Clinical and molecular significance of homologous recombination deficiency positive non-small cell lung cancer in Chinese population:An integrated genomic and transcriptional analysis

Yifei Wang ¹Yidan Ma ¹Lei He ¹Jun Du ¹Xiaoguang Li ²Peng Jiao ³Xiaonan Wu ⁴Xiaomao Xu ⁵Wei Zhou ⁵Li Yang ¹Jing Di ¹Changbin Zhu ⁶Liming Xu ⁶Tianlin Sun ⁶Lin Li ⁴Dongge Liu ¹Zheng Wang¹

扫码查看

作者信息

1. Department of Pathology,Beijing Hospital,National Center of Gerontology,Institute of Geriatric Medicine,Chinese Academy of Medical Sciences,Beijing 100730,China
2. Department of Minimally Invasive Tumor Therapies Center,Beijing Hospital,National Center of Gerontology,Institute of Geriatric Medicine,Chinese Academy of Medical Sciences,Beijing 100730,China
3. Department of Thoracic Surgery,Beijing Hospital,National Center of Gerontology,Institute of Geriatric Medicine,Chinese Academy of Medical Sciences,Beijing 100730,China
4. Department of Oncology,Beijing Hospital,National Center of Gerontology,Institute of Geriatric Medicine,Chinese Academy of Medical Sciences,Beijing 100730,China
5. Department of Respiratory and Critical Care Medicine,Beijing Hospital,National Center of Gerontology,Institute of Geriatric Medicine,Chinese Academy of Medical Sciences,Beijing 100730,China
6. Amoy Diagnostics Co.,Ltd.,Xiamen 361027,China
折叠

Abstract

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-naive 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.

Key words

Non-small cell lung cancer/homologous recombination deficiency/genetic alterations/transcriptional analysis/tumor microenvironment/prognosis

引用本文复制引用

基金项目

National High Level Hospital Clinical Research Funding(BJ-2219-195)

National High Level Hospital Clinical Research Funding(BJ-2023-090)

出版年

2024

中国癌症研究(英文版)

中国抗癌协会北京市肿瘤研究所

中国癌症研究(英文版)

CSTPCDCSCD

影响因子：1.592

ISSN：1000-9604

参考文献量1

段落导航