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Updated: May 26, 2026

Rapid Analysis of Chromosome Aberrations in Mouse B Lymphocytes by PNA-FISH
Published on: August 19, 2014
Disruption of the structural maintenance of chromosomes 5/6 complex enables tumor mutagenesis
Thi Tran1,2, Jiayi Fan3, Xiaolan Zhao3
1Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States.
Abstract:
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.
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