Why Are Some Driver Mutations Rare?

Ruth Nussinov*, Chung Jung Tsai, Hyunbum Jang

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


Understanding why driver mutations that promote cancer are sometimes rare is important for precision medicine since it would help in their identification. Driver mutations are largely discovered through their frequencies. Thus, rare mutations often escape detection. Unlike high-frequency drivers, low-frequency drivers can be tissue specific; rare drivers have extremely low frequencies. Here, we discuss rare drivers and strategies to discover them. We suggest that allosteric driver mutations shift the protein ensemble from the inactive to the active state. Rare allosteric drivers are statistically rare since, to switch the protein functional state, they cooperate with additional mutations, and these are not considered in the patient cancer-specific protein sequence analysis. A complete landscape of mutations that drive cancer will reveal tumor-specific therapeutic vulnerabilities.

Original languageEnglish
Pages (from-to)919-929
Number of pages11
JournalTrends in Pharmacological Sciences
Issue number12
StatePublished - Dec 2019


FundersFunder number
Center for Cancer Research
US government
National Institutes of HealthHHSN26120080001E
Foundation for the National Institutes of Health
National Cancer Institute
Department of Health, Australian Government


    • drug discovery
    • passenger mutations
    • pharmacology
    • precision medicine
    • precision oncology
    • rare driver mutations


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