PO.CL01.19 · 临床研究

用于胰腺癌早期检测的无创生物标志物发现与验证

Non-invasive biomarker discovery and validation for the early detection of pancreatic cancer

编号 2526 展板 1 时间 4/20 09:00–12:00 区域 Section 44 主讲 Roopali Roy, PhD

分会场 Early Detection Biomarkers 2

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作者与单位 Authors & Affiliations

Roopali Roy¹, Rama Aldakhlallah², Stephen Cobbs², Noundy Mazile³, Kiana Mahdaviani³, Matthew Kulke³, Christopher Heaphy³, Jeanette Dupree⁴, David Zurakowski⁵, Sarah Danielle Legrand⁴, Erkut Borazanci⁶, Marsha A. Moses¹

¹Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA,²Vascular Biology Program, Boston Children's Hospital, Boston, MA,³Section of Hematology and Medical Oncology, Boston University and Boston Medical Center, Boston, MA,⁴Honor Health Research Institute, Scottsdale, AZ,⁵Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA,⁶Honor Health Research Institute, John Shufeldt School of Medicine and Advanced Medical Engineering ASU, Scottsdale, AZ

摘要 Abstract

中文摘要

引言：胰腺恶性肿瘤是美国所有癌症相关死亡的第四大原因，这一高死亡率可归因于缺乏用于早期检测的诊断性检测。大多数胰腺导管腺癌（PDAC）患者因缺乏特异性症状而在确诊时已为晚期，这提示早期检测可能显著改善患者预后。CA19-9是唯一获FDA批准用于PDAC的血液生物标志物，但其对检测或监测的灵敏度和特异度均不足。本研究的目标是发现并验证用于PDAC早期检测的无创生物标志物。方法：我们建立了一项生物标志物发现计划，其目标是鉴定癌症患者尿液中差异表达的蛋白质，并验证其诊断和预后效能。对于PDAC，我们的目标人群包括I期或II期PDAC患者、高风险个体（HRI，因遗传或家族原因而接受监测的个体）以及年龄和性别匹配的健康对照（HC）。在本研究中，我们分析了包括CTGF、CYR61、TIMP1和ADAM12在内的尿液标志物，这些蛋白质据报道与PDAC的发生和进展有关，目的是确定它们区分早期（I-II期）PDAC与HC、HRI和晚期疾病（III-IV期）的潜力。结果：与HC（n=60）相比，PDAC患者（所有分期；n=64）的尿TIMP-1（uTIMP-1）水平显著升高（约19倍）；与患有良性胰腺疾病（包括IPMN[导管内乳头状黏液性肿瘤]或胰腺囊肿）者（n=10）相比，PDAC患者（所有分期）的uTIMP-1水平显著升高（约3.5倍）。将HRI队列（n=70，无疾病证据，NED）与所有组比较时，我们发现与高风险者（n=37）相比，PDAC患者（所有分期）的uTIMP-1水平显著升高（约13倍）。与HC样本相比，PDAC患者样本（所有分期）的uADAM12水平显著升高（约17倍）；与良性疾病患者相比，PDAC患者的uADAM12水平显著升高（约1.6倍）；而与HRI队列相比，PDAC患者（所有分期）的uADAM12水平显著升高（约5倍）。虽然CYR61水平在所测试的任何组之间均无差异，但与良性疾病患者相比，PDAC患者（所有分期）的CTGF水平显著升高（约700倍）；与HRI队列相比，PDAC患者（所有分期）的CTGF水平显著升高（约1500倍）。结论：综上所述，我们的结果表明，无创检测uTIMP-1、uADAM12和uCTGF水平可能对PDAC患者疾病状态的早期检测和/或临床监测具有诊断价值。 [作者衷心感谢Robert J. Kleberg, Jr.和Helen C. Kleberg基金会以及Nile Albright研究基金会的支持]

查看英文原文 English abstract

Introduction: Pancreatic malignancies are the fourth leading cause of all cancer-related deaths in the United States and this high mortality rate can be attributed to a lack of diagnostic tests for early detection. A majority of patients with pancreatic ductal adenocarcinoma (PDAC) present with advanced disease due to a lack of specific symptoms suggesting that early detection may significantly improve patient outcomes. CA19-9, the only FDA-approved blood biomarker for PDAC, is insufficiently sensitive and specific for detection or surveillance. The goal of our study is to discover and validate non-invasive biomarkers for early PDAC detection. Methods: We have established a biomarker discovery initiative whose objective is to identify differentially expressed proteins in the urine of cancer patients and validate their diagnostic and prognostic efficacy. For PDAC, our target population(s) include Stage I or II PDAC patients, high risk individuals (HRI, individuals under surveillance for genetic or familial causes) and age- and sex-matched healthy controls (HC). In this study, we have analyzed urinary markers including CTGF, CYR61, TIMP1 and ADAM12, proteins reported to contribute to PDAC development and progression, with the goal of determining their potential to differentiate early (Stage I-II) PDAC from HC, HRI and advanced disease (Stage III-IV). Results: Urinary TIMP-1 (uTIMP-1) levels were significantly (~19-fold) higher in PDAC patients (all stages; n =64) compared to HC ( n =60) and significantly (~3.5-fold) higher in PDAC patients (all stages) compared to those with benign pancreatic conditions including IPMN (intraductal papillary mucinous neoplasm) or pancreatic cysts ( n =10). When comparing the HRI cohort ( n =70, no evidence of disease, NED) to all groups, we found that uTIMP-1 levels were significantly (~13-fold) higher in PDAC patients (all stages) compared to those at high-risk ( n =37). uADAM12 levels were significantly (~17-fold) higher in PDAC patient samples (all stages) compared to those from HC and significantly (~1.6-fold) higher in PDAC patients compared to those with benign disease, whereas uADAM12 levels were significantly (~5-fold) higher in PDAC patients (all stages) compared to the HRI cohort. While CYR61 levels did not differ between any of the groups tested, CTGF levels were significantly (~700-fold) higher in PDAC patients (all stages) compared to patients with benign disease and significantly (~1500-fold) higher in PDAC patients (all stages) compared to the HRI cohort. Conclusions: Taken together, our results suggest that the non-invasive detection of uTIMP-1, uADAM12 and uCTGF levels may have diagnostic value in the early detection and/or clinical monitoring of disease status in patients with PDAC. [The authors gratefully acknowledge the support of the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation and the Nile Albright Research Foundation ]

利益披露 Disclosure

R. Roy, None.. R. Aldakhlallah, None.. S. Cobbs, None.. N. Mazile, None.. K. Mahdaviani, None.. M. Kulke, None.. C. Heaphy, None.. J. Dupree, None.. D. Zurakowski, None.. S. Legrand, None.. E. Borazanci, None.. M. A. Moses, None.

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