Systemic structural analysis of alterations reveals a common structural basis of driver mutations in cancer

Tomer Meirson*, David Bomze, Ora Schueler-Furman, Salomon M. Stemmer, Gal Markel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 73% (n = 168178) of the Catalog of Somatic Mutation in Cancer tumor samples (COSMIC). The results reveal that a single structural element––K-helix (polyproline II 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 at the protein level. This framework provides an initial scheme for a mechanistic understanding underlying the development of tumors and pinpoints key vulnerabilities.

Original languageEnglish
Article numberzcac040
JournalNAR Cancer
Volume5
Issue number1
DOIs
StatePublished - 1 Mar 2023

Funding

FundersFunder number
Samueli Foundation
Israel Science Foundation

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