Pancreatic Cancer

Overview

Pancreatic cancers are frequently associated with mutation of the KRAS oncogene and inactivating mutations of multiple tumor suppressor genes, particularly TP53, MADH4 (DPC4), CDKN2A (P16), and BRCA2. Also, overexpression of growth factors (EGF, TGF alpha, TGF beta 1-3, aFGF, bTGF) and their associated receptors are also common.

Familial clustering of pancreatic cancer has been reported, germline mutations of BRCA2 and CDKN2A predispose to pancreatic cancer. Mutations in the STk11gene also predisopse to pancreatic cancer in patients with Peutz-Jeghers Syndrome.

See also: Cancer of the Pancreas - clinical resources (22)

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (200)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

GeneLocationAliasesNotesTopicPapers
CDKN2A 9p21.3 ARF, MLM, P14, P16, P19, CMM2, INK4, MTS1, TP16, CDK4I, CDKN2, INK4A, MTS-1, P14ARF, P19ARF, P16INK4, P16INK4A, P16-INK4A Germline
-CDKN2A Mutation in Familial Pancreatic Cancer
-CDKN2A Mutation in Pancreatic Cancer
376
KRAS 12p12.1 NS, NS3, CFC2, KRAS1, KRAS2, RASK2, KI-RAS, C-K-RAS, K-RAS2A, K-RAS2B, K-RAS4A, K-RAS4B -KRAS and Pancreatic Cancer
421
MEN1 11q13.1 MEAI, SCG2 -MEN1 and Pancreatic Cancer
298
BRCA2 13q13.1 FAD, FACD, FAD1, GLM3, BRCC2, FANCD, PNCA2, FANCD1, XRCC11, BROVCA2 Germline
-BRCA2 mutations in Pancreatic Cancer
242
SMAD4 18q21.1 JIP, DPC4, MADH4, MYHRS -SMAD4 and Pancreatic Cancer
237
TP53 17p13.1 P53, BCC7, LFS1, TRP53 -TP53 and Pancreatic Cancer
180
MUC1 1q21 EMA, MCD, PEM, PUM, KL-6, MAM6, MCKD, PEMT, CD227, H23AG, MCKD1, MUC-1, ADMCKD, ADMCKD1, CA 15-3, MUC-1/X, MUC1/ZD, MUC-1/SEC Prognostic
-MUC1 overexpression in Pancreatic Cancer
85
CEACAM5 19q13.2 CEA, CD66e -CEACAM5 and Pancreatic Cancer
85
MUC6 11p15.5 MUC-6 -MUC6 and Pancreatic Cancer
53
ACHE 7q22 YT, ACEE, ARACHE, N-ACHE -ACHE and Pancreatic Cancer
42
SSTR2 17q24 -SSTR2 and Pancreatic Cancer
40
CXCR4 2q21 FB22, HM89, LAP3, LCR1, NPYR, WHIM, CD184, LAP-3, LESTR, NPY3R, NPYRL, WHIMS, HSY3RR, NPYY3R, D2S201E -CXCR4 and Pancreatic Cancer
35
CCK 3p22.1 -CCK and Pancreatic Cancer
33
MUC4 3q29 ASGP, MUC-4, HSA276359 -MUC4 and Pancreatic Cancer
33
STK11 19p13.3 PJS, LKB1, hLKB1 -STK11 and Pancreatic Cancer
32
PRSS1 7q34 TRP1, TRY1, TRY4, TRYP1 -PRSS1 and Pancreatic Cancer
31
SMAD2 18q21.1 JV18, MADH2, MADR2, JV18-1, hMAD-2, hSMAD2 -SMAD2 and Pancreatic Cancer
31
GLI1 12q13.2-q13.3 GLI -GLI1 and Pancreatic Cancer
29
CFTR 7q31.2 CF, MRP7, ABC35, ABCC7, CFTR/MRP, TNR-CFTR, dJ760C5.1 -CFTR and Pancreatic Cancer
28
PDX1 13q12.1 GSF, IPF1, IUF1, IDX-1, MODY4, PDX-1, STF-1, PAGEN1 -PDX1 and Pancreatic Cancer
27
MUC5AC 11p15.5 TBM, leB, MUC5, mucin -MUC5AC and Pancreatic Cancer
27
TGFBR1 9q22 AAT5, ALK5, ESS1, LDS1, MSSE, SKR4, ALK-5, LDS1A, LDS2A, TGFR-1, ACVRLK4, tbetaR-I -TGFBR1 and Pancreatic Cancer
26
GNAS 20q13.3 AHO, GSA, GSP, POH, GPSA, NESP, SCG6, SgVI, GNAS1, C20orf45 -GNAS and Pancreatic Cancer
26
SPINK1 5q32 TCP, PCTT, PSTI, TATI, Spink3 -SPINK1 and Pancreatic Cancer
25
TGFBR2 3p22 AAT3, FAA3, LDS2, MFS2, RIIC, LDS1B, LDS2B, TAAD2, TGFR-2, TGFbeta-RII -TGFBR2 and Pancreatic Cancer
23
ZEB1 10p11.2 BZP, TCF8, AREB6, FECD6, NIL2A, PPCD3, ZFHEP, ZFHX1A, DELTAEF1 -ZEB1 and Pancreatic Cancer
22
RRM1 11p15.4 R1, RR1, RIR1 -RRM1 and Pancreatic Cancer
22
SPARC 5q31.3-q32 ON -SPARC and Pancreatic Cancer
18
DAXX 6p21.3 DAP6, EAP1, BING2 -DAXX and Pancreatic Cancer
17
SLC29A1 6p21.1 ENT1 -SLC29A1 and Pancreatic Cancer
17
S100A4 1q21 42A, 18A2, CAPL, FSP1, MTS1, P9KA, PEL98 -S100A4 and Pancreatic Cancer
17
ATRX Xq21.1 JMS, SHS, XH2, XNP, ATR2, SFM1, MRX52, RAD54, MRXHF1, RAD54L, ZNF-HX -ATRX and Pancreatic Cancer
17
EPCAM 2p21 ESA, KSA, M4S1, MK-1, DIAR5, EGP-2, EGP40, KS1/4, MIC18, TROP1, EGP314, HNPCC8, TACSTD1 -EPCAM and Pancreatic Cancer
17
ANXA8 10q11.22 ANX8, CH17-360D5.2 -ANXA8 and Pancreatic Cancer
17
FHIT 3p14.2 FRA3B, AP3Aase -FHIT and Pancreatic Cancer
17
SIRT1 10q21.3 SIR2, hSIR2, SIR2L1 -SIRT1 and Pancreatic Cancer
16
CDX2 13q12.3 CDX3, CDX-3, CDX2/AS -CDX2 and Pancreatic Cancer
15
ABCG2 4q22 MRX, MXR, ABCP, BCRP, BMDP, MXR1, ABC15, BCRP1, CD338, GOUT1, CDw338, UAQTL1, EST157481 -ABCG2 and Pancreatic Cancer
14
S100P 4p16 MIG9 -S100P and Pancreatic Cancer
13
SMO 7q32.3 Gx, SMOH, FZD11 -SMO and Pancreatic Cancer
12
PSCA 8q24.2 PRO232 -PSCA and Pancreatic Cancer
11
MAP2K4 17p12 JNKK, MEK4, MKK4, SEK1, SKK1, JNKK1, SERK1, MAPKK4, PRKMK4, SAPKK1, SAPKK-1 -MAP2K4 and Pancreatic Cancer
10
MARCO 2q14.2 SCARA2 -MARCO and Pancreatic Cancer
10
GATA6 18q11.1-q11.2 -GATA6 and Pancreatic Cancer
10
DUSP6 12q22-q23 HH19, MKP3, PYST1 -DUSP6 and Pancreatic Cancer
10
SSTR5 16p13.3 SS-5-R -SSTR5 and Pancreatic Cancer
9
CEACAM6 19q13.2 NCA, CEAL, CD66c -CEACAM6 and Pancreatic Cancer
9
VIP 6q25 PHM27 -VIP and Pancreatic Cancer
9
SOX9 17q24.3 CMD1, SRA1, CMPD1, SRXX2, SRXY10 -SOX9 and Pancreatic Cancer
9
RHOC 1p13.1 H9, ARH9, ARHC, RHOH9 -RHOC expression in Pancreatic Cancer
8
RRM2 2p25-p24 R2, RR2, RR2M -RRM2 and Pancreatic Cancer
8
GADD45A 1p31.2 DDIT1, GADD45 -GADD45A and Pancreatic Cancer
8
MUC5B 11p15.5 MG1, MUC5, MUC9, MUC-5B -MUC5B and Pancreatic Cancer
8
