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It is widely accepted that some tumors are driven by mutually exclusive oncogenes, but surprisingly, some tumors are driven by oncogenes than present more than one driver mutation at the same time. Although the underlying mechanisms and the relevance of multiple driver mutations (MMs) in the same oncogene are not well understood, MMs occur quite frequently as the driver event.

Kataoka et al, have recently published in Nature an article where they have carried out a pan-cancer analysis on more than 60,000 cancer samples and surprisingly, they have identified 14-pan cancer and 6 cancer-type-specific oncogenes in which MMs occur more often than expected. What is worth mentioning is that MMs overrepresent functionally weak infrequent mutations, but when combined together, these MMs present enhanced oncogenicity.

As an example, we can find cells with MMs in the PIK3CA and NOTCH1 genes. These cells present stronger downstream signaling activation but also, as could be expected, also present a stronger dependency on the signal thus presenting greater sensitivity to inhibitory drugs that those with single mutations.

As the authors conclude: “Oncogenic MMs are a relatively common driver event providing the underlying mechanism for clonal selection of suboptimal mutations that are individually rare but collectively account for a substantial proportion of oncogenic mutations”.