Why Are Some Driver Mutations Rare?

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.