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Germline sequencing for presumed germline pathogenic variants via tumor-only comprehensive genomic profiling

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Abstract

Background

The European Society for Medical Oncology Precision Medicine Working Group (ESMO-PMWG) published recommendations regarding confirmatory germline testing for presumed germline pathogenic variants (PGPVs) in tumor-only comprehensive genomic profiling (CGP). However, the clinical validity of these recommendations has not been investigated in a real-world practice.

Methods

Medical records of 180 consecutive patients who obtained the results of a tumor-only CGP (FoundationOne® CDx, Foundation Medicine, Inc, Cambridge, MA, USA) between October 2018 and March 2020, were retrospectively reviewed. After excluding patients with no reported variants in 45 actionable genes (n = 6), or no archived germline DNA samples (n = 31), 143 patients were investigated. The PGPVs were selected from the CGP report and germline sequencing were performed using DNA samples archived in Clinical Bioresource Center in Kyoto University Hospital (Kyoto, Japan).

Results

A total of 195 variants were classified as PGPV based on the conventional criteria. Germline sequencing disclosed that 12 variants (6.2%) were of germline origin. In contrast, after filtering these 195 variants through the ESMO-PMWG recommendation criteria for confirmatory germline testing, following seven PGPVs, BRCA2 (n = 2), BRIP1 (n = 1), BAP1 (n = 1), PMS2 (n = 1), MSH2 (n = 1), and SDHB (n = 1) remained and six variants (85.7%) were confirmed to be of germline origin.

Conclusion

Our current data suggested that the application of ESMO-PMWG criteria is helpful in selecting PGPVs with a high likelihood of germline origin in a tumor-only CGP in daily clinical practice.

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Acknowledgements

The authors would like to thank the patients for their kind cooperation, as well as Mari Funakoshi, Hitomi Sakamoto, Kanami Ashida, Junko Suga, Momoko Sato, Kumi Mukai, and all staff members of Clinical Bioresource Center in Kyoto University Hospital for their excellent technical and secretarial assistance.

Funding

This study was supported by the Japan Agency for Medical Research and Development, AMED, under Grant number 17kk0305006h0001. This research received funding from Chugai Pharmaceutical Co., Ltd., Japan.

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Author notes

  1. Tomohiro Kondo, Yoshihiro Yamamoto and Keita Fukuyama have equally contributed.

Authors and Affiliations

  1. Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Tomohiro Kondo, Yoshihiro Yamamoto, Keita Fukuyama, Masashi Kanai, Atsushi Yamada, Junichi Matsubara, Pham Nguyen Quy, Masahiro Yoshioka, Shigemi Matsumoto & Manabu Muto

  2. Research Fellow of Japan Society for the Promotion of Science, 5-3-1 Kojimachi, Chiyoda-ku, Tokyo, 102-0083, Japan

    Tomohiro Kondo

  3. Clinical Genetics Unit, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Tomohiro Kondo, Masahiro Yoshioka, Takahiro Yamada & Shinji Kosugi

  4. Department of Medical Ethics and Medical Genetics, Kyoto University School of Public Health, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Takahiro Yamada & Shinji Kosugi

  5. Department of Diagnostic Pathology, Kyoto University Hospital, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Sachiko Minamiguchi

Authors
  1. Tomohiro Kondo
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  2. Yoshihiro Yamamoto
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  11. Shigemi Matsumoto
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Corresponding author

Correspondence to Masashi Kanai.

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Conflict of interest

Masashi Kanai received lecture fees, honoraria, and other fees from Chugai Pharmaceutical Co., Ltd. Atsushi Yamada belong to an endowed chair sponsored partly by Chugai Pharmaceutical Co., Ltd. Manabu Muto received research funding, lecture fees, honoraria, and other fees from Chugai Pharmaceutical Co., Ltd. All remaining authors have declared no conflicts of interest.

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Kondo, T., Yamamoto, Y., Fukuyama, K. et al. Germline sequencing for presumed germline pathogenic variants via tumor-only comprehensive genomic profiling. Int J Clin Oncol 27, 1256–1263 (2022). https://doi.org/10.1007/s10147-022-02176-y

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  • DOI: https://doi.org/10.1007/s10147-022-02176-y

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