Nigde Omer Halisdemir University Training and Research Hospital, Clinical Biochemistry Laboratory, Nigde, Turkey.
Nigde Omer Halisdemir University Training and Research Hospital, Clinical Biochemistry Laboratory, Nigde, Turkey; Nigde Omer Halisdemir University, Faculty of Medicine, Medical Biochemistry, Nigde, Turkey.
Comput Biol Med. 2024 Dec;183:109304. doi: 10.1016/j.compbiomed.2024.109304. Epub 2024 Oct 21.
Neuropeptide receptors are expressed in many malignancies. Effectors involved in the action mechanisms of HCRTR1, HCRTR2, NPY4R (PPYR1) may be related to breast cancer (BC). Genes encoding these receptors and PPY and PTPN11 genes were aimed to examine via bioinformatics tools in the BRCA cohort. To our knowledge, this is the first study in which these receptor genes and PP, which have not found much research in BC, are examined together with PTPN11 and analyzed comprehensively in large patient cohorts from public databases.
cBioPortal was used for gene alteration analyses, GeneMania for association analyses with other genes, Kaplan-Meier Plotter for Overall Survival (OS) and Relapse Free Survival (RFS) analyses, UALCAN for methylation analyses, TIMER2.0 for expression analyses, The Human Protein Atlas database for expression validations, TIMER for immune infiltration analyses, WEKA 3.8.6 for diagnostic classification performances of the genes based on Random Forest Classifier and Enrichr-KG for Gene Ontology (GO) Biological Process (BP) and KEGG analysis.
19 (1.9 %) nucleotide changes were found in 996 cases. Missense mutation is most common. Decreased expression levels of the HCRTR1 gene were associated with shorter OS and RFS, but decreased expression levels of the PTPN11 gene were associated with longer OS and RFS. Decreased expression levels NPY4R (PPYR1) gene were associated with shorter RFS. Increased expression levels of HCRTR2 and PPY genes were associated with longer RFS. HCRTR1 and NPY4R (PPYR1) genes were statistically hypermethylated; conversely HCRTR2 and PPY genes were hypomethylated. There was no significant change in PTPN11 gene promoter methylation level. HCRTR1, NPY4R (PPYR1) and PTPN11 gene expressions were downregulated; conversely, HCRTR2 and PPY gene expressions upregulated. Weak correlations were observed between NPY4R (PPYR1) gene expression and CD4 T Cell, Neutrophil, Dendritic Cell and between PTPN11 gene expression and CD8 T Cell, Macrophage, Neutrophil, Dendritic Cell infiltrations. Area under the receiver operating characteristics curve values of the 10-fold cross-validation and by splitting the dataset in a ratio of 80:20 models were 0.930 and 0.963 respectively. HCRTR2 and HCRTR1 belong to regulation of cytosolic calcium ion concentration, cellular calcium ion homeostasis GO BPs.
In BC patients, increases in HCRTR2 and PPY gene expressions could be considered as positive prognostic factors. Decreases in HCRTR1 and NPY4R (PPYR1) gene expressions could be considered as negative prognostic factors. Decreased expression of PTPN11 gene may have a positive prognostic factor. Changes in existing genes are likely to be both a biomarker and therapeutic target for BC. However, experimental and clinical studies are needed to elucidate the mechanisms underlying these neuropeptide receptors in terms of breast carcinogenesis.
神经肽受体在许多恶性肿瘤中表达。涉及 HCRTR1、HCRTR2、NPY4R（PPYR1）作用机制的效应子可能与乳腺癌（BC）有关。本研究旨在通过生物信息学工具在 BRCA 队列中检测这些受体基因和 PPY 以及 PTPN11 基因。据我们所知，这是首次在大型公共数据库中，同时检测这些在 BC 中研究甚少的受体基因和 PP，以及 PTPN11，并进行全面分析。
使用 cBioPortal 进行基因改变分析，使用 GeneMania 进行与其他基因的关联分析，使用 Kaplan-Meier Plotter 进行总生存（OS）和无复发生存（RFS）分析，使用 UALCAN 进行甲基化分析，使用 TIMER2.0 进行表达分析，使用 The Human Protein Atlas 数据库进行表达验证，使用 TIMER 进行免疫浸润分析，使用 WEKA 3.8.6 基于随机森林分类器对基因进行诊断分类性能分析，使用 Enrichr-KG 进行基因本体论（GO）生物过程（BP）和 KEGG 分析。
在 996 例病例中发现了 19 个（1.9%）核苷酸变化。错义突变最为常见。HCRTR1 基因表达水平降低与 OS 和 RFS 缩短有关，而 PTPN11 基因表达水平降低与 OS 和 RFS 延长有关。NPY4R（PPYR1）基因表达水平降低与 RFS 缩短有关。HCRTR2 和 PPY 基因表达水平升高与 RFS 延长有关。HCRTR1 和 NPY4R（PPYR1）基因呈统计学超甲基化；相反，HCRTR2 和 PPY 基因呈低甲基化。PTPN11 基因启动子甲基化水平无显著变化。HCRTR1、NPY4R（PPYR1）和 PTPN11 基因表达下调；相反，HCRTR2 和 PPY 基因表达上调。NPY4R（PPYR1）基因表达与 CD4 T 细胞、中性粒细胞、树突状细胞呈弱相关，PTPN11 基因表达与 CD8 T 细胞、巨噬细胞、中性粒细胞、树突状细胞浸润呈弱相关。10 倍交叉验证和数据集 80:20 分割模型的受试者工作特征曲线下面积值分别为 0.930 和 0.963。HCRTR2 和 HCRTR1 属于细胞溶质钙离子浓度调节、细胞钙离子稳态 GO BP。
在 BC 患者中，HCRTR2 和 PPY 基因表达的增加可被视为阳性预后因素。HCRTR1 和 NPY4R（PPYR1）基因表达的降低可被视为阴性预后因素。PTPN11 基因表达降低可能具有阳性预后因素。现有基因的变化可能既是 BC 的生物标志物，也是治疗靶点。然而，需要进行实验和临床研究，以阐明这些神经肽受体在乳腺癌发生中的作用机制。
