Genetic Alterations in Chromatin Regulatory Genes in Upper Tract Urothelial Carcinoma and Urothelial Bladder Cancer

IF 2.9 2区医学 Q2 ONCOLOGY

Cancer Medicine Pub Date : 2024-11-08 DOI:10.1002/cam4.70398

Shuo Wang, Xuzhi Yan, Weihua Lan, Yapeng Wang, Ze Wang, Dali Tong, Yao Zhang, Qiang Ran, Haoyang Li, Junhao Jin, Haiyang Xiao, Jing Xu, Qian Yan, Dianzheng Zhang, Qiang Ma, Hualiang Xiao, Jun Qin, Luofu Wang, Jun Jiang, Qiuli Liu

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引用次数: 0

Abstract

Purpose

Upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) share histomorphological and therapeutic features but distinct epidemiologic and clinicopathologic characteristics. We examined alterations of chromatin regulatory genes in molecular subtypes, clonal relatedness, and T-cell receptor (TCR) diversity in UTUC and UCB.

Materials and Methods

Targeted next-generation sequencing or whole-exome DNA sequencing and TCR sequencing were conducted with 34 UTUC and 49 UCB specimens from 63 patients. Tumors were subtyped based on the expression of CK5 and GATA3. Results of tissue microarray of 78 muscle-invasive bladder cancer (MIBC) samples were used as prognostic factors of different subtypes of MIBC.

Results

Chromatin regulatory genes were frequently mutated in both UTUC and UCB. Rapid relapse and progression of non-MIBC are correlated with alterations of KMT2C and EP300. Frequency of alterations in chromatin regulatory genes is higher in UTUC patients with SBS22 and SBS2 signatures and lower in UCB patients with SBS2 and SBS6 signatures. GATA3 and CK5 double-positive patients with higher frequencies of SMARCA4, ARID1A, and EP300 mutations have better prognoses than patients with basal subtypes. Although UTUC and UCB in the same patient can be either clonally related or developed independently, mutated genes in chromatin pathway were enriched in the related clones. Compared to UTUC, UCB had more deleterious mutations in DNA damage repair (DDR) genes, higher levels of tumor mutation burden (TMB) and copy number variations (CNVs), as well as higher TCR clonality and lower TCR diversity.

Conclusions

Since genetic alterations of the chromatin pathway genes are important in both UTUC and UCB, they could serve as potential biomarkers for predicting disease progression and therapeutic targets. Differences in mutation frequencies of DDR pathway, TMB, CNV, and TCR might be the contributing factors for the distinct responses to immune checkpoint inhibitor (ICI) between UTUC and UCB.

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上尿路尿道癌和尿道膀胱癌中染色质调控基因的遗传变异

目的：上尿路尿路上皮癌（UTUC）和膀胱尿路上皮癌（UCB）具有相同的组织形态学和治疗特征，但流行病学和临床病理学特征各不相同。我们研究了UTUC和UCB的分子亚型、克隆相关性和T细胞受体（TCR）多样性中染色质调控基因的改变：对63名患者的34份UTUC和49份UCB标本进行了靶向新一代测序或全外显子组DNA测序和TCR测序。根据 CK5 和 GATA3 的表达对肿瘤进行亚型分类。78份肌肉浸润性膀胱癌（MIBC）样本的组织芯片结果被用作MIBC不同亚型的预后因素：结果：染色质调控基因在UTUC和UCB中都经常发生突变。非MIBC的快速复发和进展与KMT2C和EP300的改变有关。染色质调控基因的改变频率在具有SBS22和SBS2特征的UTUC患者中较高，而在具有SBS2和SBS6特征的UCB患者中较低。GATA3和CK5双阳性、SMARCA4、ARID1A和EP300突变频率较高的患者比基底亚型患者预后更好。虽然同一患者的UTUC和UCB可能是克隆相关的，也可能是独立发展的，但染色质通路的突变基因在相关克隆中富集。与UTUC相比，UTCB的DNA损伤修复（DDR）基因有更多的有害突变，肿瘤突变负荷（TMB）和拷贝数变异（CNV）水平更高，TCR克隆性更高，TCR多样性更低：由于染色质通路基因的遗传改变在UTUC和UCB中都很重要，因此它们可以作为预测疾病进展和治疗目标的潜在生物标记物。DDR通路、TMB、CNV和TCR突变频率的差异可能是导致UTUC和UCB对免疫检查点抑制剂（ICI）产生不同反应的因素。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Medicine ONCOLOGY-

CiteScore

5.50

自引率

2.50%

发文量

907

审稿时长

19 weeks

期刊介绍： Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas: Clinical Cancer Research Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations Cancer Biology: Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery. Cancer Prevention: Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach. Bioinformatics: Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers. Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.