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Updated: Dec 19, 2025
09:58
Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
Published on: June 27, 2020
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Landscape and function of multiple mutations within individual oncogenes.
Yuki Saito1,2, Junji Koya1, Mitsugu Araki3
1Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo, Japan.
Nature
|June 5, 2020
Summary
Multiple driver mutations (MMs) in the same oncogene are common in cancer, affecting 9% of samples. These MMs enhance oncogenicity and drug sensitivity, revealing a key mechanism in cancer evolution.
Area of Science:
- Genomics
- Cancer Biology
- Oncology
Background:
- Sporadic reports indicate multiple driver mutations (MMs) in single oncogenes.
- The prevalence and significance of MMs in cancer remain largely unknown.
Purpose of the Study:
- To conduct a comprehensive pan-cancer analysis to define the landscape and relevance of MMs.
- To investigate the mutational patterns and functional impact of MMs.
Main Methods:
- Pan-cancer analysis of 60,954 cancer samples.
- Identification of oncogenes with significantly frequent MMs.
- Comparative analysis of mutational patterns and functional effects of single vs. multiple mutations.
Main Results:
- Identified 14 pan-cancer and 6 cancer-type-specific oncogenes with frequent MMs.
- MMs occur in cis and exhibit distinct mutational profiles (type, position, substitution) compared to single mutations.
- MMs involve combinations of functionally weak, infrequent mutations conferring enhanced oncogenicity.
- Cells with MMs in PIK3CA and NOTCH1 show increased dependency, signaling, and drug sensitivity.
Conclusions:
- Oncogenic MMs are a common driver event in cancer.
- MMs provide a mechanism for clonal selection of rare, suboptimal mutations.
- Understanding MMs is crucial for cancer driver event identification and therapeutic strategies.
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