Systemic structural analysis of alterations reveals a common structural basis of driver mutations in cancer
2Sackler Faculty of Medicine, Tel Aviv University, Israel
3Department of Microbiology and Molecular Genetics, Institute for Biomedical Research Israel-Canada, Faculty of Medicine, the Hebrew University of Jerusalem, Israel
4Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Israel
A major effort in cancer research is to organize the complexities of the disease into fundamental traits. Despite conceptual progress in the last decades and the synthesis of hallmark features, no organizing principles governing cancer beyond cellular features exist. We analyzed experimentally determined structures harboring the most significant and prevalent driver missense mutations in human cancer, covering >72% (n=167,450) of COSMIC tumor samples. We found that κ-helix (polyproline II helix) was the target of driver mutations in 81% (n=135,173) of the tumor samples, with significant and exclusive enrichment of κ-helix in driver mutations (OR=2.5; 95% CI, 1.7-3.6, p=5.3e-06). This is mostly attributable to κ-helix enrichment in gain-of-function mutations (OR=6.2; 95% CI, 3.8-10.0, p=2.4e-15). Overall, κ-helix was implicated in over 99% of the tumor samples when considering both the variant and the local environment (±3 flanking residues and interacting residues). The results reveal that a single structural element – κ-helix lies at the core of driver point mutations, with significant enrichment in all major anatomical sites, suggesting that a small number of molecular traits are shared by most and perhaps all types of cancer. Thus, we uncovered the lowest possible level of organization at which carcinogenesis takes place. This framework provides an initial scheme for a mechanistic understanding underlying the development of tumors and pinpoints key vulnerabilities.