Many oncogenes contain multiple individually weak mutations that collectively promote oncogenesis.

  • Major Finding: Many oncogenes contain multiple individually weak mutations that collectively promote oncogenesis.

  • Concept: Cancer cells with multiply mutated PIK3CA were dependent on PIK3CA and sensitive to PI3K inhibitors.

  • Impact: This work reveals the frequency and impact of multiple driver mutations in oncogenes across cancers.

Although there have been some reports of multiple driver mutations affecting the same oncogene, systematic searches for and detailed characterization of such alterations has been lacking. In an analysis of 60,954 samples representing all types of cancer, Saito, Koya, and colleagues found that the presence of multiple mutations was common in oncogenes, especially mutant variants of PIK3CA and EGFR, each of which was affected by multiple mutations in 10% of cases. The proportion of synonymous mutations in oncogenes with multiple mutations was low, including in oncogenes in which both mutations appeared to be under positive selection equivalent to the positive selection observed for single mutations, implying that the mutations in these oncogenes are driver–driver pairs. In most cases, multiple mutations in oncogenes were observed in cis, and a unique mutational pattern (as defined by mutation type, position, and amino acid–residue substitution) was observed in oncogenes bearing multiple mutations. Collectively, the observed mutational patterns implied that mutational selection in these oncogenes was mediated by cis-acting effects. Deeper analysis revealed six multiple mutation–positive oncogenes specific to certain cancer types; for example, multiple mutations in NOTCH1 were prevalent in T-cell acute lymphoblastic leukemia. In vitro experiments and in vivo xenotransplantation experiments demonstrated that, whereas each individual mutation in multiply mutated oncogenes may have been of little consequence, their combined effects were much more strongly oncogenic. Interestingly, cancer cell lines with PIK3CA multiple mutations were more dependent on PIK3CA and its partner AKT1 and were more susceptible to PI3K inhibitors than lines without multiple mutations in PIK3CA. In summary, this work shows that the presence of multiple mutations in the same oncogene is relatively common, and these mutations act in concert to promote oncogenesis even in the absence of strong individual effects.

Saito Y, Koya J, Araki M, Kogure Y, Shingaki S, Tabata M, et al. Landscape and function of multiple mutations within individual oncogenes. Nature 2020 Apr 8 [Epub ahead of print].

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