Xiao Zhiwen, Xu Huaxiang, Strosberg Jonathan R, Lu Renquan, Zhu Xinzhe, Deng Shengming, Ding Lei, Ni Quanxing, Warshaw Andrew L, Yu Xianjun, Luo Guopei
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Int J Cancer. 2023 Jul 1;153(1):164-172. doi: 10.1002/ijc.34499. Epub 2023 Mar 17.
pNENs are relative indolent tumors with heterogeneous clinical presentation at diagnosis. It is important to establish aggressive subgroups of pNENs and identify potential therapeutic targets. Patients with pNEN (322 cases) were included to examine the association between glycosylation biomarkers and clinical/pathological traits. The molecular and metabolic features stratified by glycosylation status were assessed by RNA-seq/whole exome sequencing and immunohistochemistry. A considerable proportion of patients had elevated glycosylation biomarkers (carbohydrate antigen [CA] 19-9, 11.9%; CA125, 7.5%; carcinoembryonic antigen [CEA], 12.8%). CA19-9 (hazard ratio [HR] = 2.26, P = .019), CA125 (HR = 3.79, P = .004) and CEA (HR = 3.16, P = .002) were each independent prognostic variables for overall survival. High glycosylation group, defined as pNENs with elevated level of circulating CA19-9, CA125 or CEA, accounted for 23.4% of all pNENs. High glycosylation (HR = 3.14, P = .001) was an independent prognostic variable for overall survival and correlated with G3 grade (P < .001), poor differentiation (P = .001), perineural invasion (P = .004) and distant metastasis (P < .001). Epidermal growth factor receptor (EGFR) was enriched in high glycosylation pNENs using RNA-seq. EGFR was expressed in 21.2% of pNENs using immunohistochemistry and associated with poor overall survival (P = .020). A clinical trial focusing on EGFR expressed pNENs was initiated (NCT05316480). Thus, pNEN with aberrant glycosylation correlates with a dismal outcome and suggests potential therapeutic target of EGFR.
胰腺神经内分泌肿瘤（pNENs）是相对惰性的肿瘤，诊断时临床表现具有异质性。确定pNENs的侵袭性亚组并识别潜在治疗靶点很重要。纳入322例pNEN患者，以研究糖基化生物标志物与临床/病理特征之间的关联。通过RNA测序/全外显子测序和免疫组织化学评估按糖基化状态分层的分子和代谢特征。相当一部分患者的糖基化生物标志物升高（糖类抗原[CA]19-9，11.9%；CA125，7.5%；癌胚抗原[CEA]，12.8%）。CA19-9（风险比[HR]=2.26，P=0.019）、CA125（HR=3.79，P=0.004）和CEA（HR=3.16，P=0.002）均为总生存期的独立预后变量。高糖基化组定义为循环CA19-9、CA125或CEA水平升高的pNENs，占所有pNENs的23.4%。高糖基化（HR=3.14，P=0.001）是总生存期的独立预后变量，与G3级（P<0.001）、低分化（P=0.001）、神经周围侵犯（P=0.004）和远处转移（P<0.001）相关。使用RNA测序发现表皮生长因子受体（EGFR）在高糖基化pNENs中富集。使用免疫组织化学检测发现EGFR在21.2%的pNENs中表达，且与总生存期差相关（P=0.020）。一项针对EGFR表达的pNENs的临床试验已启动（NCT05316480）。因此，糖基化异常的pNENs与不良预后相关，并提示EGFR可能是治疗靶点。
