Disruption of the structural maintenance of chromosomes 5/6 complex enables tumor mutagenesis

The structural maintenance of chromosomes (SMC) 5/6 complex is conserved and essential for mammalian development. SMC5/6 germline variants in cells, model organisms, and patients results in genome instability. However, the consequences of somatic SMC5/6 dysfunction in cancer are unknown. We report a pan-cancer analysis of SMC5/6 variants across three databases in which thousands of tumors across all tissue types harbored copy number alteration (CNA) and/or small variants in SMC5/6 genes. We found that deleterious variants-those predicted to cause protein disruption, but not CNAs, in SMC5/6 genes were associated with elevated tumor mutational burden (TMB). Mutagenesis in tumors with deleterious SMC5/6 variants was largely due to polymerase epsilon dysfunction and mismatch repair deficiency. Patients with SMC5/6 gene variants in tumors exhibited improved survival, in part due to a superior response to immunotherapy. Our findings demonstrate that SMC5/6 complex disruption in cancer predicts elevated TMB and susceptibility to immunotherapy, indicating the potential to use SMC5/6 gene status for prognostic implications and tailored therapeutic approaches.