Division of Endocrinology and Diabetology Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany.
Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
Eur J Endocrinol. 2021 May 4;184(6):823-835. doi: 10.1530/EJE-20-1423.
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.
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.
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.
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.
晚期肾上腺皮质癌 (ACC) 对现有化疗的反应并不令人满意，临床试验中观察到免疫治疗的反应率有限。高肿瘤突变负担 (TMB) 和存在特定的 DNA 特征是编码 mutY DNA 糖基化酶的基因 MUTYH 突变的肿瘤的特征。两者都被证明可能预测免疫治疗的反应。然而，尚未报道 ACC 细胞系模型中的高 TMB。
从原发性 ACC 肿瘤中建立了 JIL-2266 细胞系，对其进行了全面表征，并证实了由功能失调的 mutY DNA 糖基化酶引起的氧化损伤。
在这里，我们描述了一种新型的源自患者的 ACC 细胞系 JIL-2266，该细胞系缺乏依赖于 mutY 的 DNA 修复。JIL-2266 细胞具有一致的 STR 标记谱，证实与原发性 ACC 肿瘤一致。细胞以 41 ± 13 h 的倍增时间增殖。免疫组织化学显示类固醇生成因子-1 呈阳性。质谱分析未显示出显著的类固醇激素合成。JIL-2266 在肿瘤抑制基因 TP53（c.859G>T:p.E287X）和 MUTYH（c.316C>T:p.R106W）中存在杂合突变。外显子组测序显示 683 个单核苷酸变异和 4 个插入/缺失。我们发现，由于 mutY DNA 糖基化酶功能受损和 8-氧鸟嘌呤积累，导致细胞系和相应的原发性肿瘤中氧化 DNA 损伤增加。
该模型将作为具有高 TMB 的 ACC 细胞模型和研究肾上腺氧化 DNA 损伤的工具具有重要价值。
