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Cancer genetics
Original research
Genetic characterisation of sarcomatoid carcinomas reveals multiple novel actionable mutations and identifies KRAS mutation as a biomarker of poor prognosis
  1. Ying Ding1,
  2. Yang Shao2,3,
  3. Chenglong Na2,
  4. Jiani C Yin2,
  5. Hongjin Hua1,
  6. Ran Tao4,
  7. Yue Jiang5,
  8. Ran Hu1,
  9. Xiao He1,
  10. Chen Miao1,
  11. Dongqin Zhu2,
  12. Zhihong Zhang1
  1. 1Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
  2. 2Nanjing Geneseeq Technology Inc, Nanjing, Jiangsu, China
  3. 3School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China
  4. 4Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
  5. 5Department of Pathology, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, Jiangsu, China
  1. Correspondence to Professor Zhihong Zhang, Nanjing, China; zhangzh{at}njmu.edu.cn

Abstract

Background Sarcomatoid component occurs in various epithelial malignancies and is associated with an aggressive disease course and poor clinical outcome. As it is largely rare, the molecular events underlying sarcomatoid carcinomas (SCs) remain poorly characterised. Here, we performed targeted next-generation sequencing (NGS) on patients with surgically resected SCs comprising distinct tissues of origin.

Methods A total of 71 patients with pathological diagnosis of sarcomatoid carcinomas and underwent surgery were retrospectively enrolled in this study. Overall survival (OS) was defined as the time from surgery to death from any cause. Patients alive or lost to follow-up were censored. Genomic DNA from formalin-fixed paraffin-embedded samples was extracted for NGS and tumour mutation burden (TMB) analysis.

Results In general, SCs occurred more commonly in males, except those of the gallbladder. SCs of the lung and the larynx were associated with a higher proportion of smokers (p=0.0015). Alterations in TP53, RB1, TERT and KRAS were highly frequent, with KRAS mutations being a biomarker of poor prognosis (median OS=8 vs 16 months, p=0.03). Multiple alterations in potentially actionable genes, including ROS1 and NTRK1 fusions and ERBB2 amplification, were detected in the extra-pulmonary cohort. A relatively high proportion (30%) of patients with extra-pulmonary SC had high TMB, with a median of 5.39 mutations per Mb. Lastly, copy number variations were common in SCs, and were non-overlapping between the primary and metastatic tumours.

Conclusion Taken together, our results suggest that comprehensive genetic testing may be necessary to inform treatment options and identify prognostic biomarkers.

  • gene expression profiling
  • medical oncology
  • pathology

https://doi.org/10.1136/jmedgenet-2020-107083

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    Footnotes

    • Contributors ZZ and YD planned the study and wrote the manuscript. YS, CN, JCY and DZ contributed to the sequencing experiment. HH, RT, YJ, RH, XH and CM contributed to other experiments. All authors have reviewed the manuscript.

    • Funding This work was supported by the National Natural Science Foundation of China (81773109, 81502089), the Natural Science Foundation of Jiangsu Province (BK20151582, BK20151024, BK20170706), National key Clinical Specialty Construction Project (2014), Joint key project funded by Southeast University and Nanjing Medical University (2242019K3DN09, JX218GSP20190735), and the Fund of the priority Academic Program Development of Jiangsu Higher Education Institution (JX1023-1801).

    • Competing interests JCY, DZ, CN and YWS are employees of Nanjing Geneseeq Technology Inc. All other authors have declared no conflict of interests.

    • Patient consent for publication Not required.

    • Ethics approval The study was approved by the Ethical Review Board of the First Affiliated Hospital of Nanjing Medical University.

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

    • Data availability statement Data are available on reasonable request. Some or all data, models, or code generated or used during the study are available from the corresponding author (zhangzh@njmu.edu.cn) by request.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.