ADRB2 5q31-q32 BAR, B2AR, ADRBR, ADRB2R, BETA2AR -ADRB2 and Pancreatic Cancer
7
L1CAM Xq28 S10, HSAS, MASA, MIC5, SPG1, CAML1, CD171, HSAS1, N-CAML1, NCAM-L1, N-CAM-L1 -L1CAM and Pancreatic Cancer
7
RALA 7p15-p13 RAL -RALA and Pancreatic Cancer
7
LGALS1 22q13.1 GBP, GAL1 -LGALS1 and Pancreatic Cancer
7
SSTR1 14q13 SS1R, SS1-R, SRIF-2, SS-1-R -SSTR1 and Pancreatic Cancer
7
BNIP3 10q26.3 NIP3 -BNIP3 and Pancreatic Cancer
7
HBEGF 5q23 DTR, DTS, DTSF, HEGFL -HBEGF and Pancreatic Cancer
7
NDRG1 8q24.3 GC4, RTP, DRG1, NDR1, NMSL, TDD5, CAP43, CMT4D, DRG-1, HMSNL, RIT42, TARG1, PROXY1 -NDRG1 and Pancreatic Cancer
7
VAV1 19p13.2 VAV -VAV1 and Pancreatic Cancer
7
ANXA5 4q27 PP4, ANX5, ENX2, RPRGL3, HEL-S-7 -ANXA5 and Pancreatic Cancer
7
MUC16 19p13.2 CA125 -MUC16 and Pancreatic Cancer
7
NR4A1 12q13 HMR, N10, TR3, NP10, GFRP1, NAK-1, NGFIB, NUR77 -NR4A1 and Pancreatic Cancer
6
RHOB 2p24 ARH6, ARHB, RHOH6, MST081, MSTP081 -RHOB and Pancreatic Cancer
6
AGR2 7p21.3 AG2, GOB-4, HAG-2, XAG-2, PDIA17, HEL-S-116 -AGR2 and Pancreatic Cancer
6
CD68 17p13 GP110, LAMP4, SCARD1 -CD68 and Pancreatic Cancer
6
MBD1 18q21 RFT, PCM1, CXXC3 -MBD1 and Pancreatic Cancer
6
NR5A2 1q32.1 B1F, CPF, FTF, B1F2, LRH1, LRH-1, FTZ-F1, hB1F-2, FTZ-F1beta -NR5A2 and Pancreatic Cancer
6
S100A6 1q21 2A9, PRA, 5B10, CABP, CACY -S100A6 and Pancreatic Cancer
6
MIR126 9q34.3 MIRN126, mir-126, miRNA126 -MIRN126 microRNA, human and Pancreatic Cancer
6
ACCS 11p11.2 ACS, PHACS -ACCS and Pancreatic Cancer
6
TGFB2 1q41 LDS4, TGF-beta2 -TGFB2 and Pancreatic Cancer
6
UCHL1 4p14 NDGOA, PARK5, PGP95, PGP9.5, Uch-L1, HEL-117, PGP 9.5 -UCHL1 and Pancreatic Cancer
6
NAT1 8p22 AAC1, MNAT, NATI, NAT-1 -NAT1 and Pancreatic Cancer
6
STRADA 17q23.3 LYK5, PMSE, Stlk, STRAD, NY-BR-96 -STRADA and Pancreatic Cancer
6
NFATC2 20q13.2 NFAT1, NFATP -NFATC2 and Pancreatic Cancer
5
MIRLET7C 21q21.1 LET7C, let-7c, MIRNLET7C, hsa-let-7c -MicroRNA let-7cand Pancreatic Cancer
5
TFPI 2q32 EPI, TFI, LACI, TFPI1 -TFPI and Pancreatic Cancer
5
CXCR2 2q35 CD182, IL8R2, IL8RA, IL8RB, CMKAR2, CDw128b -CXCR2 and Pancreatic Cancer
5
SMAD6 15q22.31 AOVD2, MADH6, MADH7, HsT17432 -SMAD6 and Pancreatic Cancer
5
ROBO1 3p12 SAX3, DUTT1 -ROBO1 and Pancreatic Cancer
5
ADAM9 8p11.22 MCMP, MDC9, CORD9, Mltng -ADAM9 and Pancreatic Cancer
5
CLDN4 7q11.23 CPER, CPE-R, CPETR, CPETR1, WBSCR8, hCPE-R -CLDN4 and Pancreatic Cancer
5
PDPK1 16p13.3 PDK1, PDPK2, PDPK2P, PRO0461 -PDPK1 and Pancreatic Cancer
5
MSLN 16p13.3 MPF, SMRP -MSLN and Pancreatic Cancer
5
RALB 2q14.2 -RALB and Pancreatic Cancer
4
HHIP 4q28-q32 HIP -HHIP and Pancreatic Cancer
4
TFPI2 7q22 PP5, REF1, TFPI-2 -TFPI2 and Pancreatic Cancer
4
NEUROD1 2q32 BETA2, BHF-1, MODY6, NEUROD, bHLHa3 -NEUROD1 and Pancreatic Cancer
4
ABCC4 13q32 MRP4, MOATB, MOAT-B -ABCC4 and Pancreatic Cancer
4
LCN2 9q34 24p3, MSFI, NGAL -LCN2 and Pancreatic Cancer
4
RREB1 6p25 HNT, FINB, LZ321, Zep-1, RREB-1 -RREB1 and Pancreatic Cancer
4
CCKBR 11p15.4 GASR, CCK-B, CCK2R -CCKBR and Pancreatic Cancer
4
IMP3 15q24 BRMS2, MRPS4, C15orf12 -IMP3 and Pancreatic Cancer
4
GHRH 20q11.2 GRF, INN, GHRF -GHRH and Pancreatic Cancer
4
CAST 5q15 BS-17, PLACK -CAST and Pancreatic Cancer
4
LAMC2 1q25-q31 B2T, CSF, EBR2, BM600, EBR2A, LAMB2T, LAMNB2 -LAMC2 and Pancreatic Cancer
4
CXCL5 4q13.3 SCYB5, ENA-78 -CXCL5 and Pancreatic Cancer
4
MIR107 10q23.31 MIRN107, miR-107 -MicroRNA mir-107 and Pancreatic Cancer
4
KRT7 12q13.13 K7, CK7, SCL, K2C7 -KRT7 and Pancreatic Cancer
4
ITGB4 17q25 CD104 -ITGB4 and Pancreatic Cancer
4
MICB 6p21.3 PERB11.2 -MICB and Pancreatic Cancer
4
CCNG1 5q32-q34 CCNG -CCNG1 and Pancreatic Cancer
4
HOXB7 17q21.3 HOX2, HOX2C, HHO.C1, Hox-2.3 -HOXB7 and Pancreatic Cancer
4
AGTR2 Xq22-q23 AT2, ATGR2, MRX88 -AGTR2 and Pancreatic Cancer
4
GADD45B 19p13.3 MYD118, GADD45BETA -GADD45B and Pancreatic Cancer
4
MUC17 7q22.1 MUC3 -MUC17 and Pancreatic Cancer
4
RALGDS 9q34.3 RGF, RGDS, RalGEF -RALGDS and Pancreatic Cancer
4
AKR1B10 7q33 HIS, HSI, ARL1, ARL-1, ALDRLn, AKR1B11, AKR1B12 -AKR1B10 and Pancreatic Cancer
3
CDH3 16q22.1 CDHP, HJMD, PCAD -CDH3 and Pancreatic Cancer
3
SLCO1B3 12p12 LST3, HBLRR, LST-2, OATP8, OATP-8, OATP1B3, SLC21A8, LST-3TM13 -SLCO1B3 and Pancreatic Cancer
3
MUC7 4q13.3 MG2 -MUC7 and Pancreatic Cancer
3
NFATC1 18q23 NFAT2, NFATc, NF-ATC, NF-ATc1.2 -NFATC1 and Pancreatic Cancer
3
PARK7 1p36.23 DJ1, DJ-1, HEL-S-67p -PARK7 and Pancreatic Cancer
3
DEC1 9q32 CTS9 -DEC1 and Pancreatic Cancer
3
OCLN 5q13.1 BLCPMG, PPP1R115 -OCLN and Pancreatic Cancer
3
MIRLET7D 9q22.32 LET7D, let-7d, MIRNLET7D, hsa-let-7d -MicroRNA let-d and Pancreatic Cancer
3
TP53INP1 8q22 SIP, Teap, p53DINP1, TP53DINP1, TP53INP1A, TP53INP1B -TP53INP1 and Pancreatic Cancer
3
CLDN7 17p13.1 CLDN-7, CEPTRL2, CPETRL2, Hs.84359, claudin-1 -CLDN7 and Pancreatic Cancer
3
PBRM1 3p21 PB1, BAF180 -PBRM1 and Pancreatic Cancer
3
LYVE1 11p15.4 HAR, XLKD1, LYVE-1, CRSBP-1 -LYVE1 and Pancreatic Cancer
3
WNT3A 1q42 -WNT3A and Pancreatic Cancer
3
FOXE1 9q22 TTF2, FOXE2, HFKH4, HFKL5, TITF2, TTF-2, FKHL15 -FOXE1 and Pancreatic Cancer
3
UCP2 11q13.4 UCPH, BMIQ4, SLC25A8 -UCP2 and Pancreatic Cancer
3
KDM6A Xp11.2 UTX, KABUK2, bA386N14.2 -KDM6A and Pancreatic Cancer
3
