Lineage specific genomics of chromatin modifiers

Massively parallel sequencing offers the possibility to completely characterize genomic alterations in cancer genomes in a relative short period of time. Large-scale genome sequencing efforts such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) are aiming to provide comprehensive molecular portrait of cancer genomes across many tumor types. Data that have been generated by these projects already show a striking pattern of genomic alterations in chromatin modifiers. Apparently, these mutational patterns are showing a pronounced lineage-specificity. Within this subproject, we will perform an integrated analysis to decipher lineage-specific targets of mutations in chromatin modifiers. To this end, we restrict our analysis to up- and downstream targets of chromatin modifiers by excessively making use of prior-information provided by orthogonal data sources. We envision that by restricting our analysis to a curated list of target candidates results in an increased the statistical power to find biologically relevant associations between mutations in chromatin modifiers and their possible contribution to the tumorigenesis across the different lineages. In addition, several small-molecule inhibitors targeting chromatin modifiers have been proposed lately (e.g. histone acetyltransferase inhibitors); the proposed approach may therefore help to better stratify cancer patients eligible to benefit form these inhibitors therapeutically. Within this subproject, we will proceed with the following the three major aims:

  • Aim 1: Extending our cancer genome analysis pipeline a to multi-sample approach.
  • Aim 2: Classification of tumors according to their alterations in chromatin modifiers.
  • Aim 3: Deciphering lineage-specific targets of alterations in chromatin modifiers by integrative analysis.

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