Wang Xi, Bao Shengnan, Jiang Mengping, Zou Xian, Yin Yongmei
Department of Radiotherapy, Affiliated Hospital 2 of Nantong University (Nantong First People's Hospital), Nantong, 226300, Jiangsu, China.
Department of Oncology, Tumor Hospital Affiliated to Nantong University, Nantong, 226300, Jiangsu, China.
Clin Transl Oncol. 2025 Jan;27(1):233-256. doi: 10.1007/s12094-024-03547-9. Epub 2024 Jun 26.
Breast cancer (BC) is the world's largest tumor species in which hormone receptor-positive patients have relatively good prognosis. However, majority of patients will develop late resistance, one of the important factors is due to the loss of the original estrogen receptor (ER) expression.
We conducted this study in 115 patients with BC who experienced second biopsy at Jiangsu Province Hospital (JSPH) and divided patients into two subgroups ER + to - and ER + to + . First, clinicopathological characteristics between two groups were evaluated. Second, we explored candidate genes related to BC ER intratumor heterogeneity by applying next-generation sequencing (NGS) in 42 patients. Multi-omics integrative analysis of tumor transcriptomic, cancer-related pathway, diagnostic and prognostic value and immune profile were conducted. Besides, preliminary assay were also used to evaluate the correlation between KMT2C and ERα (ESR1) expression. The CCK-8, 5-Ethynyl-2'-deoxyuridine (EdU) assays, Transwell assays and the wound scratch tests were applied to explore the cellular interactions between KMT2C and BC.
We find the histological type (p = 0.008) and disease-free survival (DFS) (p = 0.004) were significantly different in two subgroups. In Cox survival analysis, metastasis (Hazard ratio (HR) > 1, p = 0.007) and neo-adjuvant (HR < 1, p < 0.001) are independent prognostic factors of DFS. Besides, by analyzing NGS results, we found four genes KMT2C, FGFR19, FGF1 and FGF4 were highly mutated genes in ER + to - subgroup. Furthermore, the gene KMT2C displayed significant diagnostic value and prognostic value in BC and pan-cancer. In addition, a positive correlation between KMT2C expression and immune infiltrating levels of T cell CD4 + , macrophage and neutrophil was found. In the end, Western blot and RT-qPCR assay were used and found KMT2C and ERα (ESR1) expressions are strongly positive correlated in mRNA and protein level. Inhibition of KMT2C significantly reduced proliferation, invasion, and migration of MCF7 cells.
People in two cohorts from JSPH presented different clinical characteristics and prognosis. The gene KMT2C may affect the progression of BC by regulating the molecular, epigenetic activity and immune infiltration. It may also serve as a novel prognostic biomarker for BC patients who underwent ER status converted from positive to negative.
乳腺癌（BC）是全球最常见的肿瘤类型，其中激素受体阳性患者预后相对较好。然而，大多数患者会出现晚期耐药，重要因素之一是原始雌激素受体（ER）表达缺失。
我们对115例在江苏省人民医院接受二次活检的BC患者进行了本研究，并将患者分为两个亚组，即ER +转 - 和ER +转 +。首先，评估两组之间的临床病理特征。其次，我们对42例患者应用二代测序（NGS）探索与BC ER肿瘤内异质性相关的候选基因。进行了肿瘤转录组学、癌症相关通路、诊断和预后价值以及免疫图谱的多组学综合分析。此外，还采用初步试验评估KMT2C与ERα（ESR1）表达之间的相关性。应用CCK-8、5-乙炔基-2'-脱氧尿苷（EdU）试验、Transwell试验和伤口划痕试验探索KMT2C与BC之间的细胞相互作用。
我们发现两个亚组的组织学类型（p = 0.008）和无病生存期（DFS）（p = 0.004）存在显著差异。在Cox生存分析中，转移（风险比（HR）>1，p = 0.007）和新辅助治疗（HR<1，p<0.001）是DFS的独立预后因素。此外，通过分析NGS结果，我们发现四个基因KMT2C、FGFR19、FGF1和FGF4是ER +转 - 亚组中的高突变基因。此外，基因KMT2C在BC和泛癌中显示出显著的诊断价值和预后价值。此外，发现KMT2C表达与T细胞CD4 +、巨噬细胞和中性粒细胞的免疫浸润水平呈正相关。最后，使用蛋白质免疫印迹和RT-qPCR试验，发现KMT2C和ERα（ESR1）在mRNA和蛋白质水平上的表达呈强正相关。抑制KMT2C可显著降低MCF7细胞的增殖、侵袭和迁移。
江苏省人民医院两个队列的患者表现出不同的临床特征和预后。基因KMT2C可能通过调节分子、表观遗传活性和免疫浸润影响BC的进展。它也可能作为ER状态从阳性转变为阴性的BC患者的新型预后生物标志物。
