南方医科大学学报

南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (10): 2270-2276.doi: 10.12122/j.issn.1673-4254.2025.10.23

• • 上一篇    

HOTAIR rs920778多态性调控乳腺癌易感性及HER2靶向治疗耐药的临床研究

张明亮1(), 孙非凡2, 韩卓琪2, 高越2, 罗毅2   

  1. 1.蚌埠医科大学第一附属医院肿瘤外科，安徽 蚌埠 233000
    2.蚌埠医科大学研究生院，安徽 蚌埠 233000
  • 收稿日期:2025-03-10 出版日期:2025-10-20 发布日期:2025-10-24
  • 作者简介:张明亮，医学博士，主任医师，副教授，博士生导师，E-mail: zhangmingliang@bbmc.edu.cn
  • 基金资助:
    安徽省高校自然科学基金重点项目(2022AH051519);北京科创医学发展基金会资助项目(KC2021-JF-0167-20)

HOTAIR rs920778 single nucleotide polymorphism is associated with breast cancer susceptibility and HER2-targeted therapy resistance in Chinese population

Mingliang ZHANG1(), Feifan SUN2, Zhuoqi HAN2, Yue GAO2, Yi LUO2   

  1. 1.Department of Surgical Oncology, First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
    2.Graduate School, Bengbu Medical University, Bengbu 233000, China
  • Received:2025-03-10 Online:2025-10-20 Published:2025-10-24

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摘要：

目的 探讨HOTAIR基因rs920778单核苷酸多态性（SNP）与皖北人群乳腺癌易感性及抗HER2靶向治疗敏感性的关联。 方法 采用TaqMan探针实时荧光定量PCR技术对287例乳腺癌患者及260例健康对照的外周血基因组DNA进行rs920778位点（chr12：54，376，218）基因分型。通过卡方检验比较两组人群的基因型（GG/GT/TT）及等位基因（G/T）分布频率，评估其与乳腺癌发病风险的相关性。进一步结合患者临床病理资料（包括肿瘤大小、淋巴结转移、ER/PR/HER2状态及分子分型），采用多因素Logistic回归分析该位点与乳腺癌侵袭性特征的关系。针对HER2阳性亚组，分析rs920778基因型与双靶向治疗（曲妥珠单抗［6 mg/kg，每3周1次］联合帕妥珠单抗［420 mg，每3周1次］＋多西他赛［75 mg/m²］方案）疗效的相关性，主要观察指标包括病理完全缓解率（pCR）、客观缓解率（ORR）及无进展生存期（PFS）。 结果 rs920778的TT基因型显著增加乳腺癌发病风险（OR=1.54，95% CI=1.09-2.19，P=0.017），且与晚期肿瘤分期（P<0.001）、淋巴结转移（P<0.001）及三阴性亚型（P<0.001）相关。HER2阳性患者中，TT基因型携带者对靶向联合化疗的客观缓解率显著降低（33.3% vs 89.3%，P=0.001），且新辅助治疗后病理完全缓解率下降（P=0.018）。 结论 HOTAIR基因rs920778的TT基因型是乳腺癌易感性和恶性进展的独立危险因素，并可能作为HER2阳性患者靶向治疗耐药的预后标志物。

关键词: HOTAIR, 单核苷酸多态性, 乳腺癌易感性, 治疗敏感性, 预后标志物

Abstract:

Objective To investigate the association of HOTAIR gene rs920778 single nucleotide polymorphism (SNP) with breast cancer susceptibility and response to HER2-targeted therapy in a Chinese population. Methods TaqMan probe-based real-time quantitative PCR was used for genotyping of the rs920778 locus (chr12:54,376,218) in peripheral blood genomic DNA from 287 breast cancer patients and 260 healthy individuals from northern Anhui Province. The genotype (GG, GT and TT) and allele (G/T) distribution frequencies were compared between the two groups to evaluate their association with breast cancer risk. Multivariate logistic regression analysis was conducted to assess the relationship between SNP at this locus and aggressive clinicopathological features (including tumor size, lymph node metastasis, ER/PR/HER2 status, and molecular subtypes) of breast cancer. For the HER2-positive subgroup, the association between rs920778 genotype and responses to dual-targeted therapy (trastuzumab [6 mg/kg q3w]+pertuzumab [420 mg q3w] + docetaxel [75 mg/m²]) was analyzed. The primary endpoints included pathological complete response rate (pCR), objective response rate (ORR), and progression-free survival (PFS). Results The TT genotype of rs920778 was associated with a significantly increased breast cancer susceptibility (OR=1.54, 95% CI: 1.09-2.19; P=0.017), an advanced tumor stage (P<0.001), lymph node metastasis (P<0.001), and the triple-negative subtype (P<0.001). In HER2-positive patients, TT genotype carriers had a markedly reduced objective response rate to dual HER2-targeted therapy (33.3% vs 89.3%, P=0.001) and a lower pathological complete response rate after neoadjuvant therapy (P=0.018). Conclusion The TT genotype of HOTAIR rs920778 serves as an independent risk factor for breast cancer susceptibility and aggressive progression in Chinese population and may predict the resistance to HER2-targeted therapies, suggesting its potential as a prognostic biomarker for precision oncology.

Key words: HOTAIR, single nucleotide polymorphism, breast cancer susceptibility, therapeutic sensitivity, prognostic biomarker