NOX4 11q14.3 KOX, KOX-1, RENOX -NOX4 and Pancreatic Cancer
3
SUV39H1 Xp11.23 MG44, KMT1A, SUV39H, H3-K9-HMTase 1 -SUV39H1 and Pancreatic Cancer
3
TRPM8 2q37.1 TRPP8, LTRPC6 -TRPM8 and Pancreatic Cancer
3
MIR10A 17q21.32 MIRN10A, mir-10a, miRNA10A, hsa-mir-10a -miR-10a and Pancreatic Cancer
3
AMFR 16q21 GP78, RNF45 -AMFR and Pancreatic Cancer
3
ING4 12p13.31 my036, p29ING4 -ING4 and Pancreatic Cancer
3
UPRT Xq13.3 UPP, FUR1 -UPRT and Pancreatic Cancer
3
TNFRSF10C 8p22-p21 LIT, DCR1, TRID, CD263, TRAILR3, TRAIL-R3, DCR1-TNFR -TNFRSF10C and Pancreatic Cancer
3
CD276 15q23-q24 B7H3, B7-H3, B7RP-2, 4Ig-B7-H3 -CD276 and Pancreatic Cancer
3
RAD54L 1p32 HR54, hHR54, RAD54A, hRAD54 -RAD54L and Pancreatic Cancer
3
PAK4 19q13.2 -PAK4 and Pancreatic Cancer
3
MIR1290 1 MIRN1290, hsa-mir-1290 -miR-1290 and Pancreatic Cancer
3
IER3 6p21.3 DIF2, IEX1, PRG1, DIF-2, GLY96, IEX-1, IEX-1L -IER3 and Pancreatic Cancer
3
CD59 11p13 1F5, EJ16, EJ30, EL32, G344, MIN1, MIN2, MIN3, MIRL, HRF20, MACIF, MEM43, MIC11, MSK21, 16.3A5, HRF-20, MAC-IP, p18-20 -CD59 and Pancreatic Cancer
3
TGFBI 5q31 CSD, CDB1, CDG2, CSD1, CSD2, CSD3, EBMD, LCD1, BIGH3, CDGG1 -TGFBI and Pancreatic Cancer
3
ID2 2p25 GIG8, ID2A, ID2H, bHLHb26 Overexpression
-ID2 Overexpression in Pancreatic Cancer
3
PLAU 10q22.2 ATF, QPD, UPA, URK, u-PA, BDPLT5 -PLAU and Pancreatic Cancer
3
FGF7 15q21.2 KGF, HBGF-7 -FGF7 and Pancreatic Cancer
3
PROX1 1q41 -PROX1 and Pancreatic Cancer
2
HSPA1B 6p21.3 HSP70-2, HSP70.2, HSP70-1B -HSPA1B and Pancreatic Cancer
2
SST 3q28 SMST -SST and Pancreatic Cancer
2
MMP10 11q22.2 SL-2, STMY2 -MMP10 and Pancreatic Cancer
2
HPSE 4q21.3 HPA, HPA1, HPR1, HSE1, HPSE1 -HPSE and Pancreatic Cancer
2
IGF2-AS 11p15.5 PEG8, IGF2AS, IGF2-AS1 -IGF2-AS and Pancreatic Cancer
2
XPO1 2p15 emb, CRM1, exp1 -XPO1 and Pancreatic Cancer
2
INHBA 7p15-p13 EDF, FRP -INHBA and Pancreatic Cancer
2
NEDD4 15q RPF1, NEDD4-1 -NEDD4 and Pancreatic Cancer
2
REG1A 2p12 P19, PSP, PTP, REG, ICRF, PSPS, PSPS1 -REG1A and Pancreatic Cancer
2
ADAMTS1 21q21.2 C3-C5, METH1 -ADAMTS1 and Pancreatic Cancer
2
OLFM4 13q14.3 GC1, OLM4, OlfD, GW112, hGC-1, hOLfD, UNQ362, bA209J19.1 -OLFM4 and Pancreatic Cancer
2
CHGA 14q32 CGA -CHGA and Pancreatic Cancer
2
HLA-B 6p21.3 AS, HLAB, SPDA1 -HLA-B and Pancreatic Cancer
2
TNFRSF25 1p36.2 DR3, TR3, DDR3, LARD, APO-3, TRAMP, WSL-1, WSL-LR, TNFRSF12 -TNFRSF25 and Pancreatic Cancer
2
CYBA 16q24 p22-PHOX -CYBA and Pancreatic Cancer
2
ULBP2 6q25 N2DL2, RAET1H, NKG2DL2, ALCAN-alpha -ULBP2 and Pancreatic Cancer
2
ZNF331 19q13.42 RITA, ZNF361, ZNF463 -ZNF331 and Pancreatic Cancer
2
MTA2 11q12.3 PID, MTA1L1 -MTA2 and Pancreatic Cancer
2
RPS6 9p21 S6 -RPS6 and Pancreatic Cancer
2
LGALS4 19q13.2 GAL4, L36LBP -LGALS4 and Pancreatic Cancer
2
RALBP1 18p11.3 RIP1, RLIP1, RLIP76 -RALBP1 and Pancreatic Cancer
2
IRAK1 Xq28 IRAK, pelle -IRAK1 and Pancreatic Cancer
2
POLB 8p11.2 -POLB and Pancreatic Cancer
2
ARL11 13q14.2 ARLTS1 -ARL11 and Pancreatic Cancer
2
ST14 11q24.3 HAI, MTSP1, SNC19, ARCI11, MT-SP1, PRSS14, TADG15, TMPRSS14 -ST14 and Pancreatic Cancer
2
CX3CL1 16q13 NTN, NTT, CXC3, CXC3C, SCYD1, ABCD-3, C3Xkine, fractalkine, neurotactin -CX3CL1 and Pancreatic Cancer
2
CXCL16 17p13 SRPSOX, CXCLG16, SR-PSOX -CXCL16 and Pancreatic Cancer
2
TNFRSF6B 20q13.3 M68, TR6, DCR3, M68E, DJ583P15.1.1 Amplification
-TNFRSF6B Amplification and Overexpression in Pancreatic Cancer
2
GAGE1 Xp11.23 CT4.1, GAGE-1 -GAGE1 and Pancreatic Cancer
2
PVT1 8q24 LINC00079, NCRNA00079, onco-lncRNA-100 -PVT1 and Pancreatic Cancer
2
CSF1 1p13.3 MCSF, CSF-1 -CSF1 and Pancreatic Cancer
2
SERPINA1 14q32.1 PI, A1A, AAT, PI1, A1AT, PRO2275, alpha1AT -SERPINA1 and Pancreatic Cancer
2
PLAT 8p12 TPA, T-PA -PLAT and Pancreatic Cancer
2
KL 13q12 -KL and Pancreatic Cancer
2
SULF1 8q13.2 SULF-1, HSULF-1 -SULF1 and Pancreatic Cancer
2
TM4SF1 3q21-q25 L6, H-L6, M3S1, TAAL6 -TM4SF1 and Pancreatic Cancer
2
CX3CR1 3p21.3 V28, CCRL1, GPR13, CMKDR1, GPRV28, CMKBRL1 -CX3CR1 and Pancreatic Cancer
2
TBX2 17q23.2 -TBX2 and Pancreatic Cancer
2
SLC9A1 1p36.1-p35 APNH, NHE1, LIKNS, NHE-1, PPP1R143 -SLC9A1 and Pancreatic Cancer
2
SSTR3 22q13.1 SS3R, SS3-R, SS-3-R, SSR-28 -SSTR3 and Pancreatic Cancer
2
CDCP1 3p21.31 CD318, TRASK, SIMA135 -CDCP1 and Pancreatic Cancer
2
HLA-C 6p21.3 HLC-C, D6S204, PSORS1, HLA-JY3 -HLA-C and Pancreatic Cancer
1
ANP32A 15q23 LANP, MAPM, PP32, HPPCn, PHAP1, PHAPI, I1PP2A, C15orf1 -ANP32A and Pancreatic Cancer
1
ST2 11p14.3-p12 -ST2 and Pancreatic Cancer
1
NOV 8q24.1 CCN3, NOVh, IBP-9, IGFBP9, IGFBP-9 -NOV and Pancreatic Cancer
1
ARID2 12q12 p200, BAF200 -ARID2 and Pancreatic Cancer
1
CEACAM7 19q13.2 CGM2 -CEACAM7 and Pancreatic Cancer
1
KDM5C Xp11.22-p11.21 MRXJ, SMCX, MRX13, MRXSJ, XE169, MRXSCJ, JARID1C, DXS1272E -KDM5C and Pancreatic Cancer
1
FOXN3 14q31.3 CHES1, PRO1635, C14orf116 -FOXN3 and Pancreatic Cancer
1
FBXO11 2p16.3 UBR6, VIT1, FBX11, PRMT9, UG063H01 -FBXO11 and Pancreatic Cancer
1
IL1RL1 2q12 T1, ST2, DER4, ST2L, ST2V, FIT-1, IL33R -IL1RL1 and Pancreatic Cancer
1
RAB8A 19p13.1 MEL, RAB8 -RAB8A and Pancreatic Cancer
1
ADAMTS9 3p14.1 -ADAMTS9 and Pancreatic Cancer
1
SMAD7 18q21.1 CRCS3, MADH7, MADH8 -SMAD7 and Pancreatic Cancer

