Synonymous mutations promote tumorigenesis by disrupting m⁶A-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 (m⁶A) 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 m⁶A modification patterns, which we refer to as "m⁶A disruption mutations (m⁶A-DMs)." These are either synonymous m⁶A-DMs (sm⁶A-DMs) or missense m⁶A-DMs (mm⁶A-DMs) mutations, and the former is enriched within tumor suppressor genes, such as CDKN2A and BRCA2. Using epitranscriptomic editing, we demonstrate that manipulating m⁶A levels at specific sm⁶A-DM sites influences mRNA stability. Furthermore, introducing CDKN2A sm⁶A-DMs into cancer cells promotes tumor growth while BRCA2 sm⁶A-DMs sensitize tumors to the poly (ADP-ribose) polymerase inhibitor (PARPi) treatment. Our findings demonstrate sm⁶A-DMs as potential oncogenic drivers, unveiling implications for synonymous mutations in tumorigenesis and beyond.