Department of Integrative Oncology, China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing University of Chinese Medicine, Beijing, China.
Neuroendocrinology. 2023;113(9):943-956. doi: 10.1159/000530968. Epub 2023 May 12.
Treatment response to the standard therapy is low for metastatic pancreatic neuroendocrine tumors (PanNETs) mainly due to the tumor heterogeneity. We investigated the heterogeneity between primary PanNETs and metastases to improve the precise treatment.
The genomic and transcriptomic data of PanNETs were retrieved from the Genomics, Evidence, Neoplasia, Information, Exchange (GENIE), and Gene Expression Omnibus (GEO) database, respectively. Potential prognostic effects of gene mutations enriched in metastases were investigated. Gene set enrichment analysis was performed to investigate the functional difference. Oncology Knowledge Base was interrogated for identifying the targetable gene alterations.
Twenty-one genes had significantly higher mutation rates in metastases which included TP53 (10.3% vs. 16.9%, p = 0.035) and KRAS (3.7% vs. 9.1%, p = 0.016). Signaling pathways related to cell proliferation and metabolism were enriched in metastases, whereas epithelial-mesenchymal transition (EMT) and TGF-β signaling were enriched in primaries. Gene mutations were highly enriched in metastases that had significant unfavorable prognostic effects included mutation of TP53 (p < 0.001), KRAS (p = 0.001), ATM (p = 0.032), KMT2D (p = 0.001), RB1 (p < 0.001), and FAT1 (p < 0.001). Targetable alterations enriched in metastases included mutation of TSC2 (15.5%), ARID1A (9.7%), KRAS (9.1%), PTEN (8.7%), ATM (6.4%), amplification of EGFR (6.0%), MET (5.5%), CDK4 (5.5%), MDM2 (5.0%), and deletion of SMARCB1 (5.0%).
Metastases exhibited a certain extent of genomic and transcriptomic diversity from primary PanNETs. TP53 and KRAS mutation in primary samples might associate with metastasis and contribute to a poorer prognosis. A high fraction of novel targetable alterations enriched in metastases deserves to be validated in advanced PanNETs.
转移性胰腺神经内分泌肿瘤（PanNETs）对标准治疗的反应较低，主要是由于肿瘤异质性。我们研究了原发 PanNETs 和转移灶之间的异质性，以改善精准治疗。
从 Genomics, Evidence, Neoplasia, Information, Exchange (GENIE) 和 Gene Expression Omnibus (GEO) 数据库分别检索 PanNETs 的基因组和转录组数据。研究了转移灶中基因突变更具预后意义的潜在作用。进行基因集富集分析以研究功能差异。查询肿瘤学知识库以鉴定可靶向的基因改变。
21 个基因在转移灶中具有更高的突变率，包括 TP53（10.3%比 16.9%，p=0.035）和 KRAS（3.7%比 9.1%，p=0.016）。与细胞增殖和代谢相关的信号通路在转移灶中富集，而上皮-间充质转化（EMT）和 TGF-β 信号在原发灶中富集。在具有显著不良预后意义的转移灶中，基因突变高度富集，包括 TP53（p<0.001）、KRAS（p=0.001）、ATM（p=0.032）、KMT2D（p=0.001）、RB1（p<0.001）和 FAT1（p<0.001）的突变。在转移灶中富集的可靶向改变包括 TSC2（15.5%）、ARID1A（9.7%）、KRAS（9.1%）、PTEN（8.7%）、ATM（6.4%）、EGFR 扩增（6.0%）、MET（5.5%）、CDK4（5.5%）、MDM2（5.0%）和 SMARCB1 缺失（5.0%）。
转移灶与原发 PanNETs 相比表现出一定程度的基因组和转录组多样性。原发样本中的 TP53 和 KRAS 突变可能与转移相关，并导致预后较差。转移灶中富集的大量新的可靶向改变值得在晚期 PanNETs 中进一步验证。