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

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MiR-451 Promotes Cell Proliferation and Metastasis in Pancreatic Cancer through Targeting CAB39.
Biomed Res Int. 2017; 2017:2381482 [PubMed] Free Access to Full Article Related Publications
Emerging evidence shows that microRNAs (miRNAs) play important roles in the regulation of various biological and pathologic processes in human cancers and the aberrant expression of miRNAs contributes to the tumor development. In this study, our findings indicate that miR-451 is significantly overexpressed in pancreatic cancer tissues and cell lines and elevated expression of miR-451 contributes to promoted cell viability (in vitro and in vivo). Moreover, overexpression of miR-451 is closely linked to poor prognosis and lymphatic metastasis. Inhibition of miR-451 dramatically suppresses cell viability and invasion, promotes cell apoptosis, and induces cell cycle arrest. Furthermore, miR-451 directly targets CAB39 and negatively regulates its expression and inhibition of CAB39 contributes to the promoted cell viability and invasion. Our findings improve our understanding of the function of miR-451 in the identification and therapy of pancreatic cancer.

Klein F, Denecke T, Faber W, et al.
DNA Cytometry for Differentiation Between Low- and Medium-grade Dysplasia in Intraductal Papillary Mucinous Neoplasms.
Anticancer Res. 2017; 37(2):735-740 [PubMed] Related Publications
BACKGROUND/AIM: The indication for resection of cystic pancreatic lesions is usually performed by sectional imaging criteria, such as the Sendai criteria. The aim of this study was to analyze a possible correlation between DNA cytometry and Sendai criteria for the differentiation between low-grade intraductal papillary mucinous neoplasms (IPMN-A) and medium-grade dysplasia (IPMN-B).
MATERIALS AND METHODS: Histopathological analysis, DNA index and preoperative Sendai criteria were determined in 16 patients who underwent pancreatic resection for IPMN.
RESULTS: All patients with IPMN-B showed aneuploid histograms with DNA indices ≥1.3, whereas three out of four patients with IPMN-A had diploid DNA indices ≤1.3. All 11 patients with one or more high-risk stigmata and aneuploid histograms had IPMN-Bs, whereas both patients who were Sendai-negative and diploid in the DNA analysis had an IPMN-A.
CONCLUSION: DNA index may be an important diagnostic tool for the differentiation of different IPMN types beyond the traditional Sendai criteria.

Backman S, Norlén O, Eriksson B, et al.
Detection of Somatic Mutations in Gastroenteropancreatic Neuroendocrine Tumors Using Targeted Deep Sequencing.
Anticancer Res. 2017; 37(2):705-712 [PubMed] Related Publications
Mutations affecting the mechanistic target of rapamycin (MTOR) signalling pathway are frequent in human cancer and have been identified in up to 15% of pancreatic neuroendocrine tumours (NETs). Grade A evidence supports the efficacy of MTOR inhibition with everolimus in pancreatic NETs. Although a significant proportion of patients experience disease stabilization, only a minority will show objective tumour responses. It has been proposed that genomic mutations resulting in activation of MTOR signalling could be used to predict sensitivity to everolimus.
PATIENTS AND METHODS: Patients with NETs that underwent treatment with everolimus at our Institution were identified and those with available tumour tissue were selected for further analysis. Targeted next-generation sequencing (NGS) was used to re-sequence 22 genes that were selected on the basis of documented involvement in the MTOR signalling pathway or in the tumourigenesis of gastroenterpancreatic NETs. Radiological responses were documented using Response Evaluation Criteria in Solid Tumours.
RESULTS: Six patients were identified, one had a partial response and four had stable disease. Sequencing of tumour tissue resulted in a median sequence depth of 667.1 (range=404-1301) with 1-fold coverage of 95.9-96.5% and 10-fold coverage of 87.6-92.2%. A total of 494 genetic variants were discovered, four of which were identified as pathogenic. All pathogenic variants were validated using Sanger sequencing and were found exclusively in menin 1 (MEN1) and death domain associated protein (DAXX) genes. No mutations in the MTOR pathway-related genes were observed.
CONCLUSION: Targeted NGS is a feasible method with high diagnostic yield for genetic characterization of pancreatic NETs. A potential association between mutations in NETs and response to everolimus should be investigated by future studies.

Martinez-Useros J, Garcia-Foncillas J
The Role of BRCA2 Mutation Status as Diagnostic, Predictive, and Prognosis Biomarker for Pancreatic Cancer.
Biomed Res Int. 2016; 2016:1869304 [PubMed] Free Access to Full Article Related Publications
Pancreatic cancer is one of the deadliest cancers worldwide, and life expectancy after diagnosis is often short. Most pancreatic tumours appear sporadically and have been highly related to habits such as cigarette smoking, high alcohol intake, high carbohydrate, and sugar consumption. Other observational studies have suggested the association between pancreatic cancer and exposure to arsenic, lead, or cadmium. Aside from these factors, chronic pancreatitis and diabetes have also come to be considered as risk factors for these kinds of tumours. Studies have found that 10% of pancreatic cancer cases arise from an inherited syndrome related to some genetic alterations. One of these alterations includes mutation in BRCA2 gene. BRCA2 mutations impair DNA damage response and homologous recombination by direct regulation of RAD51. In light of these findings that link genetic factors to tumour development, DNA damage agents have been proposed as target therapies for pancreatic cancer patients carrying BRCA2 mutations. Some of these drugs include platinum-based agents and PARP inhibitors. However, the acquired resistance to PARP inhibitors has created a need for new chemotherapeutic strategies to target BRCA2. The present systematic review collects and analyses the role of BRCA2 alterations to be used in early diagnosis of an inherited syndrome associated with familiar cancer and as a prognostic and predictive biomarker for the management of pancreatic cancer patients.

Lubeseder-Martellato C, Alexandrow K, Hidalgo-Sastre A, et al.
Oncogenic KRas-induced Increase in Fluid-phase Endocytosis is Dependent on N-WASP and is Required for the Formation of Pancreatic Preneoplastic Lesions.
EBioMedicine. 2017; 15:90-99 [PubMed] Free Access to Full Article Related Publications
Fluid-phase endocytosis is a homeostatic process with an unknown role in tumor initiation. The driver mutation in pancreatic ductal adenocarcinoma (PDAC) is constitutively active KRas(G12D), which induces neoplastic transformation of acinar cells through acinar-to-ductal metaplasia (ADM). We have previously shown that KRas(G12D)-induced ADM is dependent on RAC1 and EGF receptor (EGFR) by a not fully clarified mechanism. Using three-dimensional mouse and human acinar tissue cultures and genetically engineered mouse models, we provide evidence that (i) KRas(G12D) leads to EGFR-dependent sustained fluid-phase endocytosis (FPE) during acinar metaplasia; (ii) variations in plasma membrane tension increase FPE and lead to ADM in vitro independently of EGFR; and (iii) that RAC1 regulates ADM formation partially through actin-dependent regulation of FPE. In addition, mice with a pancreas-specific deletion of the Neural-Wiskott-Aldrich syndrome protein (N-WASP), a regulator of F-actin, have reduced FPE and impaired ADM emphasizing the in vivo relevance of our findings. This work defines a new role of FPE as a tumor initiating mechanism.

Li H, Hao X, Wang H, et al.
Circular RNA Expression Profile of Pancreatic Ductal Adenocarcinoma Revealed by Microarray.
Cell Physiol Biochem. 2016; 40(6):1334-1344 [PubMed] Related Publications
BACKGROUND/AIMS: Circular RNAs (circRNAs) are a special novel type of a stable, diverse and conserved noncoding RNA in mammalian cells. Particularly in cancer, circRNAs have been reported to be widely involved in the physiological/pathological process of life. However, it is unclear whether circRNAs are specifically involved in pancreatic ductal adenocarcinoma (PDAC).
METHODS: We investigated the expression profile of circRNAs in six PDAC cancer samples and paired adjacent normal tissues using microarray. A high-throughput circRNA microarray was used to identify dysregulated circular RNAs in six PDAC patients. Bioinformatic analyses were applied to study these differentially expressed circRNAs. Furthermore, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to confirm these results.
RESULTS: We revealed and confirmed that a number of circRNAs were dysregulated, which suggests a potential role in pancreatic cancer.
CONCLUSIONS: this study demonstrates that clusters of circRNAs are aberrantly expressed in PDAC compared with normal samples and provides new potential targets for the future treatment of PDAC and novel insights into PDAC biology.

