Abstract
The massive genomic data from The Cancer Genome Atlas (TCGA), including proteomics data from Clinical Proteomic Tumor Analysis Consortium (CPTAC), provides a unique opportunity to study cancer systematically. While most observations are made from a single type of genomics data, we apply big data analytics and systems biology approaches by simultaneously analyzing DNA amplification, mRNA and protein abundance. Using multiple genomic profiles, we have discovered widespread dosage compensation for the extensive aneuploidy observed in TCGA breast cancer samples. We do identify 11 genes that show strong correlation across all features (DNA/mRNA/protein) analogous to that of the well-known oncogene HER2 (ERBB2). These genes are generally less well-characterized regarding their role in cancer and we advocate their further study. We also discover that shRNA knockdown of these genes has an impact on cancer cell growth, suggesting a vulnerability that could be used for cancer therapy. Our study shows the advantages of systematic big data methodologies and also provides future research directions.
Highlights
The scientific literature is replete with papers highlighting the complex interplay between chromosomal instability, aneuploidy, and cancer (e.g. [1] [2] [3] [4])
We identify the prevalence of dosage compensation in The Cancer Genome Atlas (TCGA) breast cancer samples (BRCA), highlight dosage-sensitive genes, and investigate the role of these genes in cancer cell line survival
The data used in this study has been downloaded from multiple resources, including TCGA [17], Clinical Proteomic Tumor Analysis Consortium (CPTAC) [18], the Catalogue of Somatic Mutations in Cancer (COSMIC) [19], and Achilles short hairpin RNA or small hairpin RNA [20]
Summary
The scientific literature is replete with papers highlighting the complex interplay between chromosomal instability, aneuploidy, and cancer (e.g. [1] [2] [3] [4]). The scientific literature is replete with papers highlighting the complex interplay between chromosomal instability, aneuploidy, and cancer Aneuploidy, the state of having other than the canonical or “euploid” number of chromosomes—for humans, 46—is with only rare exceptions (Downs syndrome, Trisomy 18) lethal in human embryonic development [5]. Aneuploidy is observed with very high frequency in cancer, leading the eminent German biologist Theodor Boveri to speculate as early as 1902 [6] that aneuploidy might have a causative role in the disease. Is aneuploidy a cause or a side-effect of cancer? If the former, what factors associated with aneuploidy contribute to cancer cell fitness? Are there deleterious impacts of aneuploidy in cancer and how are they mitigated during tumorigenesis? What is the broader impact of aneuploidy on gene expression and resulting phenotypes?. Is aneuploidy a cause or a side-effect of cancer? If the former, what factors associated with aneuploidy contribute to cancer cell fitness? Are there deleterious impacts of aneuploidy in cancer and how are they mitigated during tumorigenesis? More generally, what is the broader impact of aneuploidy on gene expression and resulting phenotypes?
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