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Original research
Identifying novel oncogenic RET mutations and characterising their sensitivity to RET-specific inhibitors
  1. Zheng Zhao1,
  2. Tao Fu2,
  3. Jiyue Gao3,
  4. Yang Xu4,
  5. Xue Wu4,
  6. Wenjuan Chen1,
  7. Xuesong Li4,
  8. Ruoying Yu4,
  9. Yang Washington Shao5,6,
  10. Man Li7,
  11. Yu Yao8
  1. 1 Third Department of Medical Oncology, Shaanxi Provincial Cancer Hospital, Xi'an, Shaanxi, China
  2. 2 Gastrointestinal Surgery Department, Beijing Cancer Hospital, Beijing, China
  3. 3 Department of Breast Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
  4. 4 Translational Medicine Research Institute, Geneseeq Technology Inc, Toronto, Ontario, Canada
  5. 5 Nanjing Geneseeq Technology Inc, Nanjing, Jiangsu, China
  6. 6 School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
  7. 7 Department of Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
  8. 8 Internal Medicine-Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
  1. Correspondence to Dr Yu Yao, Xi'an, Shaanxi, China; 13572101611{at}; Dr Man Li; liman126126{at}


Background Rearranged during transfection (RET) is a well-known proto-oncogene. Multiple RET oncogenic alterations have been identified, including fusions and mutations. Although RET fusions have been reported in multiple cancers, RET mutations were mainly found in multiple endocrine neoplasia type 2 and medullary thyroid carcinoma. RET mutations in other cancers were underinvestigated and their functional annotation was less well studied.

Methods We retrospectively reviewed next-generation sequencing data from 37 056 patients with cancer to search for RET mutations. We excluded patients with other co-occurring known driver mutations to enrich potential activating RET mutations for further analysis. Moreover, we performed in vitro functional validation of the oncogenic property of several high frequent and novel RET mutants and their sensitivity to RET-specific inhibitors LOXO-292 and BLU-667.

Results Within 560 (1.5%) patients with cancer who harbour RET mutations, we identified 380 distinct RET mutation sites, including 252 sites without co-occurring driver mutations. RET mutations were more frequently found in thyroid cancer, mediastinal tumour and several other cancers. The mutation sites spread out through the whole protein with a few hotspots within the kinase domain. In addition, we functionally validated that 898-901del, T930P and T930K were novel RET-activating mutations and they were all sensitive to RET inhibitors.

Conclusion Our results demonstrated the frequency of RET mutations across different cancers. We reported and/or validated several previously uncharacterised RET oncogenic mutations and demonstrated their sensitivity to RET-specific inhibitors. Our results help to stratify patients with cancer based on their RET mutation status and potentially provide more targeted treatment options.

  • RET mutation, next-generation sequencing, LOXO-292, BLU-667

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  • ZZ, TF, JG and YX contributed equally.

  • Contributors Conceptualisation: XW, YWS, ML and YY; data curation: ZZ, TF, JG and YX; investigation: ZZ, TF, JG, YX and WC; methodology: ZZ, TF, JG and YX; resources: XL and RY; supervision: XW, YWS, ML and YY; validation: WC and RY; visualization: XL; writing original draft: ZZ, TF, JG and YX; writing review and editing: XW, YWS, ML and YY.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests YX, XW, XL and RY are the employees of Geneseeq Technology Inc. YWS is the employee of Nanjing Geneseeq Technology Inc. The remaining authors declare that they have no competing interests.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.