A novel patient-derived cell line of adrenocortical carcinoma shows a pathogenic role of germline MUTYH mutation and high tumour mutational burden

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  • 1 Division of Endocrinology and Diabetology, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany
  • 2 Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany
  • 3 Institute of Pathology, University of Würzburg, Würzburg, Germany
  • 4 Clinical Chemistry and Laboratory Medicine, University Hospital, University of Würzburg, Würzburg, Germany
  • 5 Department of Medicine IV, University Hospital Munich, Ludwig-Maximilians-Universität München, Munich, Germany

Correspondence should be addressed to I Weigand; Email: Isabel.Weigand@med.uni-muenchen.de

Background

The response of advanced adrenocortical carcinoma (ACC) to current chemotherapies is unsatisfactory and a limited rate of response to immunotherapy was observed in clinical trials. High tumour mutational burden (TMB) and the presence of a specific DNA signature are characteristic features of tumours with mutations in the gene MUTYH encoding the mutY DNA glycosylase. Both have been shown to potentially predict the response to immunotherapy. High TMB in an ACC cell line model has not been reported yet.

Design and methods

The JIL-2266 cell line was established from a primary ACC tumour, comprehensively characterised and oxidative damage, caused by a dysfunctional mutY DNA glycosylase, confirmed.

Results

Here, we characterise the novel patient-derived ACC cell line JIL-2266, which is deficient in mutY-dependent DNA repair. JIL-2266 cells have a consistent STR marker profile that confirmed congruousness with primary ACC tumour. Cells proliferate with a doubling time of 41 ± 13 h. Immunohistochemistry revealed positivity for steroidogenic factor-1. Mass spectrometry did not demonstrate significant steroid hormone synthesis. JIL-2266 have hemizygous mutations in the tumour suppressor gene TP53 (c.859G>T:p.E287X) and MUTYH (c.316C>T:p.R106W). Exome sequencing showed 683 single nucleotide variants and 4 insertions/deletions. We found increased oxidative DNA damage in the cell line and the corresponding primary tumour caused by impaired mutY DNA glycosylase function and accumulation of 8-oxoguanine.

Conclusion

This model will be valuable as a pre-clinical ACC cell model with high TMB and a tool to study oxidative DNA damage in the adrenal gland.

Supplementary Materials

    • Supplementary information
    • supplementary Figure1
    • supplementary Figure2
    • supplementary Figure3
    • supplementary Table S1
    • supplementary Table S2

 

     European Society of Endocrinology

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