同源重组缺陷阳性非小细胞肺癌在中国人群中的临床和分子意义:基因组和转录的综合分析

IF 7 2区 医学 Q1 ONCOLOGY Chinese Journal of Cancer Research Pub Date : 2024-06-30 DOI:10.21147/j.issn.1000-9604.2024.03.05
Yifei Wang, Yidan Ma, Lei He, Jun Du, Xiaoguang Li, Peng Jiao, Xiaonan Wu, Xiaomao Xu, Wei Zhou, Li Yang, Jing Di, Changbin Zhu, Liming Xu, Tianlin Sun, Lin Li, Dongge Liu, Zheng Wang
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引用次数: 0

摘要

目的:同源重组缺陷(HRD)在乳腺癌、卵巢癌和前列腺癌中的临床意义已经确立,但HRD在非小细胞肺癌(NSCLC)中的价值尚未得到充分研究。本研究旨在系统分析未经治疗的 NSCLC 的 HRD 状态及其与患者预后的关系,以进一步指导临床治疗:方法:共回顾性纳入了355例未经治疗的NSCLC患者。HRD状态使用AmoyDx基因组疤痕评分(GSS)进行评估,评分≥50分为HRD阳性。分析了HRD阳性和HRD阴性患者的基因组、转录组、肿瘤微环境特征和预后:结果:HRD阳性患者占25.1%(89/355)。与HRD阴性患者相比,HRD阳性患者有更多的体细胞致病性同源重组修复(HRR)突变,肿瘤突变负荷(TMB)更高(表皮生长因子受体(EGFR)/无性淋巴瘤激酶(ALK)突变NSCLC中的PMET和MYC,以及EGFR/ALK野生型NSCLC中更多的PIK3CA和AURKA)。HRD阳性的NSCLC显示出更高的肿瘤增殖和免疫抑制活性。HRD阴性NSCLC显示出主要组织相容性复合体(MHC)-II、干扰素(IFN)-γ和效应记忆CD8+ T细胞的活化特征。HRD阳性患者的预后较差,接受靶向治疗(第一代和第三代表皮生长因子受体抑制剂-TKIs)后的无进展生存期(PFS)较短(P=0.042)。此外,HRD阳性、表皮生长因子受体/ALK野生型患者对无铂免疫治疗方案的反应较低:结论:在HRD阳性NSCLC中发现了独特的基因组和转录特征。HRD阳性NSCLC预后差,对表皮生长因子受体抑制剂(EGFR-TKIs)和免疫疗法反应差。这项研究强调了HRD阳性NSCLC中潜在的可操作改变,为这些患者提出了可能的联合治疗策略。
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Clinical and molecular significance of homologous recombination deficiency positive non-small cell lung cancer in Chinese population: An integrated genomic and transcriptional analysis.

Objective: The clinical significance of homologous recombination deficiency (HRD) in breast cancer, ovarian cancer, and prostate cancer has been established, but the value of HRD in non-small cell lung cancer (NSCLC) has not been fully investigated. This study aimed to systematically analyze the HRD status of untreated NSCLC and its relationship with patient prognosis to further guide clinical care.

Methods: A total of 355 treatment-naïve NSCLC patients were retrospectively enrolled. HRD status was assessed using the AmoyDx Genomic Scar Score (GSS), with a score of ≥50 considered HRD-positive. Genomic, transcriptomic, tumor microenvironmental characteristics and prognosis between HRD-positive and HRD-negative patients were analyzed.

Results: Of the patients, 25.1% (89/355) were HRD-positive. Compared to HRD-negative patients, HRD-positive patients had more somatic pathogenic homologous recombination repair (HRR) mutations, higher tumor mutation burden (TMB) (P<0.001), and fewer driver gene mutations (P<0.001). Furthermore, HRD-positive NSCLC had more amplifications in PI3K pathway and cell cycle genes, MET and MYC in epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutant NSCLC, and more PIK3CA and AURKA in EGFR/ALK wild-type NSCLC. HRD-positive NSCLC displayed higher tumor proliferation and immunosuppression activity. HRD-negative NSCLC showed activated signatures of major histocompatibility complex (MHC)-II, interferon (IFN)-γ and effector memory CD8+ T cells. HRD-positive patients had a worse prognosis and shorter progression-free survival (PFS) to targeted therapy (first- and third-generation EGFR-TKIs) (P=0.042). Additionally, HRD-positive, EGFR/ALK wild-type patients showed a numerically lower response to platinum-free immunotherapy regimens.

Conclusions: Unique genomic and transcriptional characteristics were found in HRD-positive NSCLC. Poor prognosis and poor response to EGFR-TKIs and immunotherapy were observed in HRD-positive NSCLC. This study highlights potential actionable alterations in HRD-positive NSCLC, suggesting possible combinational therapeutic strategies for these patients.

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来源期刊
自引率
9.80%
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1726
审稿时长
4.5 months
期刊介绍: Chinese Journal of Cancer Research (CJCR; Print ISSN: 1000-9604; Online ISSN:1993-0631) is published by AME Publishing Company in association with Chinese Anti-Cancer Association.It was launched in March 1995 as a quarterly publication and is now published bi-monthly since February 2013. CJCR is published bi-monthly in English, and is an international journal devoted to the life sciences and medical sciences. It publishes peer-reviewed original articles of basic investigations and clinical observations, reviews and brief communications providing a forum for the recent experimental and clinical advances in cancer research. This journal is indexed in Science Citation Index Expanded (SCIE), PubMed/PubMed Central (PMC), Scopus, SciSearch, Chemistry Abstracts (CA), the Excerpta Medica/EMBASE, Chinainfo, CNKI, CSCI, etc.
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