Department of Breast Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
Cancer Biomark. 2022;35(2):127-142. doi: 10.3233/CBM-203103.
N6-methyladenosine (m6A) is a common RNA modification on eukaryotic mRNA and some of the m6A regulatory proteins play a crucial role in breast cancer. However, the copy number variations for m6A regulatory proteins and their role in clinicopathological characteristics and survival in breast cancer remain unclear.
In this study, we screened the m6A related genes alterations in breast cancer by analyzing the Molecular Taxonomy of Breast Cancer International Consortium and The Cancer Genome Atlas database, and further analyzed the clinical prognostic value of YTHDF1 amplification.
The YTH domain family (YTHDF3 and YTHDF1) amplification exhibited higher alteration rates among 10 m6A regulatory genes. YTHDF1 and YTHDF3 amplification resulted in higher mRNA expression (P< 0.0001). Protein expression of YTHDF1 and YTHDF3 were higher in breast cancer (P< 0.0001). YTHDF1 amplification presented a high correlation with worse clinicopathological characteristics and overall survival in patients with breast cancer. Cox regression analysis showed that YTHDF1 amplification was an independent risk factor for 10-year overall survival in breast cancer (Hazard ratio: 1.663; 95% confidence interval: 1.298-2.131; P< 0.001). Gene set enrichment analysis revealed that the downstream target of YTHDF1 may be related to MYC signaling regulation and T cell differentiation. Moreover, YTHDF1 amplification and high expression resulted in lower immune cell infiltration. YTHDF1 knockdown retrained proliferation, migration and invasion in breast cancer cells in vitro.
We found significant worse clinical characteristics and lower immune infiltrates in patients with YTHDF1 amplification. The findings indicate that YTHDF1 amplification may be a potential target for the treatment of breast cancer.
N6-甲基腺苷（m6A）是真核 mRNA 上常见的 RNA 修饰，一些 m6A 调控蛋白在乳腺癌中起着至关重要的作用。然而，m6A 调控蛋白的拷贝数变异及其在乳腺癌临床病理特征和生存中的作用尚不清楚。
本研究通过分析乳腺癌国际分子分类联盟和癌症基因组图谱数据库，筛选乳腺癌中 m6A 相关基因的改变，并进一步分析 YTHDF1 扩增的临床预后价值。
在 10 个 m6A 调控基因中，YTH 结构域家族（YTHDF3 和 YTHDF1）扩增显示出更高的改变率。YTHDF1 和 YTHDF3 扩增导致更高的 mRNA 表达（P<0.0001）。YTHDF1 和 YTHDF3 的蛋白表达在乳腺癌中更高（P<0.0001）。YTHDF1 扩增与乳腺癌患者更差的临床病理特征和总生存相关。Cox 回归分析显示，YTHDF1 扩增是乳腺癌 10 年总生存的独立危险因素（危险比：1.663；95%置信区间：1.298-2.131；P<0.001）。基因集富集分析显示，YTHDF1 的下游靶标可能与 MYC 信号调节和 T 细胞分化有关。此外，YTHDF1 扩增和高表达导致免疫细胞浸润减少。YTHDF1 敲低可恢复乳腺癌细胞在体外的增殖、迁移和侵袭能力。
我们发现 YTHDF1 扩增的患者具有显著更差的临床特征和更低的免疫浸润。这些发现表明，YTHDF1 扩增可能是治疗乳腺癌的潜在靶点。
