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MicroRNA Biomarkers in Whole Blood for Detection of Pancreatic Cancer

Nicolai A. Schultz, MD, PhD1,2,3,4; Christian Dehlendorff, PhD5; Benny V. Jensen, MD1; Jon K. Bjerregaard, MD, PhD6; Kaspar R. Nielsen, MD, PhD7; Stig E. Bojesen, MD, PhD, DMSc8; Dan Calatayud, MD4; Svend E. Nielsen, MD9; Mette Yilmaz, MD10; Niels Henrik Holländer, MD11; Klaus K. Andersen, PhD5; Julia S. Johansen, MD, DMSc1,2
[+] Author Affiliations
1Department of Oncology, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark
2Department of Medicine, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark
3Department of Gastroenterology, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark
4Department of Surgical Gastroenterology and Transplantation, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
5Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark
6Department of Oncology, Odense University Hospital, Odense, Denmark
7Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark
8Department Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark
9Department of Oncology, Hillerød Hospital, Hillerød, Denmark
10Department of Oncology, Aalborg University Hospital, Aalborg, Denmark
11Department of Oncology, Næstved Hospital, Næstved, Denmark
JAMA. 2014;311(4):392-404. doi:10.1001/jama.2013.284664.
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Importance  Biomarkers for the early diagnosis of patients with pancreatic cancer are needed to improve prognosis.

Objectives  To describe differences in microRNA expression in whole blood between patients with pancreatic cancer, chronic pancreatitis, and healthy participants and to identify panels of microRNAs for use in diagnosis of pancreatic cancer compared with the cancer antigen 19-9 (CA19-9).

Design, Setting, and Participants  A case-control study that included 409 patients with pancreatic cancer and 25 with chronic pancreatitis who had been included prospectively in the Danish BIOPAC (Biomarkers in Patients with Pancreatic Cancer) study (July 2008-October 2012) plus 312 blood donors as healthy participants. The microRNA expressions in pretreatment whole blood RNA samples were collected and analyzed in 3 randomly determined subcohorts: discovery cohort (143 patients with pancreatic cancer, 18 patients with chronic pancreatitis, and 69 healthy participants), training cohort (180 patients with pancreatic cancer, 1 patient with chronic pancreatitis, and 199 healthy participants), and validation cohort (86 patients with pancreatic cancer, 7 patients with chronic pancreatitis, and 44 healthy participants); 754 microRNAs were screened in the discovery cohort and 38 microRNAs in the training cohort and 13 microRNAs in the validation cohort.

Main Outcomes and Measures  Identification of microRNA panels (classifiers) for diagnosing pancreatic cancer.

Results  The discovery cohort demonstrated that 38 microRNAs in whole blood were significantly dysregulated in patients with pancreatic cancer compared with controls. These microRNAs were tested in the training cohort and 2 diagnostic panels were constructed comprising 4 microRNAs in index I (miR-145, miR-150, miR-223, miR-636) and 10 in index II (miR-26b, miR-34a, miR-122, miR-126*, miR-145, miR-150, miR-223, miR-505, miR-636, miR-885.5p). The test characteristics for the training cohort were index I area under the curve (AUC) of 0.86 (95% CI, 0.82-0.90), sensitivity of 0.85 (95% CI, 0.79-0.90), and specificity of 0.64 (95% CI, 0.57-0.71); index II AUC of 0.93 (95% CI, 0.90-0.96), sensitivity of 0.85 (95% CI, 0.79-0.90), and specificity of 0.85 (95% CI, 0.80-0.85); and CA19-9 AUC of 0.90 (95% CI, 0.87-0.94), sensitivity of 0.86 (95% CI, 0.80-0.90), and specificity of 0.99 (95% CI, 0.96-1.00). Performances were strengthened in the validation cohort by combining panels and CA19-9 (index I AUC of 0.94 [95% CI, 0.90-0.98] and index II AUC of 0.93 [95% CI, 0.89-0.97]). Compared with CA19-9 alone, the AUC for the combination of index I and CA19-9 was significantly higher (P = .01). The performance of the panels in patients with stage IA-IIB pancreatic cancer was index I AUC of 0.80 (95% CI, 0.73-0.87); index I and CA19-9 AUC of 0.83 (95% CI, 0.76-0.90); index II AUC of 0.91 (95% CI, 0.87-0.94); and index II and CA19-9 AUC of 0.91 (95% CI, 0.86-0.95).

Conclusions and Relevance  This study identified 2 diagnostic panels based on microRNA expression in whole blood with the potential to distinguish patients with pancreatic cancer from healthy controls. Further research is necessary to understand whether these have clinical implications for early detection of pancreatic cancer and how much this information adds to serum CA19-9.

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Figure 1.
Study Design

aThere were also 33 other periampullary cancers analyzed as part of this cohort study (15 ampullary, 12 distal common bile duct, and 6 duodenal).bIndicates low RNA yield, low absorbance, and few detectable microRNAs.

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Figure 2.
Box Plots of Indices I and II Using the Whole Blood Samples From the Discovery, Training, and Validation Cohorts

The horizontal line in the middle of each box indicates the median, whereas the top and bottom borders of the box mark the 75th and 25th percentiles, respectively. The whiskers above and below the box extend to the most extreme point no longer than 1.5 times the interquartile range from the box. The points beyond the whiskers are outliers. Index I includes miR-150, miR-636, miR-145, miR-223. Index II includes miR-26b, miR-34a, miR-122, miR-126*, miR-145, miR-150, miR-223, miR-505, miR-636, miR-885.5p. P < .001 for all comparisons (healthy participants vs patients with cancer for indices I and II for each cohort).

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Figure 3.
Reciever Operating Characteristic Curves for Performance of Indices I and II and in Combination With Serum Cancer Antigen 19-9 in the Discovery, Training, and Validation Cohorts

AUC indicates area under curve; CA19-9, cancer antigen 19-9. See legend of Figure 2 for definitions of indicies I and II.

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