Emerging role of non-invasive and liquid biopsy biomarkers in pancreatic cancer

Table 1 Cell free DNA involved in pancreatic cancer diagnostic and prognostics

Target candidate	Up/down	Sample	Potential value
CEA mRNA	Up	Whole blood	D
EGFR mRNA	Up	Serum	D
4GnT mRNA	Up	Whole blood	D
COL6A3 mRNA	Up	Serum	D/P
Mir-155	Up	Plasma	D
miR-196a	Up	Plasma	D
miR-21	Up	Plasma	D
miR-210	Up	Plasma	D
miR-155	Up	Pancreatic juice	D
miR-21	Up	Plasma	D
miR-196a	Up	Serum	D/P
miR-200a	Up	Serum	D
miR-200b	Up	Plasma	D
miR-210	Up	Plasma	D
miR-18a	Up	Plasma	D/T
miR-16	Up	Plasma	D
miR-196a	Up	Plasma	D
miR-185	Up	Serum	D
miR-191	Up	Serum	D
miR-20a	Up	Serum	D
miR-21	Up	Serum	D/P
miR-24	Up	Serum	D
miR-25	Up	Serum	D
miR-99a	Up	Serum	D
miR-1290	Up	Serum	D
miR-221	Up	Plasma	D/T/P
miR-375	Down	Plasma	D/T/P
miR-375	Up	Plasma	D
miR-27a3p	Up	Whole blood	D
miR-196a	Up	Serum	D
miR-196b	Up	Serum	D
miR-205	Up	Pancreatic juice	D/P
miR-210	Up	Saliva	D/P
miR-492	Up	Plasma	D/P
miR-1427	Up	Plasma	D/P
miR-22	Up	Plasma	D
miR-642b	Up	Plasma	D
miR-885-5p	Up	Plasma	D
Multigene index	Up	Whole blood	D
miR-483-3p	Up	Plasma	D
MIR-21	Up	Serum	D
MIR-210	Down	Serum	D
MIR-155	Up	Serum	D
miR-222	Down	Serum	D
miR-203	Down	Serum	D
miR-132	Down	Serum	D
miR-212	Down	Serum	D
miR-96	Down	Serum	D
mi-126	Down	Serum	D
mi-217	Down	Serum	D
Let-7	Down	Serum	D
miR-144	Down	Serum	D
miR-148	Down	Serum	D
miR-34a	Down	Serum	D
miR-3548	Up	Serum	D

CEA: Carcinoembryonic antigen; D: Diagnostic; P: Prognostic; T: Therapeutic; miR: MicroRNA.

Table 2 Cell free protein (secreted proteome) involved in pancreatic cancer diagnostic and prognostics

Target candidate	Up/down	Sample	Target	Pathway	Potential value
ADAMTS1	Up	Plasma	ADAMTS1	Methylation	D
BNC1	Up	Plasma	BNC1	Methylation	D
CDKN1C	Up	Plasma	CDKN1C	Methylation	D
MLH1	Down	Plasma	MLH1	Mutation	D
PGR (prox)	Up	Plasma	PGR	Cell signaling	D
SYK	Up	Plasma	SYK protein, mRNA	Cell signaling	D
CCND2	Up	Plasma	Cyclin D2	Cell signaling	D
ALX4	Up	Plasma	Transcription factor	Mutation	P
APC	Down	Plasma	APC	Mutation	P
BMP3	Up	Plasma	TGFβ	Cell signaling	P
BNC1	Up	Plasma	BNC1	Cell signaling	P
BRCA1	Up	Plasma	BRCA1	Mutation	P
CDKN2B	Up	Plasma	Ink4, p16, p14	Cell signaling	P
CHFR	Up	Plasma	E3 Ubiquitin-protein	Cell signaling, check point	P
ESR1	Up	Plasma	ESR1, Transcription factor	Cell signaling	P
EYA2	Up	Plasma	EYA2	Cell cycle	P
GSTP1	Up	Plasma	GSTP1	Cell signaling	P
HIC1	Up	Plasma	HIC ZBTB TRANSCRIPTIONAL RECEPTOR 1	Cell signaling	P
MEST1v2	Up	Plasma	Alpha/Beta hydrolase superfamily	Cell signaling	P
Foxe1	Down	Pancreatic juice	Foxe1	Methylation	D
MGMT	Up	Plasma	MGMT	Methylation	P
MLH1	Up	Plasma	MLH1	Mutation	P
NPTX2	Up	Pancreatic juice	NP, synaptic proteins	Cell signaling	P
NEUROG1	Up	Plasma	NEUROG1	Cell signaling, regulatory network	P
RARB	Up	Plasma	RARB	Cell signaling	P
RASSF1A	Down	Plasma	RAS effector protein	Methylation	P
SFRP2	Up	Plasma	SFRP2	Wnt signaling	P
SEPT9v2	Up	Plasma	Septin9	Cell cycle	P
CDID	Up	Pancreatic juice	CDID	Methylation	D
PRKC	Up	Pancreatic juice	PRKC	Methylation	D
IKZF1	Up	Pancreatic juice	IKZF1	Methylation	D
KCNK12	Up	Pancreatic juice	KCNK12	Methylation	D
CLEC11A	Up	Pancreatic juice	CLEC11A	Methylation	D/P
NDRG4	Up	Pancreatic juice	NDRG4 promoter	Methylation	D
SST	Up	Plasma	SST	Downstream signaling, transcriptional regulation	P
TFPI2	Up	Pancreatic juice	TFPI2	Gene silencing, cell adhesion plasmin signaling	P
TAC1	Up	Plasma	TAC1	Gpcr downstream, signal transduction	P
VIM	Up	Plasma	Vimentin	Cell signaling	P
WNT5A	Up	Plasma	WNT5A	Wnt signaling	P
PENK	Up	Pancreatic juice	Proenkephalin	Apoptotic, downstream signaling
DCC	Down	Plasma	Netrin-1 Receptor	Mutation	D
P16	Down	Pancreatic juice	CDKN2A	Mutation, cell cycle regulation	D
P14	Down	Plasma	CDKN2A	Cell cycle	D
DNMT1	Up	Plasma	DNMT1	Mutation	D
DNMT3A	Up	Plasma	DNMT3A	Methylation	D
DNMT3B	Up	Plasma	DNA	Methylation	D

