KDM5D拷贝数缺失可能是ATR抑制剂治疗男性肺鳞状细胞癌的预测性生物标志物。

IF 3.4 2区 医学 Q1 PATHOLOGY
Ayako Ura, Takuo Hayashi, Kazumasa Komura, Masaki Hosoya, Kazuya Takamochi, Eiichi Sato, Satomi Saito, Susumu Wakai, Takafumi Handa, Tsuyoshi Saito, Shunsuke Kato, Kenji Suzuki, Takashi Yao, the Tokyo Metropolitan Innovative Oncology Research Group (TMIG)
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引用次数: 0

摘要

由于缺乏可靶向的驱动改变,有限数量的肺鳞状细胞癌(SCC)患者从分子靶向药物中获益。我们旨在了解SCC中赖氨酸特异性去甲基化酶5D (KDM5D)拷贝数丢失的患病率和临床意义,并探索其作为失联性毛细血管扩张和rad3相关(ATR)抑制剂治疗的预测性生物标志物的潜力。我们使用荧光原位杂交技术评估了173例手术切除的男性SCCs患者的KDM5D拷贝数损失。173例患者中有75例(43%)检测到KDM5D拷贝数丢失。从17个SCCs中获得了转录起始位点(tss)的全基因组表达谱,并对其进行了基因表达测定的cap分析,揭示了KDM5D拷贝数丢失的肿瘤中上调的基因与“细胞周期”相关,而KDM5D拷贝数丢失的肿瘤中下调的基因与“免疫反应”相关。临床病理学上,KDM5D拷贝数缺失的SCCs与病理分期晚期(p = 0.0085)和间质含量高(p = 0.0254)相关。多重荧光免疫组化显示,KDM5D拷贝数丢失的SCCs中,肿瘤浸润的CD8+ /T-bet+ T细胞数量低于野生型肿瘤。总之,大约40%的男性SCC患者表现出KDM5D拷贝数丢失。表现出这种独特表型的患者的肿瘤可能是“冷肿瘤”,其特征是肿瘤t细胞浸润的缺乏,通常对免疫治疗没有反应。因此,它们可能是ATR抑制剂试验的候选药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Copy number loss of KDM5D may be a predictive biomarker for ATR inhibitor treatment in male patients with pulmonary squamous cell carcinoma

Copy number loss of KDM5D may be a predictive biomarker for ATR inhibitor treatment in male patients with pulmonary squamous cell carcinoma

A limited number of patients with lung squamous cell carcinoma (SCC) benefit clinically from molecular targeted drugs because of a lack of targetable driver alterations. We aimed to understand the prevalence and clinical significance of lysine-specific demethylase 5D (KDM5D) copy number loss in SCC and explore its potential as a predictive biomarker for ataxia-telangiectasia and Rad3-related (ATR) inhibitor treatment. We evaluated KDM5D copy number loss in 173 surgically resected SCCs from male patients using fluorescence in situ hybridization. KDM5D copy number loss was detected in 75 of the 173 patients (43%). Genome-wide expression profiles of the transcription start sites (TSSs) were obtained from 17 SCCs, for which the cap analysis of gene expression assay was performed, revealing that upregulated genes in tumors with the KDM5D copy number loss are associated with ‘cell cycle’, whereas downregulated genes in tumors with KDM5D copy number loss were associated with ‘immune response’. Clinicopathologically, SCCs with KDM5D copy number loss were associated with late pathological stage (p = 0.0085) and high stromal content (p = 0.0254). Multiplexed fluorescent immunohistochemistry showed that the number of tumor-infiltrating CD8+/T-bet+ T cells was lower in SCCs with KDM5D copy number loss than in wild-type tumors. In conclusion, approximately 40% of the male patients with SCC exhibited KDM5D copy number loss. Tumors in patients who show this distinct phenotype can be ‘cold tumors’, which are characterized by the paucity of tumor T-cell infiltration and usually do not respond to immunotherapy. Thus, they may be candidates for trials with ATR inhibitors.

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来源期刊
Journal of Pathology Clinical Research
Journal of Pathology Clinical Research Medicine-Pathology and Forensic Medicine
CiteScore
7.40
自引率
2.40%
发文量
47
审稿时长
20 weeks
期刊介绍: The Journal of Pathology: Clinical Research and The Journal of Pathology serve as translational bridges between basic biomedical science and clinical medicine with particular emphasis on, but not restricted to, tissue based studies. The focus of The Journal of Pathology: Clinical Research is the publication of studies that illuminate the clinical relevance of research in the broad area of the study of disease. Appropriately powered and validated studies with novel diagnostic, prognostic and predictive significance, and biomarker discover and validation, will be welcomed. Studies with a predominantly mechanistic basis will be more appropriate for the companion Journal of Pathology.
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