Full Professor, Department of Cellular & Molecular Medicine Faculty of Medicine, University of Ottawa The SMC5/6 complex: Folding chromosomes back into shape when genomes take a break High-level folding of chromatin is a key determinant of the shape and functional state of chromosomes. During normal cell division cycles, structural maintenance of chromosome (SMC) complexes ensure the large-scale folding of chromatin into visible chromosomes. While it is known that cancer cells experience important changes in genome architecture, it is still unclear if mutations in core regulators of chromosome structure can lead to cancer-promoting loss in genome stability. To address this question, we conducted a systematic analysis of mutations affecting a global regulator of chromosome biology –the SMC5/6 complex– in cancer genomics cohorts. Analysis of 64,959 cancer samples spanning 144 tissue types and 199 different cancer genome studies revealed that the SMC5/6 complex is frequently altered in breast cancer patients. Patient-derived mutations targeting this complex associate with strong phenotypic outcomes such as loss of ploidy control and reduced overall survival. Remarkably, the phenotypic impact of several patient mutations can be observed in a heterozygous context, hence providing an explanation for a prominent role of SMC5/6 mutations in breast cancer pathogenesis. Overall, our findings suggest that genes encoding global effectors of chromosome architecture can act as key contributors to cancer development in humans.
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