Structural Maintenance of Chromosomes 5/6 complex dysfunction enables tumor mutagenesis

The Structural Maintenance of Chromosomes (SMC) 5/6 complex is highly conserved and essential for mammalian development. SMC5/6 dysfunction in cells, model organisms, and patients with germline variants results in genome instability, though the exact function of the complex in genome maintenance remains enigmatic. Despite the importance of SMC5/6 in maintaining genome stability, the prevalence and consequences of somatic inactivation of SMC5/6 in cancer is understudied. Here we report a pan-cancer analysis of SMC5/6 dysfunction in cancer across three large databases. We identified thousands of tumors across all tissue types with copy number alteration and/or small variants in SMC5/6 genes. We found that deleterious variants in SMC5/6, but not copy number alterations, are associated with elevated tumor mutational burden (TMB). Mutagenesis in tumors with SMC5/6 variants was caused by polymerase epsilon (POLE) dysfunction and mismatch repair deficiency (MMRd). Patients in which SMC5/6 gene variants occur in tumor genomes exhibited improved survival relative to patients with non-altered SMC5/6 genes. This survival benefit was explained in part by a superior response to immunotherapy in a cohort of patients with colorectal cancer. Our findings demonstrate that dysfunction of SMC5/6 is predictive of elevated TMB and susceptibility to immunotherapy, indicating that SMC5/6 gene status should be considered in cancer diagnostic studies for prognostic implications and tailored therapeutics.