Loss of m1acp3Ψ Ribosomal RNA Modification Is a Major Feature of Cancer

The ribosome is an RNA-protein complex that is essential for translation in all domains of life. The structural and catalytic core of the ribosome is its ribosomal RNA (rRNA). While mutations in ribosomal protein (RP) genes are known drivers of oncogenesis, oncogenic rRNA variants have remained elusive. We identify a cancer-specific single-nucleotide variation in 18S rRNA at nucleotide 1248.U in up to 45.9% of patients with colorectal carcinoma (CRC) and present across >22 cancer types. This is the site of a unique hyper-modified base, 1-methyl-3-α-amino-α-carboxyl-propyl pseudouridine (m¹acp³Ψ), a >1-billion-years-conserved RNA modification at the peptidyl decoding site of the ribosome. A subset of CRC tumors we call hypo-m¹acp³Ψ shows sub-stoichiometric m¹acp³Ψ modification, unlike normal control tissues. An m¹acp³Ψ knockout model and hypo-m¹acp³Ψ patient tumors share a translational signature characterized by highly abundant ribosomal proteins. Thus, m¹acp³Ψ-deficient rRNA forms an uncharacterized class of “onco-ribosome” which may serve as a chemotherapeutic target for treating cancer patients.