Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas.
Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas.
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DOI：
10.1136/gutjnl-2014-308252
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发表时间：
2015-11
期刊：
影响因子：
24.5
通讯作者：
Tan P
中科院分区：
文献类型：
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作者：
Lin SJ;Gagnon-Bartsch JA;Tan IB;Earle S;Ruff L;Pettinger K;Ylstra B;van Grieken N;Rha SY;Chung HC;Lee JS;Cheong JH;Noh SH;Aoyama T;Miyagi Y;Tsuburaya A;Yoshikawa T;Ajani JA;Boussioutas A;Yeoh KG;Yong WP;So J;Lee J;Kang WK;Kim S;Kameda Y;Arai T;Zur Hausen A;Speed TP;Grabsch HI;Tan P
在亚洲和非亚洲国家，胃癌(GC)患者临床结果的差异历来被归因于临床治疗的多样性。然而，最近的国际第三阶段试验表明，即使采用标准化治疗，GC结果也因地理位置而不同。在这里，我们调查了亚洲和非亚洲GC之间的基因表达差异，以及这些分子差异是否可能影响临床结果。我们比较了来自6个亚洲GC队列和3个非亚洲GC队列的1016个GC的基因表达谱，使用两阶段荟萃分析设计和一种新的生物统计学方法(RUV-4)来调整队列之间的技术差异。我们通过对来自亚洲和非亚洲地区的两个独立的组织微阵列(TMA)队列(n=665)进行计算机免疫组织化学分析，进一步验证了我们的发现。在亚洲人和非亚洲人之间差异表达的基因特征与免疫功能和炎症有关。非亚洲GC显著富含与T细胞生物学相关的信号，包括CTLA-4信号。同样，在TMA队列中，非亚洲GC的T细胞标志物(CD3、CD45R0、CD8)的表达显著高于亚洲GC(p<；0.05)，而免疫抑制T细胞标志物FOXP3的表达显著低于亚洲GC(p<；0.05)。炎症细胞标志物CD66b和CD68也显示出显著的队列差异(p<；0.05)。探索性分析显示，肿瘤免疫因素、特定地理位置的预后和化疗后的结果之间存在显著的关系。对>；1600个GC的分析表明，亚洲和非亚洲GC表现出与T细胞功能相关的不同的肿瘤免疫特征。这些差异可能会影响临床结果的地域差异，以及未来试验的设计，特别是在免疫肿瘤学方面。
Differences in gastric cancer (GC) clinical outcomes between patients in Asian and non-Asian countries has been historically attributed to variability in clinical management. However, recent international Phase III trials suggest that even with standardised treatments, GC outcomes differ by geography. Here, we investigated gene expression differences between Asian and non-Asian GCs, and if these molecular differences might influence clinical outcome. We compared gene expression profiles of 1016 GCs from six Asian and three non-Asian GC cohorts, using a two-stage meta-analysis design and a novel biostatistical method (RUV-4) to adjust for technical variation between cohorts. We further validated our findings by computerised immunohistochemical analysis on two independent tissue microarray (TMA) cohorts from Asian and non-Asian localities (n=665). Gene signatures differentially expressed between Asians and non-Asian GCs were related to immune function and inflammation. Non-Asian GCs were significantly enriched in signatures related to T-cell biology, including CTLA-4 signalling. Similarly, in the TMA cohorts, non-Asian GCs showed significantly higher expression of T-cell markers (CD3, CD45R0, CD8) and lower expression of the immunosuppressive T-regulatory cell marker FOXP3 compared to Asian GCs (p<0.05). Inflammatory cell markers CD66b and CD68 also exhibited significant cohort differences (p<0.05). Exploratory analyses revealed a significant relationship between tumour immunity factors, geographic locality-specific prognosis, and postchemotherapy outcomes. Analyses of >1600 GCs suggest that Asian and non-Asian GCs exhibit distinct tumour immunity signatures related to T-cell function. These differences may influence geographical differences in clinical outcome, and the design of future trials particularly in immuno-oncology.