Abstract
Mutations in genes that confer a selective advantage to hematopoietic stem cells (HSCs) drive clonal hematopoiesis (CH). While some CH drivers have been identified, the compendium of all ...genes able to drive CH upon mutations in HSCs remains incomplete. Exploiting signals of positive selection in blood somatic mutations may be an effective way to identify CH driver genes, analogously to cancer. Using the tumor sample in blood/tumor pairs as reference, we identify blood somatic mutations across more than 12,000 donors from two large cancer genomics cohorts. The application of IntOGen, a driver discovery pipeline, to both cohorts, and more than 24,000 targeted sequenced samples yields a list of close to 70 genes with signals of positive selection in CH, available at
http://www.intogen.org/ch
. This approach recovers known CH genes, and discovers other candidates.
Mutation rates along the genome are highly variable and influenced by several chromatin features. Here, we addressed how nucleosomes, the most pervasive chromatin structure in eukaryotes, affect the ...generation of mutations. We discovered that within nucleosomes, the somatic mutation rate across several tumor cohorts exhibits a strong 10 base pair (bp) periodicity. This periodic pattern tracks the alternation of the DNA minor groove facing toward and away from the histones. The strength and phase of the mutation rate periodicity are determined by the mutational processes active in tumors. We uncovered similar periodic patterns in the genetic variation among human and Arabidopsis populations, also detectable in their divergence from close species, indicating that the same principles underlie germline and somatic mutation rates. We propose that differential DNA damage and repair processes dependent on the minor groove orientation in nucleosome-bound DNA contribute to the 10-bp periodicity in AT/CG content in eukaryotic genomes.
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•Somatic and germline mutation rates show a 10-bp periodicity in nucleosome-occupied DNA•This periodicity tracks DNA minor groove facing toward and away from the histones•The orientation of the periodicity depends on the mutational processes active in the tissue•This has contributed to the AT/CG 10-bp periodicity in eukaryotic genomes
The pattern of exposure of the minor groove of the DNA wrapped around nucleosomes determines a periodicity of the somatic and germline mutation rate, providing broad insights into the human cancer mutational landscape and eukaryotic genome evolution.
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.
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