A migration signature and plasma biomarker panel for pancreatic adenocarcinoma.
Pancreatic ductal adenocarcinoma is a disease of extremely poor prognosis for which there are no reliable markers of asymptomatic disease. To identify pancreatic cancer biomarkers, we focused on a genomic interval proximal to the most common fragile site in the human genome, chromosome 3p12, which undergoes smoking-related breakage, loss of heterozygosity, and homozygous deletion as an early event in many epithelial tumors, including pancreatic cancers. Using a functional genomic approach, we identified a seven-gene panel (TNC, TFPI, TGFBI, SEL-1L, L1CAM, WWTR1, and CDC42BPA) that was differentially expressed across three different expression platforms, including pancreatic tumor/normal samples. In addition, Ingenuity Pathways Analysis (IPA) and literature searches indicated that this seven-gene panel functions in one network associated with cellular movement/morphology/development, indicative of a "migration signature" of the 3p pathway. We tested whether two secreted proteins from this panel, tenascin C (TNC) and tissue factor pathway inhibitor (TFPI), could serve as plasma biomarkers. Plasma ELISA assays for TFPI/TNC resulted in a combined area under the curve (AUC) of 0.88 and, with addition of CA19-9, a combined AUC for the three-gene panel (TNC/TFPI/CA19-9), of 0.99 with 100% specificity at 90% sensitivity and 97.22% sensitivity at 90% specificity. Validation studies using TFPI only in a blinded sample set increased the performance of CA19-9 from an AUC of 0.84 to 0.94 with the two-gene panel. Results identify a novel 3p pathway-associated migration signature and plasma biomarker panel that has utility for discrimination of pancreatic cancer from normal controls and promise for clinical application.
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Seetharaman
S
Balasenthil
Nanyue
N
Chen
Steven T
ST
Lott
Jinyun
J
Chen
Jennifer
J
Carter
William E
WE
Grizzle
Marsha L
ML
Frazier
Subrata
S
Sen
Ann McNeill
AM
Killary
D000230:Adenocarcinoma / Q000097:blood* / Q000235:genetics / Q000473:pathology; D014408:Biomarkers, Tumor / Q000097:blood*; D015153:Blotting, Western; D018395:CA-19-9 Antigen / Q000097:blood; D021441:Carcinoma, Pancreatic Ductal / Q000097:blood* / Q000235:genetics / Q000473:pathology; D002465:Cell Movement; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D006801:Humans; D008074:Lipoproteins / Q000097:blood; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000097:blood* / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D013382:Subtraction Technique; D019063:Tenascin / Q000097:blood
D014408:Biomarkers, Tumor; D018395:CA-19-9 Antigen; D008074:Lipoproteins; D012333:RNA, Messenger; D019063:Tenascin; C051928:lipoprotein-associated coagulation inhibitor