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Cancer genetics
Original research
Shared germline genomic variants in two patients with double primary gastrointestinal stromal tumours (GISTs)
  1. David S Moura1,
  2. Daniel López López2,3,
  3. Davide di Lernia1,
  4. Marta Martin-Ruiz1,
  5. Maria Lopez-Alvarez4,
  6. Rafael Ramos5,
  7. Jose Merino6,
  8. Joaquin Dopazo2,3,4,
  9. Jose Lopez-Guerrero7,
  10. Jose L Mondaza-Hernandez1,
  11. Pablo Romero1,
  12. Nadia Hindi1,8,9,
  13. Jesus Garcia-Foncillas1,8,
  14. Javier Martin-Broto1,8,9
  1. 1 Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, Spain
  2. 2 Computational Medicine Platform, Fundación progreso y salud (FPS), Hospital Virgen del Rocío, Seville, Spain
  3. 3 Bioinformatics in Rare Diseases (BiER), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), FPS, Hospital Virgen del Rocio, Seville, Spain
  4. 4 Instituto de Biomedicina de Sevilla (IBiS; HUVR, CSIC, US), Sevilla, Spain
  5. 5 Pathology Department, University Hospital Son Espases, Mallorca, Spain
  6. 6 Pathology Department, Fundación Jimenez Diaz University Hospital, Madrid, Spain
  7. 7 Laboratory of Molecular Biology, Fundación Instituto Valenciano de Oncologia, Valencia, Spain
  8. 8 Medical Oncology Department, Fundación Jimenez Diaz University Hospital, Madrid, Spain
  9. 9 General de Villalba University Hospital, Madrid, Spain
  1. Correspondence to Dr Javier Martin-Broto; jmartin{at}atbsarc.org

Abstract

Background Gastrointestinal stromal tumours (GISTs) are prevalent mesenchymal tumours of the gastrointestinal tract, commonly exhibiting structural variations in KIT and PDGFRA genes. While the mutational profiling of somatic tumours is well described, the genes behind the susceptibility to develop GIST are not yet fully discovered. This study explores the genomic landscape of two primary GIST cases, aiming to identify shared germline pathogenic variants and shed light on potential key players in tumourigenesis.

Methods Two patients with distinct genotypically and phenotypically GISTs underwent germline whole genome sequencing. CNV and single nucleotide variant (SNV) analyses were performed.

Results Both patients harbouring low-risk GISTs with different mutations (PDGFRA and KIT) shared homozygous germline pathogenic deletions in both CFHR1 and CFHR3 genes. CNV analysis revealed additional shared pathogenic deletions in other genes such as SLC25A24. No particular pathogenic SNV shared by both patients was detected.

Conclusion Our study provides new insights into germline variants that can be associated with the development of GISTs, namely, CFHR1 and CFHR3 deep deletions. Further functional validation is warranted to elucidate the precise contributions of identified germline mutations in GIST development.

  • Genotype
  • Sequence Analysis, DNA
  • Human Genetics
  • Germ-Line Mutation

Data availability statement

Data are available upon reasonable request. Dataset sequencing is available from the corresponding author on reasonable request.

https://doi.org/10.1136/jmg-2024-110109

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    Data availability statement

    Data are available upon reasonable request. Dataset sequencing is available from the corresponding author on reasonable request.

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    Footnotes

    • DSM, DLL and DdL contributed equally.

    • Contributors Conceptualisation: DSM and JM-B. Methodology: DSM, DLL, DdL, MM-R, ML-A, RR, JM, JLM-H, PR, JG-F and JM-B. Validation: DSM, DLL, DdL. Formal analysis: DSM, DLL, DdL and JM-B. Investigation: All the authors. Resources: All the authors. Data curation: DSM and JM-B. Writing — original draft preparation: DSM, DLL, DdL and JM-B. Writing—review and editing: All the authors. Visualisation: All the authors. Supervision: JM-B. Project administration: JM-B. Funding acquisition: DSM and JM-B. Guarantor: JM-B.

    • 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 DSM reports institutional research grants from PharmaMar, Eisai, Immix BioPharma and Novartis, outside the submitted work; travel support from PharmaMar, Eisai, Celgene, Bayer, Biosplice and Pfizer; and personal fees from Tecnopharma, outside the submitted work. NH reports grants, personal fees and non-financial support from PharmaMar; personal fees from Lilly and Tecnopharma; grants from Eisai and Novartis, outside the submitted work; and research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint, Nektar, Forma, Amgen and Daichii-Sankyo. JM-B reports research grants from PharmaMar, Eisai, Immix BioPharma and Novartis, outside the submitted work; honoraria for advisory board participation and expert testimony from PharmaMar, Eli Lilly and Company, Bayer, GSK, Novartis, Boehringer Ingelheim, Amgen, Roche, Tecnofarma and Asofarma; and research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, BMS, Pfizer, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Celgene, Novartis, Blueprint, Adaptinmune, Nektar, Forma, Amgen, Daichii-Sankyo, Ran Therapeutics, INHIBRX, Ayala Pharmaceuticals, Philogen, Cebiotex, PTC Therapeutics, Inc. and SpringWorks therapeutics. The remaining authors declare no competing interests.

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

    • 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.