A common germline 3' UTR variant controls DDIT4 translation efficiency and stress responses in cancer cells.

Systematic strategies for identifying and classifying variants that directly modulate ribosome engagement are lacking. Here, we develop and extensively validate a pipeline to identify translation-associated single-nucleotide polymorphisms (tranSNPs) by integrating analysis of total and polysome-associated mRNAs. Common variants showing allele-specific enrichment in polysomes, without corresponding changes in mRNA levels, were uncovered. We focused on rs1053639, a frequent germline SNP located in the 3' UTR of DNA damage-inducible transcript 4 (DDIT4), a key negative regulator of mTORC1. Using edited cell models, we showed that this variant controls DDIT4 protein output. Mechanistically, the two rs1053639 alleles differ in their interaction with the RNA-binding protein RBMX, leading to altered mRNA subcellular localization and translation. Functionally, allele-specific regulation of DDIT4 translation impacts stress-dependent mTORC1 repression and autophagy, resulting in divergent competitive fitness in co-culture or xenograft assays and response to therapeutic perturbations. Analysis of cancer patient datasets revealed an association between rs1053639 genotype and clinical outcome in colorectal cancer.