Open reading frames associated with cancer in the dark matter of the human genome.

BACKGROUND: The uncharacterized proteins (open reading frames, ORFs) in the human genome offer an opportunity to discover novel targets for cancer. A systematic analysis of the dark matter of the human proteome for druggability and biomarker discovery is crucial to mining the genome. Numerous data mining tools are available to mine these ORFs to develop a comprehensive knowledge base for future target discovery and validation. MATERIALS AND METHODS: Using the Genetic Association Database, the ORFs of the human dark matter proteome were screened for evidence of association with neoplasms. The Phenome-Genome Integrator tool was used to establish phenotypic association with disease traits including cancer. Batch analysis of the tools for protein expression analysis, gene ontology and motifs and domains was used to characterize the ORFs. RESULTS: Sixty-two ORFs were identified for neoplasm association. The expression Quantitative Trait Loci (eQTL) analysis identified thirteen ORFs related to cancer traits. Protein expression, motifs and domain analysis and genome-wide association studies verified the relevance of these OncoORFs in diverse tumors. The OncoORFs are also associated with a wide variety of human diseases and disorders. CONCLUSIONS: Our results link the OncoORFs to diverse diseases and disorders. This suggests a complex landscape of the uncharacterized proteome in human diseases. These results open the dark matter of the proteome to novel cancer target research.

A novel transmembrane glycoprotein cancer biomarker present in the X chromosome.

BACKGROUND: The uncharacterized proteins of the human proteome offer an untapped potential for cancer biomarker discovery. Numerous predicted open reading frames (ORFs) are present in diverse chromosomes. The mRNA and protein expression data, as well as the mutational and variant information for these ORF proteins are available in the cancer-related bioinformatics databases. MATERIALS AND METHODS: ORF proteins were mined using bioinformatics and proteomic tools to predict motifs and domains, and cancer relevance was established using cancer genome, transcriptome and proteome analysis tools. RESULTS: A novel testis-restricted ORF protein present in chromosome X called CXorf66 was detected in the serum, plasma and neutrophils. This gene is termed secreted glycoprotein in chromosome X (SGPX). The SGPX gene is up-regulated in cancer of the brain, lung and in leukemia, and down-regulated in liver and prostate cancer. Brain cancer in female patients exhibited elevated copy numbers of the SGPX gene. CONCLUSION: The SGPX gene is a putative novel cancer biomarker. Our results demonstrate the feasibility of mining the 'dark matter' of the cancer proteome for rapid cancer biomarker discovery.