Yin H, Wang S, Zhang YH, et al.
Analysis of Important Gene Ontology Terms and Biological Pathways Related to Pancreatic Cancer.
Biomed Res Int. 2016; 2016:7861274 [PubMed] Free Access to Full Article Related Publications
Pancreatic cancer is a serious disease that results in more than thirty thousand deaths around the world per year. To design effective treatments, many investigators have devoted themselves to the study of biological processes and mechanisms underlying this disease. However, it is far from complete. In this study, we tried to extract important gene ontology (GO) terms and KEGG pathways for pancreatic cancer by adopting some existing computational methods. Genes that have been validated to be related to pancreatic cancer and have not been validated were represented by features derived from GO terms and KEGG pathways using the enrichment theory. A popular feature selection method, minimum redundancy maximum relevance, was employed to analyze these features and extract important GO terms and KEGG pathways. An extensive analysis of the obtained GO terms and KEGG pathways was provided to confirm the correlations between them and pancreatic cancer.

Hayashi H, Nishihara H
[A Novel Treatment Strategy for Pancreatic Cancer Based on Gene Profiles].
Gan To Kagaku Ryoho. 2016; 43(11):1326-1331 [PubMed] Related Publications
Pancreatic cancer has one of the highest rates of mortality among malignancies and the development of promising future therapies is strongly required. Recently, the utility of gene aberrations as biomarkers for determining therapeutic strategies has been demonstrated in several types of cancer. The detection of druggable mutations that aid in the selection of effective molecular targeting drugs is feasible in clinical settings for certain cancers. On the other hand, personalized therapy for pancreatic cancer guided by genomic biomarkers has not yet been realized and suitable molecular targets for the disease have been unclear until now. KRAS, CDKN2A, TP53, and SMAD4 have been recognized as major driver genes in pancreatic carcinogenesis. However, it is considered difficult to develop treatment strategies to target genetic aberrations of these four genes. In recent years, genome sequencing has progressively revealed the molecular biological characteristics of pancreatic cancer, including the discovery of novel potential therapeutic targets and low-frequency druggable genetic aberrations. Gene profilebased novel treatment strategies and subsequent attempts to realize precision medicine for pancreatic cancer are steadily ongoing in an effort to achieve improved treatment outcomes.

Tatarian T, Winter JM
Genetics of Pancreatic Cancer and Its Implications on Therapy.
Surg Clin North Am. 2016; 96(6):1207-1221 [PubMed] Related Publications
Over the past decade, emerging technologies have provided new insights into the genomic landscape of pancreatic ductal adenocarcinoma (PDA). In addition to the commonly recognized genetic drivers of pancreatic carcinogenesis (KRAS, CDKN2A, TP53, SMAD4), new genes and pathways have been implicated. However, these efforts have not identified any new high-frequency actionable mutations, limiting the success of mutation-targeted therapy in PDA. This article provides a report on the current landscape of pancreas cancer genetics and targeted therapeutics.

Yonemori K, Seki N, Kurahara H, et al.
ZFP36L2 promotes cancer cell aggressiveness and is regulated by antitumor microRNA-375 in pancreatic ductal adenocarcinoma.
Cancer Sci. 2017; 108(1):124-135 [PubMed] Free Access to Full Article Related Publications
Due to its aggressive nature, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and hard-to-treat malignancies. Recently developed targeted molecular strategies have contributed to remarkable improvements in the treatment of several cancers. However, such therapies have not been applied to PDAC. Therefore, new treatment options are needed for PDAC based on current genomic approaches. Expression of microRNA-375 (miR-375) was significantly reduced in miRNA expression signatures of several types of cancers, including PDAC. The aim of the present study was to investigate the functional roles of miR-375 in PDAC cells and to identify miR-375-regulated molecular networks involved in PDAC aggressiveness. The expression levels of miR-375 were markedly downregulated in PDAC clinical specimens and cell lines (PANC-1 and SW1990). Ectopic expression of miR-375 significantly suppressed cancer cell proliferation, migration and invasion. Our in silico and gene expression analyses and luciferase reporter assay showed that zinc finger protein 36 ring finger protein-like 2 (ZFP36L2) was a direct target of miR-375 in PDAC cells. Silencing ZFP36L2 inhibited cancer cell aggressiveness in PDAC cell lines, and overexpression of ZFP36L2 was confirmed in PDAC clinical specimens. Interestingly, Kaplan-Meier survival curves showed that high expression of ZFP36L2 predicted shorter survival in patients with PDAC. Moreover, we investigated the downstream molecular networks of the miR-375/ZFP36L2 axis in PDAC cells. Elucidation of tumor-suppressive miR-375-mediated PDAC molecular networks may provide new insights into the potential mechanisms of PDAC pathogenesis.

Previdi MC, Carotenuto P, Zito D, et al.
Noncoding RNAs as novel biomarkers in pancreatic cancer: what do we know?
Future Oncol. 2017; 13(5):443-453 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
Pancreatic cancer is an aggressive cancer of the digestive system, which is becoming a serious health problem worldwide. Overall survival for patients with pancreatic cancer is poor, mainly due to a lack of biomarkers to enable early diagnosis and a lack of prognostic markers that can inform decision-making, facilitating personalized treatment and an optimal clinical outcome. ncRNAs play an important role in pancreatic carcinogenesis. Here we review the literature on the role of ncRNAs as biomarkers in pancreatic cancer. We focus on the significance of ncRNAs as markers for early diagnosis, as prognostic biomarkers able to inform clinical management and as targets for novel therapeutics for patients with pancreatic cancer.

Angsuwatcharakon P, Rerknimitr R, Kongkam P, et al.
Identification of Pancreatic Cancer in Biliary Obstruction Patients by FRY Site-specific Methylation.
Asian Pac J Cancer Prev. 2016; 17(9):4487-4490 [PubMed] Related Publications
BACKGROUND: Methylation at cg 16941656 of FRY is exclusively found in normal pancreatic tissue and has been proven to be specific for pancreatic-in-origin among several adenocarcinomas. Here, we investigated methylated DNA in the bile as a biomarker to differentiate the cause of obstruction between pancreatic cancer and benign causes.
MATERIALS AND METHODS: Bile samples of 45 patients with obstructive jaundice who underwent ERCP were collected and classified into pancreatic cancer (group 1) and benign causes (group 2) in 24 and 21 patients, respectively. DNA was extracted from bile and bisul te modification was performed. After, methylation in cg 16941656 of FRY was identified by real-time PCR, with beta-actin used as a positive control.
RESULTS: Methylated DNA was identified in 10/24 (41.67%) and 1/21 (4.8%) of cases in groups 1 and 2, respectively (P= 0.012). The sensitivity, specificity, positive predictive value and negative predictive value to differentiate pancreatic cancer from benign causes were 42%, 95%, 91%, and 59%, respectively.
CONCLUSIONS: Detecting a methylation at cg 16941656 of FRY in bile has high specificity, with an acceptable positive likelihood rate, and may therefore be helpful in distinguishing pancreatic cancer from benign strictures.

Taniuchi K, Furihata M, Naganuma S, et al.
Podocalyxin-like protein, linked to poor prognosis of pancreatic cancers, promotes cell invasion by binding to gelsolin.
Cancer Sci. 2016; 107(10):1430-1442 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
The cell-adhesion glycoprotein PODXL is associated with an aggressive tumor phenotype in several forms of cancer. Here, we report that high PODXL expression was an independent predictor of worse overall survival of pancreatic cancer patients, and that PODXL promoted pancreatic cancer cell motility and invasion by physically binding to the cytoskeletal protein gelsolin. Suppression of PODXL or gelsolin decreased membrane protrusions with abundant peripheral actin structures, and in turn inhibited cell motility and invasion. Transfection of a PODXL-rescue construct renewed the expression of gelsolin bound to peripheral actin structures in cell protrusions, and abrogated the decreased cell protrusions caused by the knockdown of PODXL. Furthermore, transfection of a PODXL-rescue construct into pancreatic cancer cells in which both PODXL and gelsolin were suppressed failed to increase the formation of the protrusions. Thus, PODXL enhances motility and invasiveness through an increase in gelsolin-actin interactions in cell protrusions.

