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Comparative analysis of cancer gene mutations using targeted sequencing in matched primary and recurrent gastric cancers after chemotherapy

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Abstract

Background

Investigation of responsiveness-associated genes using longitudinal mutation analyses after standard treatments in recurrent gastric cancer (GC) is limited.

Objective

To evaluate the somatic mutations associated with resistance to combined treatment involving fluorouracil (FU) or platinum (PL) in advanced GC.

Methods

Samples from patients with advanced GC treated with FU or PL alone, or surgery plus FU/PL, were studied. GC patients who relapsed after standard chemotherapy (FU/PL) and with presence of tumor samples from initial diagnosis and recurrence were included. Targeted sequencing analysis of 143 cancer-related genes was performed using an Oncomine Comprehensive Cancer Panel.

Results

Matched samples of primary and recurrent lesions were analyzed in sixteen patients with GC. When genes with recurrent mutations in two or more patients were used as specific findings, a total of 26 genes were found. TP53 was the most predominantly increased allele frequency (AF) in recurrent GCs after standard treatment. The mutational AF of ERBB2, PTEN, and BRCA2 also commonly increased, suggesting the role of these mutations in treatment resistance, whereas the mutational AF of VLH, NF1, and STK11 frequently decreased in recurrent tumors, suggesting the role of these mutations in increasing sensitivity to treatment. TCGA gastric cancer data (n = 436) were analyzed, and mutation sites detected in 16 GC patients in this study were in agreement with TCGA cohort with some exceptions. Overall survival according to gene expression associated with chemotherapy responsiveness exhibited compatible patterns with gain or loss-of-function mutations of each gene.

Conclusions

Mutations in TP53, ERBB2, PTEN, BRCA2, VHL, NF1, and STK11 are candidate somatic alterations related to chemoresistance in GC.

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Acknowledgements

This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2021R1A2C3008021) and 2017 Young Medical Science Researcher Grants from Ewha Womans University College of Medicine.

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Author notes

  1. Yeon-Ju Huh and Sung-Yup Cho contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Ewha Womans University School of Medicine, Anyangcheon-ro, Yangcheon-gu, 1071, Seoul, Korea

    Yeon-Ju Huh & Joo-Ho Lee

  2. Department of Surgery, Seoul National University Hospital, Seoul, Korea

    Yeon-Ju Huh

  3. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea

    Sung-Yup Cho

  4. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

    Sung-Yup Cho

  5. Medical Research Center, Genomic Medicine Institute (GMI), Seoul National University, Seoul, Korea

    Sung-Yup Cho

  6. Department of pathology, Ewha Womans University School of Medicine, Seoul, Korea

    Min-Sun Cho

  7. Department of oncology, Ewha Womans University School of Medicine, Seoul, Korea

    Kyoung-Eun Lee

  8. Department of Surgery, Nowon Eulji Medical Center, Eulji University School of Medicine, 68, Hangeulbiseok-ro, Nowon-gu, Seoul, Korea

    Joo-Ho Lee

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  1. Yeon-Ju Huh
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Correspondence to Joo-Ho Lee.

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Conflict of interest

Yeon-Ju Huh, Sung-Yup Cho, Min-Sun Cho, Kyoung-Eun Lee, and Joo-Ho Lee declare that they have no conflict of interest.

Ethical approval

This study had been approved by the institutional review board of Ewha Womans University Mokdong Hospital in accordance with the Declaration of Helsinki (IRB No. 2018-04-031).

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Huh, YJ., Cho, SY., Cho, MS. et al. Comparative analysis of cancer gene mutations using targeted sequencing in matched primary and recurrent gastric cancers after chemotherapy. Genes Genom 44, 1425–1435 (2022). https://doi.org/10.1007/s13258-022-01248-7

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  • DOI: https://doi.org/10.1007/s13258-022-01248-7

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