PO.CL01.18 · 临床研究

血液代谢组的前瞻性研究以识别胆道癌的风险生物标志物

Prospective investigation of the blood metabolome to identify risk biomarkers for biliary tract cancer

编号 LB371 展板 27 时间 4/19 02:00–05:00 区域 Section 43 主讲 Valerie Gunchick, BS;MS

分会场 Early Detection Biomarkers 1

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作者与单位 Authors & Affiliations

Valerie Gunchick¹, Wei Zheng¹, Chris Haiman², Caroline Um³, Roger Milne⁴, Rachel Solomon⁵, Yu Chen⁶, Andrew Chan⁷, Qiuyin Cai¹, Xiao-Ou Shu, on behalf of the BTC Metabolomic Consortium¹

¹Vanderbilt University Medical Center, Nashville, TN,²Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA,³Department of Population Science, American Cancer Society, Atlanta, GA,⁴Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia,⁵Division of Cancer Epidemiology & Genetics, NCI, Shady Grove, MD,⁶Division of Epidemiology, Department of Population Health, NYU Grossman School of Medicine, New York, NY,⁷Immunology and Infectious Diseases, Harvard University T. H. Chan School of Public Health, Boston, MA

摘要 Abstract

中文摘要

胆道癌（BTC）是一组罕见且侵袭性强的恶性肿瘤；大多数（约80%）患者在诊断时已为转移性疾病，其五年生存率为3%。更好地理解BTC的病因和生物学对于设计具有成本效益的预防策略至关重要。许多已知的BTC风险因素，如肥胖、糖尿病和慢性炎症，都与代谢紊乱有关，提示代谢扰动在BTC发病机制中起重要作用。因此，对循环代谢物进行系统性研究可提供有关BTC病因生物学机制的宝贵信息，并识别潜在的风险生物标志物。我们开展了一项个体匹配的病例对照研究，嵌套于来自澳大利亚、中国和美国的八项前瞻性队列研究中，评估了诊断前血样中循环代谢物与BTC风险的关联。代谢物分两批使用Metabolon的Global Discovery Panel检测进行测定。共检测到1,997种生化物质，其中1,593种在≥1项研究中被检出。我们识别出146个主成分，占我们数据中1,593种代谢物代谢组学方差的99.5%。因此，将p值3.42×10⁻⁰⁴（即0.05/146）设定为多重比较校正的显著性阈值。在这1,593种中，有1,466种（1,202种已知和264种未知）存在于≥70%的参与者中并纳入本研究分析。在每个队列中，代谢物水平被修剪至三个标准差，不可检测值以最小值填补，进行对数转换（x+1.0）并进行z-score标准化。我们按检测批次进行条件逻辑回归，并采用固定效应meta分析对结果进行合并。本研究共纳入1,383名参与者，包括836名对照与547例BTC病例相匹配：33.1%为胆囊癌，15.0%为肝内胆管癌（CCA），22.7%为肝外CCA，29.3%为Vater壶腹及未特指的BTC病例。研究参与者的基线中位年龄为61[四分位距（IQR）12]岁，57.1%为女性，从采血到BTC诊断的中位[IQR]时间为9.6[4.1]年。在校正多重比较后，我们发现多种代谢物与BTC风险相关，包括谷氨酸、鞘磷脂和胆汁酸通路中的代谢物。与BTC的部分显著关联（每增加1个标准差的OR（95% CI），p值）为：谷氨酸：1.32（1.17-1.49），p=6.3×10⁻⁰⁶；鞘磷脂（10）：0.76（0.67-0.86），p=3.3×10⁻⁰⁵；以及甘氨脱氧胆酸3-硫酸盐：1.23（1.10-1.38），p=2.72×10⁻⁰⁴。这是第一项系统性搜索血液代谢组以寻找BTC风险生物标志物的前瞻性研究。我们提供了有力证据，表明胆汁酸和其他代谢通路在BTC病因中发挥关键作用。我们正在利用来自更多队列研究的数据扩展分析，以进一步验证这些发现。

查看英文原文 English abstract

Biliary tract cancer (BTC) is a group of rare and aggressive malignancies; most (~80%) patients are diagnosed with metastatic disease, which has a five-year survival rate of 3%. A better understanding of BTC etiology and biology is critical for designing cost-effective prevention strategies. Many known risk factors for BTC, such as obesity, diabetes, and chronic inflammation, are related to metabolic disturbance, suggesting a significant role of metabolic perturbation in BTC pathogenesis. Thus, a systemic investigation of circulating metabolites could provide valuable information regarding biological mechanisms of BTC etiology and identify potential risk biomarkers.We conducted an individually matched case-control study nested in eight prospective cohort studies from Australia, China, and the United States, and evaluated associations of circulating metabolites in pre-diagnostic blood samples with BTC risk. Metabolites were measured in two batches using Metabolon's Global Discovery Panel assay . A total of 1,997 biochemicals were detected, of which 1,593 were detected in ≥1 study. We identified 146 principal components that account for 99.5% of the metabolomic variance in 1,593 metabolites in our data. Thus, a p-value of 3.42x10 -04 (i.e., 0.05 /146) was set as the significance threshold for multiple comparison adjustment. Of the 1,593, 1,466 (1,202 known and 264 unknown) were present in ≥70% of participants and were analyzed herein. Within each cohort, metabolite levels were trimmed to three standard deviations, undetectable values were imputed with the minimum, log-transformed (x+1.0), and z-scored. We conducted conditional logistic regression by assay batch and meta-analyzed results together with fixed-effects meta-analysis.This study included 1,383 total participants, comprising 836 controls matched to 547 BTC cases: 33.1% gallbladder cancer, 15.0% intrahepatic cholangiocarcinoma (CCA), 22.7% extrahepatic CCA, and 29.3% Ampulla of Vater and unspecified BTC cases. Study participants had a median baseline age of 61 [interquartile range (IQR) 12] years old, 57.1% were female, and had a median [IQR] 9.6 [4.1] years from blood collection to BTC diagnosis. We found multiple metabolites associated with BTC risk, including those in the glutamate, sphingomyelin, and bile acid pathways, after adjusting for multiple comparisons. Selected significant associations (OR (95% CI) for every 1-SD increase, p-value) with BTC are glutamate: 1.32 (1.17-1.49), p=6.3x10 -06 ; sphingomyelin (10): 0.76 (0.67-0.86), p=3.3x10 -05 ; and glycodeoxycholate 3-sulfate: 1.23 (1.10-1.38), p=2.72x10 -04 .This is the first prospective study to systematically search the blood metabolome for biomarkers of BTC risk. We provide strong evidence that bile acid and other metabolic pathways play critical roles in BTC etiology. We are expanding the analysis with data from additional cohort studies to further validate the findings.

利益披露 Disclosure

V. Gunchick, Servier ). Cornerstone Pharmaceuticals ). W. Zheng, None.. C. Haiman, None.. C. Um, None.. R. Milne, None.. R. Solomon, None.. Y. Chen, None.. A. Chan, None.. Q. Cai, None.. X. Shu, on behalf of the BTC Metabolomic Consortium, None.

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