PO.CL01.17 · 临床研究
胰腺癌肝转移中CD276（B7H3）的临床和分子特征
Clinical and molecular features of CD276 (B7H3) in liver metastases of pancreatic cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：CD276（B7-H3）是一种通过影响钙黏蛋白表达来调节肿瘤微环境的分子，在包括胰腺导管腺癌（PDAC）在内的不同类型癌症中具有预后影响。在转移性PDAC中，CD276的这些作用尚未被充分理解。利用肝转移（LM）来源的转录组和反相蛋白阵列（RPPA）数据，我们评估了LM的CD276表达对转移性PDAC临床结局和分子特征的影响。
方法：采集PDAC未经治疗LM的针吸活检标本用于蛋白质和RNA提取。在RPPA上测量435种蛋白质的表达。使用单变量Cox回归风险模型检验以中位值分层的每种蛋白质水平的影响。在多变量Cox回归风险模型中评估前3个预后蛋白质以及东部肿瘤协作组体能状态（ECOG-PS）和血清C反应蛋白（CRP）水平等临床预后因素。为研究CD276的临床相关性，我们根据cDNA微阵列检测到的CD276 mRNA表达水平的中位值对研究人群进行分层，随后在两组之间进行差异基因表达分析和后续基因本体（GO）分析，探查CD276高相关基因/通路。
结果：从42例患者的LM中获得RPPA数据（男性：64.2%；中位年龄：66岁）。肿瘤蛋白质组数据显示，与不具有这些蛋白高表达的患者相比，肿瘤内Aurora-A、PGDFR-beta和CD276高表达的患者总生存时间延长。多变量分析中，CD276高表达（风险比：0.148 [95%置信区间：0.005至0.434]）、ECOG-PS 1或以上（4.651 [1.713至12.63]）和CRP高（6.440 [2.498至16.60]）具有独立的预后影响。在42例LM中的40例中评估了转录组数据。鉴定出116个基因为CD276高相关基因。与CD276高相关的GO条目为钙黏蛋白结合（GO:0045296）、细胞黏附分子结合（GO:0050839）和蛋白质结合（GO:0005515）。与CD276蛋白低表达者相比，CD276蛋白高表达的LM显示E-cadherin蛋白高表达（P<0.001），且N-cadherin蛋白表达趋于偏低（P=0.097）。
结论：PDAC肝转移中CD276蛋白高表达是一个独立的有利预后因素，并与肿瘤中E-cadherin表达增加相关。需要进一步研究以探索CD276在转移性PDAC中的作用。
查看英文原文 English abstract
Introduction: CD276 (B7-H3), a modulator of tumor-microenvironment as affecting cadherin expression, has a prognostic impact in the different types of cancers including pancreatic ductal adenocarcinoma (PDAC). In metastatic PDAC, these roles in CD276 have not been fully understood. Using liver metastasis (LM)-derived transcriptome and reversed-phased protein array (RPPA) data, we evaluated CD276 expressions of LMs on clinical outcomes and molecular features in metastatic PDAC.
Methods: Needle-biopsied specimens from treatment-naïve LMs of PDAC were collected for protein and RNA extraction. A 435-protein expression was measured on RPPA. The impact of each protein level stratified with median value was tested using univariate Cox regression hazard model. The top 3 prognostic proteins and clinical prognostic factors such as Eastern Cooperative Oncology Group Performance Status (ECOG-PS) and serum level of C-reactive protein (CRP) were evaluated in multivariate Cox regression hazard model. To investigate clinical relevance of CD276, our study population was stratified based on the median value of CD276 mRNA expression level detected on cDNA microarray, followed by differential gene expression analysis and subsequent Gene Ontology (GO) analysis between the two groups surveying for CD276 high-related genes/ pathways.
Results: RPPA data was obtained from LMs of 42 patients (Male: 64.2%; median age: 66 years). The tumor proteome data showed that overall survival times were prolonged in the patients with intratumoral high expression of Aurora-A, PGDFR-beta, and CD276 as compared to those without. Independent prognostic impacts were found in CD276 high (hazard ratio: 0.148 [95% confidence interval: 0.005 to 0.434]), ECOG-PS 1 or more (4.651 [1.713 to 12.63]), and CRP high (6.440 [2.498 to 16.60]) in multivariate analysis. Transcriptome data were evaluated in 40 of 42 LMs. The 116 genes were identified as CD276 high-related genes. GO terms associated with CD276 high were cadherin binding (GO:0045296), cell adhesion molecule binding (GO:0050839), and protein binding (GO:0005515). LMs with high CD276 protein expression showed high protein expression in E-cadherin (P<0.001) and tended to be low in protein expression of N-cadherin (P=0.097) as compared to those with low CD276 protein expression.
Conclusion: High expression of CD276 protein in liver metastasis of PDAC was an independent favorable prognostic factor and related to increasing E-cadherin expression in tumor. Further study is needed to explore the roles of CD276 in metastatic PDAC.
利益披露 Disclosure
G. Igarashi, None.
S. Mitsunaga,
Toray Industries, Inc ).
Ajinomoto Co., Inc ).
Mitsui Chemicals, Inc ).
Taiho Innovations, LLC ).
Taiho Pharmaceutical Co., Ltd ).
Tensegrity Pharma, Inc ).
Pfizer Japan Inc ).
Ono Pharmaceutical Co.,Ltd ).
Astellas Pharma Inc ).
Chugai Pharmaceutical Co., Ltd ).
N. Okumura, None..
K. Inoue, None..
T. Taira, None..
T. Shibuki, None.
T. Satake,
Ono ).
Servier ).
M. Amisaki,
GxD Inc ).
M. Sasaki,
AstraZeneca ).
Boehringer Ingelheim ).
MSD ).
Nihon Servier ).
Taiho ).
H. Takahashi, None.
H. Imaoka,
Ono Pharmaceutical ).
Servier ).
Novartis ).
Boehringer Ingelheim ).
M. Ikeda,
AstraZeneca ).
Abbvie ).
Amgen ).
Bristol Myers Squibb ).
Chugai ).
Chiome Bioscience ).
Delta-Fly Pharma ).
Eisai ).
Eli Lilly Japan ).
Invitae ).
MSD ).
J-Pharma ).
Merck biopharma ).
Merus N.V. ).
Novartis ).
Nihon Servier ).
Ono ).
Syneos Health ).
Rakuten Medical ).
Taiho ).