Lee J, Lee J, Yun JH, et al.
DUSP28 links regulation of Mucin 5B and Mucin 16 to migration and survival of AsPC-1 human pancreatic cancer cells.
Tumour Biol. 2016; 37(9):12193-12202 [PubMed] Related Publications
The prognosis of pancreatic cancer has not improved despite considerable and continuous effort. Dual-specificity phosphatase 28 (DUSP28) is highly expressed in human pancreatic cancers and exerts critical effects. However, knowledge of its function in pancreatic cancers is extremely limited. Here, we demonstrate the peculiar role of DUSP28 in pancreatic cancers. Analysis using the Gene Expression Omnibus public microarray database indicated higher DUSP28, MUC1, MUC4, MUC5B, MUC16 and MUC20 messenger RNA (mRNA) levels in pancreatic cancers compared with normal pancreas tissues. DUSP28 expression in human pancreatic cancer correlated positively with those of MUC1, MUC4, MUC5B, MUC16 and MUC20. In contrast, there were no significant correlations between DUSP28 and mucins in normal pancreas tissues. Decreased DUSP28 expression resulted in down-regulation of MUC5B and MUC16 at both the mRNA and protein levels; furthermore, transfection with small interfering RNA (siRNA) for MUC5B and MUC16 inhibited the migration and survival of AsPC-1 cells. In addition, transfection of siRNA for MUC5B and MUC16 resulted in a significant decrease in phosphorylation of FAK and ERK1/2 compared with transfection with scrambled-siRNA. These results collectively indicate unique links between DUSP28 and MUC5B/MUC16 and their roles in pancreatic cancer; moreover, they strongly support a rationale for targeting DUSP28 to inhibit development of malignant pancreatic cancer.

Chen P, Wan D, Zheng D, et al.
Long non-coding RNA UCA1 promotes the tumorigenesis in pancreatic cancer.
Biomed Pharmacother. 2016; 83:1220-1226 [PubMed] Related Publications
The contribution of long non-coding RNAs (lncRNAs) to tumorigenesis and metastasis of pancreatic cancer (PC) remains largely unknown. Urothelial cancer-associated 1 (UCA1), which is an originally identified lncRNA in bladder cancer, has be proved to play a pivotal role in bladder cancer progression and embryonic development. In this study, we detected the mRNA expression of UCA1 in 128 PC patients by qRT-PCR, and found that UCA1 expression was significantly, up-regulated in tumor tissues than that in matched adjacent non-tumor tissues (p<0.05). Clinicopathological analysis demonstrated that UCA1 expression in PC significantly correlated with malignant potential factors such as tumor size (p=0.021), depth of invasion (p=0.033), CA19-9 level (p=0.034) and tumor stage (p=0.013). Cox proportional hazards regression analysis also confirmed that high UCA1 expression was an independent prognostic biomarker of PC (p=0.046), which led to an obviously shorter 5-year overall survival (OS) compared to those patients with low UCA1 expressions (p=0.018). Furthermore, we effectively down-regulated UCA1 mRNA expression by transfecting RNA interfere fragments into SW-1990 cells, and our results in vitro indicated that down-regulation of UCA1 could effectively inhibit the cell proliferative activities, induce apoptotic rate and cause cell cycle arrest in PC cells (p<0.05). Meanwhile, UCA1 expression negative-correlated with p27 in PC tissues (r(2)=0.46, p<0.01), and knockdown of p27 partly abrogated the cell proliferative activities caused by UCA1 (p<0.05). Our results raised the possibility of using UCA1 as a potential prognostic biomarker and therapy target of PC, and down-regulation of UCA1 might be considered to be a novel molecular treatment strategy for patients with PC.

Peng W, Jiang A
Long noncoding RNA CCDC26 as a potential predictor biomarker contributes to tumorigenesis in pancreatic cancer.
Biomed Pharmacother. 2016; 83:712-717 [PubMed] Related Publications
Pancreatic cancer (PC) is the fourth most common cancer worldwide and has the least patient survival rate of any cancer. Emerging studies have demonstrated that long noncoding RNAs (lncRNAs) were present in cancer patients and have shown great potential as powerful markers and therapeutic targets. However, little is known about the role of lncRNAs in PC. The present study aimed to investigate the expression pattern, clinical significance and biological function of lncRNA CCDC26 (CCDC26) in PC. With quantitative real-time PCR, we analyzed CCDC26 expression levels in 40 PC patients. We found that the CCDC26 expression was significantly higher in PC tissues than in normal tissues. CCDC26 levels were correlated with tumor size, tumor number, and reduced overall survival (OS). Univariate and multivariate analysis showed that CCDC26 expression is an independent prognostic factor of OS in patients with PC. Additionally, ROC(AUC) of CCDC26 was up to 0.663, implicating that CCDC26 could be a diagnostic marker for distinguishing PC from normal. Knockdown of CCDC26 expression by small interfering RNA significantly promoted growth arrest and apoptosis. Moreover, we found that the expression of CCDC26 was positively correlated with PCNA and Bcl2. Our data suggest that CCDC26 may be identified as a novel oncogene in PC, and responsible for growth and apoptosis of cancer cell, partly by regulating the PCNA and Bcl2 expression. This work provides a novel biomarker and therapeutic target of PC for cancer clinic in future.

Yang HW, Liu GH, Liu YQ, et al.
Over-expression of microRNA-940 promotes cell proliferation by targeting GSK3β and sFRP1 in human pancreatic carcinoma.
Biomed Pharmacother. 2016; 83:593-601 [PubMed] Related Publications
Increasing study reports that Wnt/β-catenin signaling pathway plays an essential role in numerous cancers growth, progression and metastasis. Aberrant miR-940 expression has been studied in gastric and breast cancer. However, the molecular mechanism of miR-940 enhancing proliferation and metastatic ability in human pancreatic carcinoma is far from to know. Real-time PCR was used to quantify miR-940 expression. Luciferase reporter assays here were performed to verify the activity of Wnt/β-catenin signaling pathway and targeting gene relationships, and immunofluorescence assay was applied to observe β-catenin expressed intensity. Bioinformatics analysis together with in vivo and vitro functional analysis indicated the potential targeting genes of miR-940. Specimens from 15 pairs of patients with human pancreatic carcinoma were involoved to confirm the relationship between miR-940 expression and the GSK3β/sFRP1 through real-time PCR and western blot assays. Bioinformatics combined with cell luciferase function researches determined the possible regulation of miR-940 on the 3'-UTR of the GSK3β and sFRP1 genes, resulting in the Wnt/β-catenin signaling activation. Further, miR-940 knockdown significantly recovered GSK3β and sFRP1 expression and relieved Wnt/β-catenin-mediated cell invasion, migration, metastasis and proliferation. The ectopic up-regulation of miR-940 significantly suppressed GSK3β/sFRP1 expression and promoted pancreatic carcinoma proliferation and invasion. Our study suggested mechanistic relationship between miR-940 and Wnt/β-catenin in the development and progression of pancreatic carcinoma through regulation of GSK3β and sFRP1.

Notta F, Chan-Seng-Yue M, Lemire M, et al.
A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns.
Nature. 2016; 538(7625):378-382 [PubMed] Related Publications
Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.

Panic N, Larghi A, Amore R, et al.
Single Nucleotide Polymorphisms within the 8Q24 Region are Not Associated with the Risk of Intraductal Papillary Mucinous Neoplasms of the Pancreas.
J Gastrointestin Liver Dis. 2016; 25(3):311-5 [PubMed] Related Publications
BACKGROUND AND AIMS: Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas have been reported to be associated with an increased risk of developing extra-pancreatic malignancies. A common genetic background has been hypothesised to be responsible for such an association. Human chromosomal region 8q24 has been associated with many types of cancer. The majority of these associations lie at approximately 128 Mb on chromosome 8. We conducted a study in order to examine the association between IPMN and single nucleotide polymorphisms (SNPs) from the 8q24 region, namely rs10505477, rs6983267, rs7014346, rs6993464, previously reported to influence general cancer susceptibility.
METHODS: The study was performed on 117 IPMN cases and 231 controls. Cases were enrolled at the Digestive Endoscopy Unit, Policlinico Agostino Gemelli from January, 2010 to June, 2011, with either a prevalent or incident IPMN diagnosis. Status of SNPs was determined using a StepOne Real-time PCR system (Applied Biosystems) and TaqMan SNP Genotyping Assay™ 40X. Unconditional multiple logistic regression models were used to estimate odds ratios and 95% confidence intervals for the association of selected SNPs and IPMNs.
RESULTS: Cases were more likely to report a 1st degree family history of cancer (p<0.001), as well as heavy smoking (p=0.001) and heavy drinking habits (p<0.001). No significant association was observed between IPMN and selected SNPs. The results were confirmed also when stratified according to any 1st-degree family history of cancer.
CONCLUSION: Patients with IPMN do not have a higher prevalence of SNPs in the human chromosomal region 8q24 in respect to the control population.

