmic i la seva reparació s’associen amb les característiques de la cromatina i altres processos cel·lulars com la replicació de l’ADN o la transcripció.Programa de Doctorat en Biomedicin

Mapping chromatin accessibility and active regulatory elements reveals pathological mechanisms in human gliomas

Chromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We perform whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we create an atlas of active enhancers and promoters in benign and malignant gliomas. We explore these elements and intersect with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas. Gliomas are tumors often associated with epigenetics-related gene deregulation. Here the authors reveal an atlas of active enhancers and promoters in benign and malignant gliomas by performing whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples