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中华乳腺病杂志(电子版) ›› 2024, Vol. 18 ›› Issue (05) : 274 -280. doi: 10.3877/cma.j.issn.1674-0807.2024.05.004

论 著

FAM91A1 可能是乳腺癌患者的独立预后因子
王睿1, 邓俊2, 施廷鑫3, 张志兆1, 王成方1, 张毅1, 齐晓伟1,()   
  1. 1.400038 重庆,陆军军医大学第一附属医院乳腺甲状腺外科
    2.400020 重庆,陆军军医大学第一附属医院江北院区心胸外科
    3.400038 重庆,陆军军医大学基础医学院
  • 收稿日期:2023-10-18 出版日期:2024-10-01
  • 通信作者: 齐晓伟
  • 基金资助:
    国家重点研发计划子课题(2022YFC2403401)重庆市杰出青年自然科学基金(CSTB2023NSCQ-JQX0012)重庆市技术创新与应用发展重点项目(CSTB2022TIAD-KPX0168)

FAM91A1 is a potential prognostic factor in breast cancer

Rui Wang1, Jun Deng2, Tingxin Shi3, Zhizhao Zhang1, Chengfang Wang1, Yi Zhang1, Xiaowei Qi1,()   

  1. 1.Department of Breast and Thyroid Surgery, First Affiliated Hospital of Army Medical University, Chongqing 4000038,China
    2.Department of Cardiothoracic Surgery of Jiangbei Campus,First Affiliated Hospital of Army Medical University, Chongqing 4000020, China
    3.School of Basic Medical Sciences, Army Medical University,Chongqing 4000038, China
  • Received:2023-10-18 Published:2024-10-01
  • Corresponding author: Xiaowei Qi
引用本文:

王睿, 邓俊, 施廷鑫, 张志兆, 王成方, 张毅, 齐晓伟. FAM91A1 可能是乳腺癌患者的独立预后因子[J/OL]. 中华乳腺病杂志(电子版), 2024, 18(05): 274-280.

Rui Wang, Jun Deng, Tingxin Shi, Zhizhao Zhang, Chengfang Wang, Yi Zhang, Xiaowei Qi. FAM91A1 is a potential prognostic factor in breast cancer[J/OL]. Chinese Journal of Breast Disease(Electronic Edition), 2024, 18(05): 274-280.

目的

研究FAM91A1 表达是否能作为乳腺癌独立预后因子,并探讨其可能的影响机制。

方法

利用UALCAN 数据库中的“TCGA”模块获得FAM91A1 在乳腺癌各个分型中的mRNA 表达,同时从TCGA 数据库获得1101 例乳腺癌患者表达谱及临床数据,将患者按FAM91A1 表达量中位值(37.653)分成低表达组(n =550)和高表达组(n =551)。 使用R 4.4.1 软件包进行生存分析,比较FAM91A1 高、低表达的乳腺癌患者的OS 差异。 采用Cox 回归分析寻找乳腺癌患者OS 的影响因素。 分析FAM91A1 与免疫检查点的相关性,同时使用Spearman 相关性分析描述FAM91A1 与肿瘤突变负荷的相关性。 利用STRING 网站及GEPIA2 数据库构建FAM91A1 相关基因数据集,采用GO 及KEGG 富集分析研究FAM91A1 功能及相关通路,利用MiRTarbase 数据库构建FAM91A1 相关ceRNA 网络并用StarBase 数据库进行验证。

结果

TCGA 数据库中FAM91A1 mRNA 在正常人群、Luminal 型、HER-2 阳性型及三阴型乳腺癌患者中的表达差异有统计学意义(P<0.001)。 生存分析显示, FAM91A1 基因高表达组患者与低表达组患者的OS 比较差异没有统计学意义(HR =1.36,95%CI:0.91 ~2.05,P =0.133)。Cox 回归分析显示年龄(HR=1.453,95%CI:1.128~1.875,P =0.004)、临床分级(HR =1.773,95%CI:1.125~2.794,P=0.014)、M 分期(HR =2.155,95%CI: 1.365 ~3.403,P<0.001)和FAM91A1 表达(HR =1.297,95%CI:1.031~1.631,P =0.026)是1101 例乳腺癌患者OS 的影响因素。 免疫检查点LGLEC15、LAG3、PDCD1、HAVCR2、CD274、PDCD1LG2 表达在FAM91A1 高、低表达组间具有明显差异(P 均<0.001),FAM91A1 表达与肿瘤突变负荷呈正相关(P <0.001)。 GO 功能富集分析发现FAM91A1 相关基因数据集多富集在小分子与脂质等代谢生物过程,在外部封装结构、细胞单元格边沿等细胞成分中,以及酶激活剂活性、GTP 酶激活剂活性、金属肽酶活性等分子功能中。 在KEGG 通路富集分析中,FAM91A1 相关基因多富集在ABC 转运蛋白通路、脂肪酸代谢通路等。 利用在线数据库,共得到1 个miRNA(hsa-mir-15a-5p)和7 个lncRNA(LINC01128、ERI3-IT1、FGD5-AS1、LINC02035、TUG1、XIST、ARMCX5-GPRASP2)组成的FAM91A1 相关ceRNA 网络。

结论

FAM91A1 可能是乳腺癌的独立预后因子,且与免疫浸润、ABC 转运蛋白通路及脂肪酸代谢密切相关。

Objective

To investigate the potential of FAM91A1 as an independent prognostic factor in breast cancer and explore the mechanism.

Methods

The expression of FAM91A1 in various breast cancer subtypes were obtained from the “TCGA” module of the UALCAN database, and the expression profiles and clinical data of 1101 breast cancer patients were downloaded from the TCGA database. The patients were divided into low expression group (n=550) and high expression group (n=551) according to the median value of FAM91A1 expression (37.653). Using R 4.4.1 software, survival analysis was conducted to compare the OS between breast cancer patients with high and low FAM91A1 expression, and Cox regression analysis was used to find the influencing factors of OS in breast cancer patients. The correlation between FAM91A1 and immune checkpoints was analyzed, and Spearman method was used to analyze the correlation between FAM91A1 and tumor mutation burden. The STRING website and GEPIA2 database were used to construct FAM91A1-related gene dataset. The GO and KEGG enrichment analysis were used to find the FAM91A1 function and related pathways. FAM91A1-related ceRNA network was constructed using the MiRTarbase database and validated with the StarBase database.

Results

There was a statistically significant difference in FAM91A1 mRNA expression between normal control, luminal, HER-2-positive, and triple negative breast cancer patients in the TCGA database (P <0.001).The results of the survival analysis indicated no significant difference in OS between FAM91A1 high expression group and low expression group (HR =1.36,95%CI:0.91-2.05,P =0.133). Cox regression analysis revealed that age (HR =1.453,95%CI:1.128-1.875,P =0.004), clinical grade (HR =1.773, 95%CI:1.125-2.794, P =0.014), M stage (HR =2.155, 95% CI:1.365-3.403, P<0.001), and FAM91A1 expression (HR =1.297, 95%CI:1.031-1.631, P =0.026)were independent factor affecting OS in1101 breast cancer patients. The expression of immune checkpoints (LGLEC15, LAG3, PDCD1, HAVCR2,CD274, PDCD1LG2) was significantly different between FAM91A1 expression group and low expression group(all P <0.001). The expression of FAM91A1 was positively correlated with tumor mutation burden (P <0.001). The Gene Ontology (GO) functional enrichment analysis revealed that gene datasets related to FAM91A1 were predominantly enriched in the following metabolic processes (small molecule and lipid metabolism), cellular components (external encapsulated structures, cellular unit cell edges) and molecular functions (enzyme activator activity, GTPase activator activity, and metallopeptidase activity). In the KEGG pathway enrichment analysis, the genes related to FAM91A1 were predominantly enriched in the ABC transporter protein pathway,fatty acid metabolism pathway,etc. By the online database,one miRNA (hsa-mir-15a-5p) and seven lncRNAs (LINC01128, ERI3-IT1, FGD5-AS1, LINC02035, TUG1, XIST, ARMCX5-GPRASP2) were identified within the FAM91A1-associated ceRNA network.

Conclusions

FAM91A1 may serve as an independent prognostic factor in breast cancer, exhibiting a strong correlation with immune infiltration, ABC transporter protein pathway and fatty acid metabolism.

表1 1101 例乳腺癌患者总生存率的单因素、多因素Cox 回归分析
图1 TCGA 数据库中FAM91A1 mRNA 在正常人群、Luminal型、HER-2 阳性型及三阴型乳腺癌患者中的表达差异 注: P<0.001(在线网站未显示相应的统计量)
图2 FAM91A1 高、低表达的乳腺癌患者总生存率比较 注: HR=1.36,95%CI:0.91~2.05,P=0.133
图3 FAM91A1 高、低表达组中不同免疫检查点基因表达差异 注:*表示P<0.05,**表示P<0.01,***表示P<0.001
图4 FAM91A1 表达水平与肿瘤突变负荷的相关性(P=4.39×10-5 注:每个黑点代表1 例患者,红色区域代表FAM91A1 基因表达密度分布锋图,蓝色区域代表肿瘤突变负荷分数密度分布锋图
图5 FAM91A1 相关基因分析 a 图表示利用STRING 工具预测的FAM91A1 基因的互作蛋白;b 图中蓝色表示通过STRING 网站得到的FAM91A1 基因相关的15 个互作蛋白,红色表示通过GEPIA2 数据库获取的与FAM91A1 相关性最强的前100 个基因
图6 FAM91A1 相关基因的GO/KEGG 富集分析结果 a、b、c 图分别显示GO 生物过程、细胞成分及分子功能富集分析;d 图为KEGG 信号通路富集分析 注:横坐标代表富集到某条通路基因的比例,纵坐标代表基因富集通路或功能的名称;每个气泡代表富集到这个通路或功能中的基因数目,气泡越大表示富集到该功能或通路的基因越多,气泡颜色代表校正之后的P 值,颜色越靠近蓝色,P 值越小,代表基因富集在此通路或功能的可能性越大;GO 为基因本体数据库,KEGG 为京都基因与基因组百科全书
图7 基于FAM91A1 基因构建的ceRNA 网络 注:红色图标表示mRNA,绿色图标表示miRNA,黄色图标表示lncRNA
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