Co-expression Patterns Explain how a Basic Transcriptional Role for MYC Modulates Wnt and MAPK Pathways in Colon and Lung Adenocarcinomas

Genome duplication begins at many epigenetically determined sites by pre-replication, pre-initiation, and replisome complexes; co-expression of their components must be optimally timed for S phase to occur. Oscillations of cyclin dependent kinases (Cdks) and regulator cyclins control cell cycling, many are pharmacological targets in cancer. This study examines gene expression relationships between drivers, cell cycle components, and a subset of proliferation genes in colon (COAD) and lung (LUAD) adenocarcinomas. Several known drivers of COAD and LUAD including APC, CTNNB1, KRAS, MYC, Braf, TP53, Rb1, and EGFR are also observed with focus on Wnt and MAPK signaling activation. Wnt signaling activation has relevance for immune checkpoint inhibitor therapy, as it provides cancer cells with escape mechanisms. MYC and KRAS co-expressed directly with far fewer proliferation genes in LUAD than COAD, suggesting their expression is ectopic to S phase in lung tumors. APC indirectly co-expressed with the same factors in both COAD and LUAD, but was found co-expressed indirectly with MYC and mutated only in COAD. Other Wnt signaling components also co-expressed in low MYC context in COAD, had significantly higher mutation frequencies. These data suggest Wnt signaling activation to be the indirect result of decreased MYC availability in COAD, and ectopic overexpression of MYC in LUAD. Cyclins CCNH, CCNC, and CCNK, co-expressed with far fewer proliferation genes in LUAD. Conversely, Braf had direct co-expression with many proliferation factors in non EGFR activated LUAD. Proliferation in EGFR activated LUAD was completely deregulated with E2F(s) 4/5/6 expression, potentially explaining their low proliferative ability.