Intra-tumour heterogeneity is a major cause of treatment failure and high mortality in cancer patients. This heterogeneity is genetic and transcriptional, and the identification and characterisation of the different tumour subclones is essential for understanding the evolution of cancer, and for the development of better and personalised treatments. In clinical and phylogenetic studies, somatic mutations are usually only screened in DNA. In a previous study of ours, on the allele expression of mutations of the PIK3CA gene, we found that the allele expression ratios of mutants vs the wild-type allele correlated with clinical features of breast tumours. Additionally, it was found that the coexistence of mutations in certain genes may be dependent on the preferred expression of the mutated allele compared to the wild-type. Thus, we hypothesise that it is clinically/evolutionarily relevant if somatic mutations are expressed at the level of RNA and/or protein, and how much they are expressed. Recently, an entire genome study on five different types of cancer, including breast cancer, confirmed that the allelic imbalance of somatic mutations was a widespread feature in cancer. Our goal with this project is to unveil the contribution of the allelic imbalance in the expression of somatic mutations (mutAI), in the intra-tumour heterogeneity and the clinical implications. To achieve this, we will integrate two current concepts in the field of cancer: allelic expression imbalance and evolutionary intra-tumour analysis. We therefore propose the following specific goals: 1. Reveal the extent to which mutAI contributes to determining the co-occurrence of mutations in breast tumours, as well as their clinical characteristics. Here, we will apply dimension reduction techniques to the existing SEQ and RNA-seq data from the METABRIC and TCGA projects (http://cancergenome.nih.gov/), to test for the existence of specific combinatorial mutational signatures, defined by levels of expression mutant allele. We will also test the clinical relevance of mutational signatures within breast tumours. 2. Reveal the contribution of mutAI to tumour clonal evolution, through the integration of allele expression data in phylogenetic reconstruction and in the quantification of breast tumour heterogeneity. To this end, we will analyse DNA-seq and RNA-seq data from multiple regions of breast tumours, and metastases, when available.
Universidade do Algarve
How satisfied are you with the experience of using the new ualg.pt?