An Exosome-based Transcriptomic Signature for Noninvasive, Early Detection of Patients With Pancreatic Ductal Adenocarcinoma: A Multicenter Cohort Study

被引:66
作者
Nakamura, Kota [1 ]
Zhu, Zhongxu [1 ,2 ,3 ]
Roy, Souvick [1 ]
Jun, Eunsung [4 ,5 ]
Han, Haiyong [6 ]
Munoz, Ruben M. [6 ]
Nishiwada, Satoshi [1 ]
Sharma, Geeta [1 ]
Cridebring, Derek [6 ]
Zenhausern, Frederic [7 ]
Kim, Seungchan [8 ]
Roe, Denise J. [9 ]
Darabi, Sourat [10 ]
Han, In-Woong [11 ]
Evans, Douglas B. [12 ]
Yamada, Suguru [13 ]
Demeure, Michael J. [6 ,10 ]
Becerra, Carlos [14 ]
Celinski, Scott A. [14 ]
Borazanci, Erkut [15 ]
Tsai, Susan [12 ]
Kodera, Yasuhiro [13 ]
Park, Joon Oh [16 ]
Bolton, John S. [17 ]
Wang, Xin [2 ]
Kim, Song Cheol [4 ,5 ]
Von Hoff, Daniel [6 ]
Goel, Ajay [1 ,18 ]
机构
[1] Beckman Res Inst City Hope, Dept Mol Diagnost & Expt Therapeut, Monrovia, CA 91016 USA
[2] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Surg, Hong Kong, Peoples R China
[3] City Univ Hong Kong, Dept Biomed Sci, Hong Kong, Peoples R China
[4] Ulsan Univ, Coll Med, Dept Surg, Div Hepatobiliary & Pancreat Surg, Seoul, South Korea
[5] Asan Med Ctr, Seoul, South Korea
[6] Translat Genom Res Inst, 445 N Fifth St, Phoenix, AZ 85004 USA
[7] Univ Arizona, Coll Med Phoenix, Ctr Appl NanoBiosci & Med, Phoenix, AZ USA
[8] Prairie View A&M Univ, Roy G Perry Coll Engn, Dept Elect & Comp Engn, Prairie View, TX USA
[9] Univ Arizona, Dept Epidemiol & Biostat, Tucson, AZ USA
[10] Hoag Family Ctr Inst, Newport Beach, CA USA
[11] Sungkyunkwan Univ, Samsung Med Ctr, Sch Med, Div Hepatobiliary Pancreat Surg,Dept Surg, Seoul, South Korea
[12] Med Coll Wisconsin, Dept Surg, 8700 W Wisconsin Ave, Milwaukee, WI 53226 USA
[13] Nagoya Univ, Grad Sch Med, Dept Gastroenterol Surg, Nagoya, Aichi, Japan
[14] Baylor Univ, Med Ctr, Baylor Scott & White Res Inst, Dallas, TX USA
[15] HonorHlth Res Inst, Scottsdale, AZ USA
[16] Sungkyunkwan Univ, Samsung Med Ctr, Sch Med, Div Hematol Oncol,Dept Med, Seoul, South Korea
[17] Ochsner Clin Fdn, Dept Surg, New Orleans, LA USA
[18] City Hope Comprehens Canc Ctr, Duarte, CA USA
基金
中国国家自然科学基金; 美国国家卫生研究院;
关键词
miRNA Signature; Exosome; Pancreatic Cancer; Diagnostic Biomarker; Liquid Biopsy; CANCER; BIOMARKERS; CA19-9; GEMCITABINE; DIAGNOSIS; MIRNA; FOLFIRINOX; PROGNOSIS; PROTEIN; DNA;
D O I
10.1053/j.gastro.2022.06.090
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) incidence is rising worldwide, and most patients present with an unresectable disease at initial diagnosis. Measurement of carbohydrate antigen 19-9 (CA19-9) levels lacks adequate sensitivity and specificity for early detection; hence, there is an unmet need to develop alternate molecular diagnostic biomarkers for PDAC. Emerging evidence suggests that tumor-derived exosomal cargo, particularly micro RNAs (miRNAs), offer an attractive platform for the development of cancer-specific biomarkers. Herein, genomewide profiling in blood specimens was performed to develop an exosome-based transcriptomic signature for noninvasive and early detection of PDAC. METHODS: Small RNA sequencing was undertaken in a cohort of 44 patients with an early-stage PDAC and 57 nondisease controls. Using machine-learning algorithms, a panel of cell-free (cf) and exosomal (exo) miRNAs were prioritized that discriminated patients with PDAC from control subjects. Subsequently, the performance of the biomarkers was trained and validated in independent cohorts (n = 191) using quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. RESULTS: The sequencing analysis initially identified a panel of 30 overexpressed miRNAs in PDAC. Subsequently using qRT-PCR assays, the panel was reduced to 13 markers (5 cf-and 8 exo-miRNAs), which successfully identified patients with all stages of PDAC (area under the curve [AUC] = 0.98 training cohort; AUC = 0.93 validation cohort); but more importantly, was equally robust for the identification of early-stage PDAC (stages I and II; AUC = 0.93). Furthermore, this transcriptomic signature successfully identified CA19-9 negative cases (<37 U/mL; AUC = 0.96), when analyzed in combination with CA19-9 levels, significantly improved the overall diagnostic accuracy (AUC = 0.99 vs AUC = 0.86 for CA19-9 alone). CONCLUSIONS: In this study, an exosome-based liquid biopsy signature for the noninvasive and robust detection of patients with PDAC was developed.
引用
收藏
页码:1252 / +
页数:17
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