D: Diagnostic; P: Prognostic.

Table 3 Cell-free RNA involved in pancreatic cancer diagnostic and prognostics

Target candidate	Up/down	Sample	Target	Pathway	Potential value
ERBB2	Up	Plasma	Ch 12, KRAS	Mutation	D
CDKN2A	Down	Plasma	Gene, Ch 9p21	Mutation	D
SMAD4	Down	Plasma	TGFβ	Cell signaling	D
TP53	Down	Plasma	P53 protein	Mutation/cell signaling	D
EGFR	Up	Plasma	Exon 19, 21	Cell signaling/mutation	D
PBRM1	Down	Plasma	SWI/SNF ch remodeling comp	Mutation, immune checkpoint blockade	D
KMT2D	Down	Plasma	FOX1-miR-1224, HIF/GATA5-miR-133a	Mutation	D
RNF43	Down	Plasma	RNF43PROTEIN	Wnt signaling	D
TP63	Down	Plasma	P63 protein	Cell signaling	D
MTOR	Up	Plasma	mTOR	mTOR signaling	D
NRAS	Up	Plasma	NRAS	Mutation	D
HRAS	Up	Plasma	HRAS	Mutation	D
BRCA1	Down	Plasma	BRCA1	Signaling	D
BRCA2	Down	Plasma	BRCA2	Signaling	D
PALB2	Up	Plasma	PALB2	Signaling/mutation	D
GPC1	Up	Serum	MAPK, PI3K-AKT-mTOR, Hedgehog signaling	Cell signaling	D
PFAA	Up	Serum	MAPK, PI3K-AKT-mTOR, Hedgehog signaling	Cell signaling	D
OPNT+TIMP-1	Up	Serum	MAPK, PI3K-AKT-mTOR, signaling	Cell signaling	D
CPA4	Up	Serum	MAPK, mTOR, Hedgehog signaling	Cell signaling	D
MUC5 AC	Up	Urine/pancreatic juice	MAPK, PI3K-AKT-mTOR, Hedgehog signaling	Cell signaling	D/P
C4BPA	Up	Serum	MAPK, PI3K-AKT-mTOR, Hedgehog signaling	Cell signaling	D
OPN	Up	Serum	OPN	Cell signaling	P
TIMP-1	Up	Serum	TIMP-1	Cell signaling	D
NGAL	Up	Urine	Receptor binding protein	Cell signaling	D
ARG2	Down	Pancreatic juice	Beta cell function	Cell signaling	D
LYVE-1	Up	Urine	Receptor binding glycoprotein		D
TFF1	Up	Urine	Regulation of transcription factor	Promoter modeling	D
REG1A	Up	Urine	REG1A protein	Cell signaling	D

NGAL: Neutrophil gelatinase-associated lipocalin; miR: MicroRNA; D: Diagnostic; P: Prognostic.

Table 4 Cell-free biomarkers involved in distinguishing pancreatic cancer from other pancreatic benign diseases

Biomarkers	CP	AIP	PanIN	IPMN	MCN
PENK DNA	Yes	No	Yes	Yes	Yes
CUX2	Yes	No	No	No	No
REGIA	Yes	No	No	No	No
TFP12	Yes	No	Yes	Yes	Yes
FOXE1	Yes	No	Yes	Yes	Yes
P16	Yes	No	Yes	Yes	Yes
NPTX2	Yes	No	Yes	Yes	Yes
PENK	Yes	No	Yes	Yes	Yes
CYCLIN D2	Yes	No	Yes	Yes	Yes
CDO1	No	Yes	No	No	No
HAS-mIR-23a	No	No	No	Yes	No
HAS-mIR-23b	No	No	No	Yes	No
HAS-mIR-210	Yes	No	No	No	No
Let-7c	Yes	No	No	No	No
S100A9	Yes	No	No	No	No
BNCI	No	No	Yes	No	No
ADAMTS1	No	No	No	No	No
BNC1	No	No	No	No	No
9-Sep	No	No	No	No	No
GPC1	No	No	No	No	No
PFAA	No	No	No	No	No
OPNT + TIMP-1	No	No	No	No	No
CPA4	No	No	No	No	No
MUC5 AC	No	No	No	No	No
C4BPA	No	No	No	No	No

AIP: Autoimmune pancreatitis; CP: Chronic pancreatitis; IPMN: Intrapapillary mucinous neoplasia; MCN: Mucinous cystic neoplasm; PanCa: Pancreatic cancer; PanIN: Pancreatic intraepithelial neoplasia.