Coppola Domenico, Balducci Lodovico, Chen Dung-Tsa, Loboda Andrey, Nebozhyn Michael, Staller Aileen, Fulp William J, Dalton William, Yeatman Timothy, Brem Steven
Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA; Experimental Therapeutics, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA; Gastrointestinal, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA; M2Gen, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA.
Senior Oncology Programs, H. Lee Moffitt Cancer Center, Tampa, FL 33612-9497, USA.
J Geriatr Oncol. 2014 Oct 1;5(4):389-99. doi: 10.1016/j.jgo.2014.08.003. Epub 2014 Sep 11.
Senescence-associated genes (SAGs) are responsible for the senescence-associated secretory phenotype, linked in turn to cellular aging, the aging brain, and the pathogenesis of cancer.
We hypothesized that senescence-associated genes are overexpressed in older patients, in higher grades of glioma, and portend a poor prognosis.
Forty-seven gliomas were arrayed on a custom version of the Affymetrix HG-U133+2.0 GeneChip, for expression of fourteen senescence-associated genes: CCL2, CCL7, CDKN1A, COPG, CSF2RB, CXCL1, ICAM-1, IGFBP-3, IL-6, IL-8, SAA4, TNFRSF-11B, TNFSF-11 and TP53. A combined "senescence score" was generated using principal component analysis to measure the combined effect of the senescence-associated gene signature.
An elevated senescence score correlated with older age (r=0.37; P=.01) as well as a higher degree of malignancy, as determined by WHO, histological grade (r=0.49; P<.001). There was a mild association with poor prognosis (P=.06). Gliosarcomas showed the highest scores. Six genes independently correlated with either age (IL-6, TNFRSF-11B, IGFBP-3, SAA4, and COPG), prognosis (IL-6, SAA4), or the grade of the glioma (IL-6, IL-8, ICAM-1, IGFBP-3, and COPG).
We report: 1) a novel molecular signature in human gliomas, based on cellular senescence, translating the concept of SAG to human cancer; 2) the senescence signature is composed of genes central to the pathogenesis of gliomas, defining a novel, aggressive subtype of glioma; and 3) these genes provide prognostic biomarkers, as well as targets, for drug discovery and immunotherapy.
衰老相关基因（SAGs）导致衰老相关分泌表型，进而与细胞衰老、脑衰老及癌症发病机制相关。
我们假设衰老相关基因在老年患者、高级别胶质瘤中过表达，并预示预后不良。
47例胶质瘤样本被置于定制版的Affymetrix HG-U133+2.0基因芯片上，用于检测14种衰老相关基因的表达：CCL2、CCL7、CDKN1A、COPG、CSF2RB、CXCL1、ICAM-1、IGFBP-3、IL-6、IL-8、SAA4、TNFRSF-11B、TNFSF-11和TP53。使用主成分分析生成一个综合“衰老评分”，以衡量衰老相关基因特征的综合效应。
衰老评分升高与年龄较大相关（r = 0.37；P = 0.01），也与世界卫生组织（WHO）确定的更高恶性程度、组织学分级相关（r = 0.49；P < 0.001）。与预后不良存在轻度关联（P = 0.06）。胶质肉瘤的评分最高。六个基因分别独立地与年龄（IL-6、TNFRSF-11B、IGFBP-3、SAA4和COPG）、预后（IL-6、SAA4）或胶质瘤分级（IL-6、IL-8、ICAM-1、IGFBP-3和COPG）相关。
我们报告：1）基于细胞衰老，在人类胶质瘤中发现一种新的分子特征，将衰老相关基因的概念转化到人类癌症中；2）衰老特征由胶质瘤发病机制的核心基因组成，定义了一种新的、侵袭性的胶质瘤亚型；3）这些基因可作为预后生物标志物以及药物研发和免疫治疗的靶点。
