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Updated: Aug 6, 2025
Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing
Published on: July 5, 2019
Multiple Mutations within Individual Oncogenes: Examples and Clinical Implications
Keisuke Kataoka1,2, Yuki Saito2,3
1Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
Abstract:
Gain-of-function mutations had been believed to function as a single mutation in oncogenes, although some secondary mutations, such as EGFR T790M mutations, are frequently acquired in patients that are resistant to tyrosine kinase inhibitor treatment. Recently, we and other investigators have reported that multiple mutations (MMs) frequently occur in the same oncogene before any therapy. In a recent pan-cancer study, we identified 14 pan-cancer oncogenes (such as PIK3CA and EGFR) and 6 cancer type-specific oncogenes that are significantly affected by MMs. Of these, 9% of cases with at least one mutation have MMs that are cis-presenting on the same allele. Interestingly, MMs show distinct mutational patterns in various oncogenes relative to single mutations in terms of mutation type, position, and amino acid substitution. Specifically, functionally weak, uncommon mutations are overrepresented in MMs, which enhance oncogenic activity in combination. Here, we present an overview of the current understanding of oncogenic MMs in human cancers and provide insights into their underlying mechanisms and clinical implications.
Insights
Multiple mutations (MMs) in oncogenes, not just single mutations, are common in cancer. These MMs, often on the same gene allele, have unique patterns and enhance cancer-driving activity.
Area of Science:
- Oncology
- Cancer Genomics
- Molecular Biology
Background:
- Traditionally, oncogenic mutations were viewed as single events.
- Secondary mutations, like EGFR T790M, arise during treatment resistance.
- Recent findings indicate multiple mutations (MMs) frequently occur in the same oncogene prior to therapy.
Approach:
- Conducted a pan-cancer study to identify oncogenes affected by MMs.
- Analyzed mutation type, position, and amino acid substitution patterns of MMs.
- Investigated the co-occurrence of MMs on the same oncogene allele (cis-presentation).
Key Points:
- Identified 14 pan-cancer and 6 cancer-specific oncogenes frequently impacted by MMs.
- Observed that 9% of cases with mutations harbor MMs cis-presenting on the same allele.
- MMs exhibit distinct mutational patterns compared to single mutations, overrepresenting weaker mutations that combine for enhanced oncogenic activity.
Conclusions:
- Multiple mutations in oncogenes are a significant factor in human cancers.
- MMs possess unique characteristics and mechanisms that contribute to oncogenesis.
- Understanding MMs offers new insights into cancer mechanisms and potential clinical implications.
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