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Development of a genomic predictive model for cholangiocarcinoma using copy number alteration data
  1. Inês Tavares1,
  2. Ricardo Martins2,3,4,5,
  3. Ilda Patrícia Ribeiro1,2,5,6,
  4. Luísa Esteves1,
  5. Francisco Caramelo7,
  6. Ana Margarida Abrantes2,4,5,6,
  7. Rita Neves2,4,5,
  8. Rui Caetano-Oliveira5,8,
  9. Maria Filomena Botelho2,4,5,6,
  10. Joana Barbosa de Melo1,2,5,6,
  11. Dulce Diogo3,5,
  12. José Guilherme Tralhão2,3,4,5,
  13. Isabel Marques Carreira1,2,5,6
  1. 1 University of Coimbra, Cytogenetics and Genomics Laboratory, Institute of Cellular and Molecular Biology, Faculty of Medicine, Coimbra, Portugal
  2. 2 University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) and Center of Investigation on Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, Coimbra, Portugal
  3. 3 Surgery Department, Centro Hospitalar e Universitario de Coimbra EPE (CHUC), Coimbra, Portugal
  4. 4 University of Coimbra, Institute of Biophysics, Faculty of Medicine, Coimbra, Portugal
  5. 5 Clinical Academic Center of Coimbra, CACC, Coimbra, Portugal
  6. 6 University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal
  7. 7 University of Coimbra, Laboratory of Biostatistics and Medical Informatics, IBILI, Faculty of Medicine, Coimbra, Portugal
  8. 8 Pathology Department, Centro Hospitalar e Universitario de Coimbra EPE (CHUC), Coimbra, Portugal
  1. Correspondence to Professor Isabel Marques Carreira, Cytogenetics and Genomics Laboratory, Institute of Cellular and Molecular Biology, University of Coimbra Faculty of Medicine, Coimbra 3000-354, Portugal; citogenetica{at}fmed.uc.pt

Abstract

Aims Cholangiocarcinoma (CC) is a rare tumour arising from the biliary tract epithelium. The aim of this study was to perform a genomic characterisation of CC tumours and to implement a model to differentiate extrahepatic (ECC) and intrahepatic (ICC) cholangiocarcinoma.

Methods DNA extracted from tumour samples of 23 patients with CC, namely 10 patients with ECC and 13 patients with ICC, was analysed by array comparative genomic hybridisation. A support vector machine algorithm for classification was applied to the genomic data to distinguish between ICC and ECC. A survival analysis comparing both groups of patients was also performed.

Results With these whole genome results, we observed several common alterations between tumour samples of the same CC anatomical type, namely gain of Xp and loss of 3p, 11q11, 14q, 16q, Yp and Yq in ICC tumours, and gain of 16p25.3 and loss of 3q26.1, 6p25.3–22.3, 12p13.31, 17p, 18q and Yp in ECC tumours. Gain of 2q37.3 was observed in the samples of both tumour subtypes, ICC and ECC. The developed genomic model comprised four chromosomal regions that seem to enable the distinction between ICC and ECC, with an accuracy of 71.43% (95% CI 43% to 100%). Survival analysis revealed that in our cohort, patients with ECC survived on average 8 months less than patients with ICC.

Conclusions This genomic characterisation and the introduction of genomic models to clinical practice could be important for patient management and for the development of targeted therapies. The power of this genomic model should be evaluated in other CC populations.

  • cholangiocarcinoma
  • genetics
  • comparative genomic hybridisation
  • DNA
  • molecular biology

https://doi.org/10.1136/jclinpath-2020-207346

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    Footnotes

    • Handling editor Runjan Chetty.

    • IT and RM contributed equally.

    • Presented at Part of the results of this paper has previously been presented as an abstract in the CIMAGO Meeting – Challenges in Oncobiology Coimbra, 31 January 2020, published in 'Medicine: June 05, 2020'.

    • Contributors IT and RM contributed to the conception, design and follow-up of the work, as well as to the writing, drafting, data acquisition, analysis and interpretation, and revising, editing and reviewing the manuscript. LE and FC contributed to data analysis and interpretation and bioinformatic analysis, as well as revising, editing and reviewing the manuscript. DD and RM contributed to sample collection and revising, editing and reviewing the manuscript. IPR, AMA, RN, RC-O, MFB, JBdM, JGT and IMC contributed to conception, design and follow-up of the work, as well as drafting, revising, editing and reviewing the manuscript.

    • Funding This work was supported by two research grants from the ‘Núcleo Regional do Centro da Liga Portuguesa Contra o Cancro’: Dr. Rocha Alves 2019 - HCC DRAMA. Project: Diagnosis prognosis and treatment new biomarkers solving hepatocellular cancer; Oncology research grant NRC-LPCC/CIMAGO. Project: Genomic and epigenetic profile in Cholangiocarcinoma and Hepatocellular Carcinoma.

    • Competing interests None declared.

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