Synonymous mutations promote tumorigenesis by disrupting mA-dependent mRNA metabolism.

Cancer cells acquire numerous mutations during tumorigenesis, including synonymous mutations that do not change the amino acid sequence of a protein. RNA N6-methyladenosine (mA) is a post-transcriptional modification that plays critical roles in oncogenesis. Herein, we identified 12,849 mutations in the cancer genome with the potential to perturb mA modification patterns, which we refer to as "mA disruption mutations (mA-DMs)." These are either synonymous mA-DMs (smA-DMs) or missense mA-DMs (mmA-DMs) mutations, and the former is enriched within tumor suppressor genes, such as CDKN2A and BRCA2. Using epitranscriptomic editing, we demonstrate that manipulating mA levels at specific smA-DM sites influences mRNA stability. Furthermore, introducing CDKN2A smA-DMs into cancer cells promotes tumor growth while BRCA2 smA-DMs sensitize tumors to the poly (ADP-ribose) polymerase inhibitor (PARPi) treatment. Our findings demonstrate smA-DMs as potential oncogenic drivers, unveiling implications for synonymous mutations in tumorigenesis and beyond.