Landscape and function of multiple mutations within individual oncogenes

Yuki Saito, Junji Koya, Mitsugu Araki, Yasunori Kogure, Sumito Shingaki, Mariko Tabata, Marni B. McClure, Kota Yoshifuji, Shigeyuki Matsumoto, Yuta Isaka, Hiroko Tanaka, Takanori Kanai, Satoru Miyano, Yuichi Shiraishi, Yasushi Okuno and Keisuke Kataoka ()
Additional contact information
Yuki Saito: National Cancer Center Research Institute
Junji Koya: National Cancer Center Research Institute
Mitsugu Araki: Kyoto University
Yasunori Kogure: National Cancer Center Research Institute
Sumito Shingaki: National Cancer Center Research Institute
Mariko Tabata: National Cancer Center Research Institute
Marni B. McClure: National Cancer Center Research Institute
Kota Yoshifuji: National Cancer Center Research Institute
Shigeyuki Matsumoto: Technology and Innovation Hub
Yuta Isaka: Foundation for Biomedical Research and Innovation
Hiroko Tanaka: The University of Tokyo
Takanori Kanai: Keio University School of Medicine
Satoru Miyano: The University of Tokyo
Yuichi Shiraishi: National Cancer Center
Yasushi Okuno: Kyoto University
Keisuke Kataoka: National Cancer Center Research Institute

Nature, 2020, vol. 582, issue 7810, 95-99

Abstract: Abstract Sporadic reports have described cancer cases in which multiple driver mutations (MMs) occur in the same oncogene1,2. However, the overall landscape and relevance of MMs remain elusive. Here we carried out a pan-cancer analysis of 60,954 cancer samples, and identified 14 pan-cancer and 6 cancer-type-specific oncogenes in which MMs occur more frequently than expected: 9% of samples with at least one mutation in these genes harboured MMs. In various oncogenes, MMs are preferentially present in cis and show markedly different mutational patterns compared with single mutations in terms of type (missense mutations versus in-frame indels), position and amino-acid substitution, suggesting a cis-acting effect on mutational selection. MMs show an overrepresentation of functionally weak, infrequent mutations, which confer enhanced oncogenicity in combination. Cells with MMs in the PIK3CA and NOTCH1 genes exhibit stronger dependencies on the mutated genes themselves, enhanced downstream signalling activation and/or greater sensitivity to inhibitory drugs than those with single mutations. Together 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.

Date: 2020
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DOI: 10.1038/s41586-020-2175-2

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