Functions of about 10% of all the proteins and their associations with diseases are poorly annotated or not annotated at all. Among these proteins, there is a group of uncharacterized chromosome-specific open-reading frame genes (CxORFx) from the ‘Tdark’ category. The aim of the work was to reveal associations of CxORFx gene expression and ORF proteins’ subinteractomes with cancer-driven cellular processes and molecular pathways. We performed systems biology and bioinformatic analysis of 219 differentially expressed CxORFx genes in cancers, an estimation of prognostic significance of novel transcriptomic signatures and analysis of subinteractome composition using several web servers (GEPIA2, KMplotter, ROC-plotter, TIMER, cBioPortal, DepMap, EnrichR, PepPSy, cProSite, WebGestalt, CancerGeneNet, PathwAX II and FunCoup). The subinteractome of each ORF protein was revealed using ten different data sources on physical protein–protein interactions (PPIs) to obtain representative datasets for the exploration of possible cellular functions of ORF proteins through a spectrum of neighboring annotated protein partners. A total of 42 out of 219 presumably cancer-associated ORF proteins and 30 cancer-dependent binary PPIs were found. Additionally, a bibliometric analysis of 204 publications allowed us to retrieve biomedical terms related to ORF genes. In spite of recent progress in functional studies of ORF genes, the current investigations aim at finding out the prognostic value of CxORFx expression patterns in cancers. The results obtained expand the understanding of the possible functions of the poorly annotated CxORFx in the cancer context.