ABSTRACT
Cancer cells harbor molecular alterations at all levels of information processing. Genomic/epigenomic and transcriptomic alterations are inter-related between genes, within and across cancer types and may affect clinical phenotypes. Despite the abundant prior studies of integrating cancer multi-omics data, none of them organizes these associations in a hierarchical structure and validates the discoveries in extensive external data. We infer this Integrated Hierarchical Association Structure (IHAS) from the complete data of The Cancer Genome Atlas (TCGA) and compile a compendium of cancer multi-omics associations. Intriguingly, diverse alterations on genomes/epigenomes from multiple cancer types impact transcriptions of 18 Gene Groups. Half of them are further reduced to three Meta Gene Groups enriched with (1) immune and inflammatory responses, (2) embryonic development and neurogenesis, (3) cell cycle process and DNA repair. Over 80% of the clinical/molecular phenotypes reported in TCGA are aligned with the combinatorial expressions of Meta Gene Groups, Gene Groups, and other IHAS subunits. Furthermore, IHAS derived from TCGA is validated in more than 300 external datasets including multi-omics measurements and cellular responses upon drug treatments and gene perturbations in tumors, cancer cell lines, and normal tissues. To sum up, IHAS stratifies patients in terms of molecular signatures of its subunits, selects targeted genes or drugs for precision cancer therapy, and demonstrates that associations between survival times and transcriptional biomarkers may vary with cancer types. These rich information is critical for diagnosis and treatments of cancers.
ABSTRACT
Principal Component Analysis (PCA) projects high-dimensional genotype data into a few components that discern populations. Ancestry Informative Markers (AIMs) are a small subset of SNPs capable of distinguishing populations. We integrate these two approaches by proposing an algorithm to identify necessary informative loci whose removal from the data deteriorates the PCA structure. Unlike classical AIMs, necessary informative loci densely cover the genome, hence can illuminate the evolution and mixing history of populations. We conduct a comprehensive analysis to the genotype data of the 1000 Genomes Project using necessary informative loci. Projections along the top seven principal components demarcate populations at distinct geographic levels. Millions of necessary informative loci along each PC are identified. Population identities along each PC are approximately determined by weighted sums of minor (or major) alleles over the informative loci. Variations of allele frequencies are aligned with the history and direction of population evolution. The population distribution of projections along the top three PCs is recapitulated by a simple demographic model based on several waves of founder population separation and mixing. Informative loci possess locational concentration in the genome and functional enrichment. Genes at two hot spots encompassing dense PC 7 informative loci exhibit differential expressions among European populations. The mosaic of local ancestry in the genome of a mixed descendant from multiple populations can be inferred from partial PCA projections of informative loci. Finally, informative loci derived from the 1000 Genomes data well predict the projections of an independent genotype data of South Asians. These results demonstrate the utility and relevance of informative loci to investigate human evolution.