Lian Y, Wang J, Feng J, et al.
Long non-coding RNA IRAIN suppresses apoptosis and promotes proliferation by binding to LSD1 and EZH2 in pancreatic cancer.
Tumour Biol. 2016; 37(11):14929-14937 [PubMed] Related Publications
Long non-coding RNA (lncRNA) modulates gene expression, while lncRNA dysregulation is associated with human cancer. Furthermore, while recent studies have shown that lncRNA IRAIN plays an important role in other malignancies, the role of IRAIN in pancreatic cancer (PC) progression remains unclear. In this study, we found that upregulation of lncRNA IRAIN was significantly correlated with tumor size, TNM stage, and lymph node metastasis in a cohort of 37 PC patients. In vitro experiments showed that knockdown of IRAIN by small interfering RNA (siRNA) significantly induced cell apoptosis and inhibited cell proliferation in both BxPC-3 and PANC-1 cells. Further mechanism study showed that, by binding to histone demethylase lysine-specific demethylase 1 (LSD1), an enhancer of zeste homolog 2 (EZH2), IRAIN reduced PC tumor cell apoptosis and induced growth arrest by silencing the expression of Kruppel-like factor 2 (KLF2) and P15. Moreover, IRAIN expression was inversely correlated with that of KLF2 and P15 in PC tissues. To our knowledge, this is the first report elucidating the role and mechanism of IRAIN in PC progression.

Chang W, Liu M, Xu J, et al.
MiR-377 inhibits the proliferation of pancreatic cancer by targeting Pim-3.
Tumour Biol. 2016; 37(11):14813-14824 [PubMed] Related Publications
MicroRNAs (miRNAs) play important roles in the regulation of various tumor biological processes including proliferation and apoptosis. MiR-377 has been implicated in many types of cancer, whereas its expressional feature and potential biological function in pancreatic ductal adenocarcinoma (PDAC) remains unclear. In this study, we scanned the global miRNA expression profiles in PDAC from The Cancer Genome Atlas (TCGA) and found miR-377 was down-regulated significantly in PDAC. Then, its expression was measured in both pancreatic cancer tissues and cells; the data showed that miR-377 was de-regulated and inversely correlated with pathologic parameters of tumor growth or metastasis. We generated PDAC cell lines with stable overexpression or inhibition of miR-377, and our results indicated that miR-377 up-regulation significantly promoted cell viability, proliferation, and migration in PDAC cells, and also induced cell apoptosis and cell cycle arrest simultaneously. Binding-site predictions by bioinformatics showed that Pim-3 might be a potential target of miR-377. Luciferase reporter assay ulteriorly identified that miR-377 suppressed Pim-3 expression by binding the 3'-UTR. In tumor tissues, we also showed that the Pim-3 expression was inversely correlated with that of miR-377. Furthermore, stable ectopic miR-377 expression in pancreatic cancer cell lines suppressed Pim-3 expression, leading to the attenuation of Bad phosphorylation level at its Ser(112) and promoting cell apoptosis. Overall, these results reveal that miR-377 may have tumor growth suppression function by down-regulating Pim-3 kinase expression to inhibit both pancreatic tumor growth and migration, and induce cell apoptosis. Hence, miR-377 may be a potential diagnostic marker and therapeutic target.

Yu Y, Liu L, Ma R, et al.
MicroRNA-127 is aberrantly downregulated and acted as a functional tumor suppressor in human pancreatic cancer.
Tumour Biol. 2016; 37(10):14249-14257 [PubMed] Related Publications
Pancreatic carcinoma is one of the most malignant human cancers. In this study, we intended to explore the molecular functional of microRNA-127 (miR-127) in regulating pancreatic cancer development both in vitro and in vivo. Quantitative real-time PCR (qRT-PCR) was performed to evaluate endogenous miR-127 expression in in vitro pancreatic cancer cell lines and in vivo clinical samples of pancreatic carcinoma. Lentiviral technology was applied to overexpress miR-127 in capan-1 and PANC-1 cells. Pancreatic cancer proliferation, cell-cycle progression, and invasion were assessed in vitro, and capan-1-derived tumorigenicity was evaluated in vivo. Dual-luciferase reporter assay and qRT-PCR were performed to assess the downstream target gene of miR-127 in pancreatic cancer, human Bcl-2-associated athanogene 5 (BAG5). BAG5 was subsequently upregulated in miR-127-overexpressed capan-1 and PANC-1 cells to evaluate its effect on pancreatic cancer progression. MiR-127 was preferentially downregulated in both pancreatic carcinoma cell lines and human pancreatic tumors. In lentivirus-infected capan-1 and PANC-1 cells, miR-127 overexpression significantly inhibited cancer progression, cell-cycle transition and invasion in vitro, as well as tumorigenicity in vivo. Human BAG5 was confirmed to be the downstream target of miR-127 in pancreatic cancer. Forced overexpression of BAG5 in capan-1 and PANC-1 cells reversed the tumor-suppressing effect of miR-127 on cancer development. MiR-127 is downregulated and acting as a tumor suppressor in pancreatic carcinoma. The functional regulation of miR-127 in pancreatic carcinoma is very likely through the inverse correlation of its downstream target gene of BAG5.

Nakao H, Wakai K, Ishii N, et al.
Associations between polymorphisms in folate-metabolizing genes and pancreatic cancer risk in Japanese subjects.
BMC Gastroenterol. 2016; 16(1):83 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
BACKGROUND: Evidence supporting the associations between folate metabolizing gene polymorphisms and pancreatic cancer has been inconclusive. We examined their associations in a case-control study of Japanese subjects.
METHODS: Our case-control study involved 360 newly diagnosed pancreatic cancer cases and 400 frequency-matched, non-cancer control subjects. We genotyped four folate metabolizing gene polymorphisms, including two polymorphisms (rs1801133 and rs1801131) in the methylenetetrahydrofolate (MTHFR) gene, one polymorphism (rs1801394) in the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene and one polymorphism (rs1805087) in the 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) gene. Genotyping was performed using Fluidigm SNPtype assays. Unconditional logistic regression methods were used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the associations between folate metabolizing gene variants and pancreatic cancer risk.
RESULTS: Overall we did not observe a significant association between these four genotypes and pancreatic cancer risk. For rs1801133, compared with individuals with the CC genotype of MTHFR C677T, the OR for those with the CT genotype and TT genotype was 0.87 (0.62-1.22) and 0.99 (0.65-1.51), respectively. For rs1801131, individuals with the CC genotype had approximately 1.2-fold increased risk compared with those with the AA genotype, but the association was not statistically significant. In analyses stratified by smoking and drinking status, no significant associations were noted for C677T genotypes. No significant interactions were observed with smoking and drinking with respect to pancreatic cancer risk.
CONCLUSIONS: Our data did not support the hypothesis that MTHFR polymorphisms or other polymorphisms in the folate metabolizing pathway are associated with pancreatic cancer risk.

Lian S, Zhai X, Wang X, et al.
Elevated expression of growth-regulated oncogene-alpha in tumor and stromal cells predicts unfavorable prognosis in pancreatic cancer.
Medicine (Baltimore). 2016; 95(30):e4328 [PubMed] Article available free on PMC after 01/02/2018 Related Publications
Growth-regulated oncogene-alpha (GRO-α) has been reported to be over-expressed in a series of human cancers including colorectal cancer, melanoma, gastric cancer, hepatocellular carcinoma, and ovarian cancer and was known to regulate multiple biologic activities associated with tumor progression. But the role in human pancreatic cancer remains unclear. To examine the expression of GRO-α and its clinical significance in pancreatic cancer (PC), a total of 12 fresh PC specimens and 12 surrounding normal tissues to detect GRO-α mRNA expression were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis of GRO-α protein was performed in 160 formalin-fixed, paraffin-embedded PC tissue samples and 68 control specimens, including 37 matched normal surgical margins and 31 benign pancreatic lesions. Kaplan-Meier survival and Cox regression analyses were performed to evaluate the prognosis of PC patients.Expression of GRO-α mRNA in PC tissues was significantly compared with that in adjacent normal tissues (1.399 ± 0.165 vs. 0.870 ± 0.103 t = 1.75, P = 0.012), GRO-α protein expression in cytoplasm of cancer cells and stroma was detected in 41.88% and 40.63% PC specimens, respectively, and was significantly higher than that in corresponding normal tissues (P = 0.008, P = 0.002, respectively). High GRO-α expression in the cytoplasm of cancer cells was related to tumor location (P = 0.047), tumor status (T classification; P = 0.001), distant metastasis (P < 0.001), and tumor node metastasis (TNM) stage (P < 0.001). High GRO-α expression in the stroma correlated with perineural invasion (P = 0.010), T classification (P = 0.006) and TNM stage (P = 0.004), and was marginally associated with metastasis (P = 0.056). Elevated expression of GRO-α in cytoplasm of cancer cells (hazard ratio [HR] = 5.730, P = 0.007) and stroma (HR = 3.120, P = 0.022) were independent prognostic factors of pancreatic cancer. T classification (HR = 2.130, P = 0.023), lymphatic metastasis (HR = 4.211, P = 0.009) and TNM classification (HR = 0.481, P = 0.031) were also prognostic predictors in PC patients.GRO-α expression was elevated in pancreatic cancer tissues and might be a potential therapeutic target and prognostic marker in patients with pancreatic cancer.

