Mao Xueyan, Ma Kang, Wang Yunjie, Long Cheng, Tan Xuejing, Chen Xi, Chen Bo
Institute of Clinical Anatomy & Reproductive Medicine, Hengyang Medical School, University of South China, Hengyang, 421000, Hunan, China.
Department of Breast Cancer, School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China.
Virchows Arch. 2025 Aug 14. doi: 10.1007/s00428-025-04218-y.
Breast cancer is a leading cause of cancer-related morbidity and mortality among women worldwide, with increasing incidence in China. The neurofibromatosis type 1 (NF1) gene, a critical tumor suppressor regulating the Ras/MAPK pathway, has been implicated in aggressive breast cancer phenotypes, yet its somatic alterations in Asian populations remain poorly characterized. This study integrates genomic, transcriptomic, and clinicopathological data from a Chinese breast cancer cohort (GDPH, n = 680), The Cancer Genome Atlas (TCGA), and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) consortium to elucidate the role of NF1 in breast cancer. We identified somatic NF1 alterations in 5.9% of the GDPH cohort, with truncating mutations (41.03%) and co-occurring TP53 (72.5%) and PIK3CA (55.0%) mutations being predominant. Comparative analysis revealed ethnic variations, with higher NF1 mutation frequencies in the GDPH cohort (5.00%) compared to TCGA (2.80%) and METABRIC (3.75%). NF1-altered tumors exhibited elevated tumor mutational burden (TMB) and distinct co-alterations in DNA repair and chromatin remodeling pathways. Survival analysis indicated worse outcomes in NF1-mutated METABRIC patients (HR = 0.747, p = 0.0165). Functional enrichment analysis linked NF1 deficiency to metabolic reprogramming, immune dysregulation, and T-cell dysfunction, supported by murine models showing resistance to anti-PD-1 therapy upon NF1 knockdown. Our findings highlight NF1 as a key modulator of breast cancer progression, immune evasion, and therapeutic response, with implications for precision oncology in diverse populations. This study comprehensively characterizes somatic NF1 alterations and identifies potential therapeutic vulnerabilities in NF1-deficient breast cancers.
乳腺癌是全球女性癌症相关发病和死亡的主要原因，在中国其发病率呈上升趋势。1型神经纤维瘤病（NF1）基因是调控Ras/MAPK通路的关键肿瘤抑制基因，与侵袭性乳腺癌表型有关，但其在亚洲人群中的体细胞改变仍未得到充分表征。本研究整合了来自中国乳腺癌队列（GDPH，n = 680）、癌症基因组图谱（TCGA）和国际乳腺癌分子分类联盟（METABRIC）的基因组、转录组和临床病理数据，以阐明NF1在乳腺癌中的作用。我们在5.9%的GDPH队列中发现了体细胞NF1改变，其中截短突变（41.03%）以及同时发生的TP53（72.5%）和PIK3CA（55.0%）突变最为常见。比较分析揭示了种族差异，GDPH队列中NF1突变频率（5.00%）高于TCGA（2.80%）和METABRIC（3.75%）。NF1改变的肿瘤表现出肿瘤突变负担（TMB）升高，并且在DNA修复和染色质重塑途径中存在明显的共改变。生存分析表明，METABRIC队列中NF1突变患者的预后较差（HR = 0.747，p = 0.0165）。功能富集分析将NF1缺陷与代谢重编程、免疫失调和T细胞功能障碍联系起来，小鼠模型显示敲低NF1后对抗PD - 1治疗产生抗性，支持了这一结果。我们的研究结果突出了NF1作为乳腺癌进展、免疫逃逸和治疗反应的关键调节因子，对不同人群的精准肿瘤学具有重要意义。本研究全面表征了体细胞NF1改变，并确定了NF1缺陷型乳腺癌的潜在治疗弱点。
