Development of Integrative Mutational Signatures Analysis Platform and Database for Cancer Research

Cancer is a genetic disease caused by somatic mutations. However, understanding the causative biological processes of these mutations is limited. Researchers from the Wellcome Trust Sanger Institute (WTSI) have analyzed somatic mutation spectra from over 7,000 cancers and revealed more than 20 distinct signatures using the algorithm of WTSI Mutational Signature Framework, providing a better understanding of cancer biology by linking signatures to endogenous processes such as the enzymatic activity of DNA cytidine deaminases (APOBECs), the deficiency of DNA mismatch repair, or mutations in POLE and to exogenous mutagens like tobacco, ultraviolet light and toxic chemicals. Thus, deciphering known and novel signatures in human cancer is a new trend in the community of cancer research. Due to the ubiquitous nature of many signatures found across cancer types, researchers are interested in interrogating the presence and prevalence in their tumor samples. The Cancer Genomics Cloud (CGC) is one of the three pilot projects funded by the National Cancer Institute (NCI), which has established new approaches for researchers to access the massive TCGA alongside the tools and sufficient computational resources to analyze them, making large-scale cancer genomics studies not limited to research centers or institutes. Users can add their own data to analyze alongside TCGA using predefined workflows or their own tools. Over 1,500 researchers from across the globe are currently using the CGC to explore and analyze TCGA. Accordingly, we plan to transfer our developed tools to the CGC environment to ensure a reproducible, portable and scalable analysis, making mutational signature analyses more accessible to general researchers and speeding up research in this area.The present 4 years proposal aims to establish an integrative analysis platform for identifying NOVEL mutational signatures as well as associating new mechanism to signature with unknown etiology. The proposed project aimed to:1. Establish cloud-based analysis platform for deciphering NOVEL mutational signatures of mutational processes from whole-exome and whole-genome sequencing data.2. Identify NOVEL mutational signatures in 73 TCGA/ICGC cancer projects from 50 cancer types and construct the most comprehensive de novo mutational signature database across the globe.3. Establish high throughput pipeline to validate somatic genetic mutations associated with distinct mutation signatures in shotgun proteomics.4. Identify pan-cancer and patient-specific tumor neo-antigens as a basis for precision medicine.5. Construct pan-cancer and patient-specific tumor neo-antigens database.The goal of this proposal is to develop an integrative analysis platform to provide comprehensive insights into the common biological processes underlying the development of cancers, to connect tumor-derived genomic and proteomic measurements from a central-dogma perspective, to identify new diagnostic markers, and to better understanding of cancer biology.

Project ID:PC10708-0856
External Project ID:MOST107-2314-B182-062