Cao J, Yang JC, Ramachandran V, et al.
TM4SF1 Regulates Pancreatic Cancer Migration and Invasion In Vitro and In Vivo.
Cell Physiol Biochem. 2016; 39(2):740-50 [PubMed] Related Publications
BACKGROUND/AIMS: The cell surface protein transmembrane 4 L6 family member 1 (TM4SF1) has been detected in various tumors and plays a major role in the development of cancer. We aimed to investigate the effects of TM4SF1 on the migration and invasion of pancreatic cancer in vitro and in vivo and explore its related molecular mechanisms.
METHODS: qRT-PCR and immunohistochemical analyses were used to measure the expression of TM4SF1 in pancreatic cancer tissues and adjacent tissues. TM4SF1 was silenced using siRNA and shRNA to investigate the role of this protein in the proliferation and metastasis of pancreatic cancer cells. MTS and Transwell assays were used to examine the effect of TM4SF1 on pancreatic cancer cell lines. The expression and activity of MMP-2 and MMP-9 were determined by qRT-PCR, western blots and gelatin zymography. In vivo, orthotopic pancreatic tumor models were used to examine the formation of metastasis.
RESULTS: qRT-PCR and immunohistochemical analyses showed that TM4SF1 was highly expressed in pancreatic cancer tissues compared with the adjacent tissues. In in vitro experiments the silencing of TM4SF1 reduced cell migration and invasion and down-regulated the expression and activity of MMP-2 and MMP-9. However, no significant difference in cell proliferation was detected after silencing TM4SF1. Additionally, knocking down TM4SF1 decreased the formation of lung and liver metastases in orthotopic pancreatic tumor models.
CONCLUSION: Our results demonstrate that the expression of TM4SF1 is higher in pancreatic cancer tissues and pancreatic cancer cell lines than controls. Knockdown of TM4SF1 inhibited the migration and invasion of pancreatic cancer cells by regulating the expression and activity of MMP-2 and MMP-9, which suggests that TM4SF1 may play a significant role in metastasis in pancreatic cancer.

Long LM, Zhan JK, Wang HQ, et al.
The Clinical Significance of miR-34a in Pancreatic Ductal Carcinoma and Associated Molecular and Cellular Mechanisms.
Pathobiology. 2017; 84(1):38-48 [PubMed] Related Publications
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) exhibits poor prognosis and resistance to chemotherapy. This study was to identify the biomarkers associated with the progression, poor prognosis and chemoresistance of PDAC.
METHODS: miR-34a and miR-150 levels in the plasma and tissues from PDAC patients were measured by real-time PCR. Xenograft PDAC tumor models were established in mice by inoculation of CD133+ stem cells isolated from PDAC tumors. Protein expression was measured by Western blot.
RESULTS: The plasma miR-34a and miR-150 levels were significantly lower in PDAC patients than in patients with benign pancreatic lesions and in healthy subjects. The miR-34a and miR-150 levels in the tumor tissues were significantly lower than in pancreatic tissues with benign lesions. The protein levels of CD133, Notch1, Notch2 and Notch4 receptors in PDAC tumor tissues were significantly higher than in pancreatic tissues with benign lesions. miR-34a injection significantly inhibited the tumor growth of PDAC tumors and sensitized the anticancer effects of 5-fluorouracil (5-FU). miR-34a significantly inhibited Notch1, Notch2 and Notch4 expression in xenograft tumor tissues in vivo and BxPC-3 cells in vitro. miR-34a and miR-150 significantly induced apoptosis and inhibited proliferation, invasion and migration in BxPC-3 cells. miR-34a, but not miR-150, significantly sensitized the anticancer effect of 5-FU in BxPC-3 cells in vitro.
CONCLUSION: A loss of expression of miR-34a, but not of miR-150, is associated with disease progression and poor prognosis in PDAC patients, and may be involved in the chemoresistance of PDAC cells.

Schmitt AM, Marinoni I, Blank A, Perren A
New Genetics and Genomic Data on Pancreatic Neuroendocrine Tumors: Implications for Diagnosis, Treatment, and Targeted Therapies.
Endocr Pathol. 2016; 27(3):200-4 [PubMed] Related Publications
The recent findings on the roles of death-associated protein 6/α-thalassemia/mental retardation X-linked (DAXX/ATRX) in the development of pancreatic neuroendocrine tumors (PanNETs) have led to major advances in the molecular understanding of these rare tumors and open up completely new therapeutic windows. This overview aims at giving a simplified view on these findings and their possible therapeutic implications. The importance of epigenetic changes in PanNET is also underlined by recent findings of a cross-species study on microRNA (miRNA) and messenger RNA (mRNA) profiles in PanNETs.

Ma D, Jing X, Shen B, et al.
Leukemia inhibitory factor receptor negatively regulates the metastasis of pancreatic cancer cells in vitro and in vivo.
Oncol Rep. 2016; 36(2):827-36 [PubMed] Related Publications
Pancreatic cancer (PC) is one of the leading causes of cancer-related deaths worldwide. Frequent metastasis and recurrence are the main reasons for the poor prognosis of PC patients. Thus, the discovery of new biomarkers and wider insights into the mechanisms involved in pancreatic tumorigenesis and metastasis is crucial. In the present study, we report that leukemia inhibitory factor receptor (LIFR) suppresses tumorigenesis and metastasis of PC cells both in vitro and in vivo. LIFR expression was significantly lower in PC tissues and was associated with local invasion (P=0.047), lymph node metastasis (P=0.014) and tumor-node-metastasis (TNM) stage (P=0.002). Overexpression of LIFR significantly suppressed PC cell colony formation (P=0.005), migration (P=0.003), invasion (P=0.010) and wound healing ability (P=0.013) in vitro, while opposing results were observed after LIFR was silenced. Furthermore, animal xenograft and metastasis models confirm that the in vivo results were consistent with the outcomes in vitro. Meanwhile, LIFR inhibited the expression of β-catenin, vimentin and slug and induced the expression of E-cadherin, suggesting that the epithelial-mesenchymal transition regulation pathway may underlie the mechanism. These results indicate that LIFR negatively regulates the metastasis of PC cells.

Dreyer C, Afchain P, Trouilloud I, André T
[New molecular classification of colorectal cancer, pancreatic cancer and stomach cancer: Towards "à la carte" treatment?].
Bull Cancer. 2016 Jul-Aug; 103(7-8):643-50 [PubMed] Related Publications
This review reports 3 of recently published molecular classifications of the 3 main gastro-intestinal cancers: gastric, pancreatic and colorectal adenocarcinoma. In colorectal adenocarcinoma, 6 independent classifications were combined to finally hold 4 molecular sub-groups, Consensus Molecular Subtypes (CMS 1-4), linked to various clinical, molecular and survival data. CMS1 (14% MSI with immune activation); CMS2 (37%: canonical with epithelial differentiation and activation of the WNT/MYC pathway); CMS3 (13% metabolic with epithelial differentiation and RAS mutation); CMS4 (23%: mesenchymal with activation of TGFβ pathway and angiogenesis with stromal invasion). In gastric adenocarcinoma, 4 groups were established: subtype "EBV" (9%, high frequency of PIK3CA mutations, hypermetylation and amplification of JAK2, PD-L1 and PD-L2), subtype "MSI" (22%, high rate of mutation), subtype "genomically stable tumor" (20%, diffuse histology type and mutations of RAS and genes encoding integrins and adhesion proteins including CDH1) and subtype "tumors with chromosomal instability" (50%, intestinal type, aneuploidy and receptor tyrosine kinase amplification). In pancreatic adenocarcinomas, a classification in four sub-groups has been proposed, stable subtype (20%, aneuploidy), locally rearranged subtype (30%, focal event on one or two chromosoms), scattered subtype (36%,<200 structural variation events), and unstable subtype (14%,>200 structural variation events, defects in DNA maintenance). Although currently away from the care of patients, these classifications open the way to "à la carte" treatment depending on molecular biology.

Li Y, Huang AW, Chen YZ, et al.
Mitochondrial tRNALeu(CUN) A12307G variant may not be associated pancreatic cancer.
Genet Mol Res. 2016; 15(2) [PubMed] Related Publications
Mitochondrial DNA mutations that lead to mitochondrial dysfunction have long been proposed to play important roles in the development of pancreatic cancer. Of these, alterations to mitochondrial tRNA genes constitute the largest group. Most recently, a variation at position 12307 in the gene encoding tRNA(Leu(CUN)) has been reported to be associated with this disease. However, the molecular mechanism underlying this relationship remains poorly understood. To assess this association, we evaluated this variant by evolutionary conservation analysis, measurements of allelic frequencies among control subjects, and use of several bioinformatic tools to estimate potential structural and functional alterations. We found this residue to have a high conservation index; however, the presence of the A12307G variation in control subjects revealed by a literature search suggested it to be common in human populations. Moreover, RNAfold results showed that this variant did not alter the secondary structure of tRNA(Leu(CUN)). Through the application of a pathogenicity scoring system, this variant was determined to be a "neutral polymorphism," with a score of only 4 points based on current data. Thus, the contribution of the A12307G variant to pancreatic cancer needs to be addressed in further experimental studies.

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