Prognostic biomarkers for pancreatic ductal adenocarcinoma: A contemporary systematic review and modelling study

Table 2 Prognostic strength of biomarkers in pancreatic ductal adenocarcinoma (57 biomarker studies; 14 interventional trials are presented separately in Table 3)

Biomarker	Type	Outcome	Multivariable analysis	Independent prognostic association	Validation	Internal descriptive category	Ref.
UFM1	Single protein	OS/PFS	Yes	Yes	Limited	B	Wang et al[14]
9-gene signature	Multi-gene	OS	Yes	Yes	External	A-	Wang et al[15]
3-gene MRS	Multi-gene	OS	Yes	Yes	External	A	Li et al[16]
LMRGS	Multi-gene ML	OS	Yes	Yes	Multi-cohort	A	Ge et al[17]
PCLM-BM signature	Multi-gene	OS	Yes	Yes	External	A-	Zhou et al[18]
MCMBP	Single gene	OS	Yes	Yes	External	A	Zhang et al[19]
APOBEC score	Genomic	OS	Yes	Yes	External	A	Yu et al[20]
JUP	Single gene	OS	Yes	Likely	Limited	B	Yang et al[21]
Manganese metabolism signature	Multi-gene	OS	Yes	Yes	External	A	Xiong et al[22]
ALDH family	Multi-gene	OS	Yes	Likely	Limited	B	Wu et al[23]
EFFscore/P2RY6	Multi-gene	OS	Yes	Yes	External	A	Wang et al[24]
mCAF signature	Multi-gene	OS	Yes	Yes	Multi-cohort	A	Wang et al[25]
18-gene immune signature	Multi-gene	OS	Yes	Yes	External	A	Wang et al[26]
PCD signature	Multi-gene	OS	Yes	Yes	Multi-cohort	A	Wang et al[27]
ICD signature (AJM1)	Multi-gene	OS	Yes	Yes	External	A	Ma et al[28]
MDRG/CITED4	Multi-gene	OS	Yes	Likely	Limited	B	Liu et al[29]
IGFBP signature	Multi-gene	OS	Yes	Yes	External	A	Guan et al[30]
A2ML1 subtype model	Multi-gene	OS	Yes	Yes	Multi-cohort	A	Ge et al[31]
BM-related signature (LAMA3/ITGA3/ITGB6)	Multi-gene	OS	Yes	Yes	External	A	Ge et al[32]
ER stress-related TF signature	Multi-gene	OS	Yes	Yes	External	A	Gao et al[33]
PLAAT2	Single gene	OS	Yes	Yes	External	A	Chen et al[34]
LY6D (stem-like, gastric-like cell-state marker)	Single gene	OS	Yes	Yes	Limited	B	Shi et al[35]
Disulfidptosis-related gene signature; key genes: RPN1, PML; Model genes: NDUFA11, MYH14, TRIP6, ACTN1, ANP32E, PML, CD2AP, RPN1	Multi-gene signature	OS	Yes	Yes	External	A-	Pei et al[36]
Palmitoylation-related gene signature (7 genes: DCBLD2, CXCL5, ASPH, LAMC2, KRT6A, TOP2A, NPNT); Upstream regulators: ZDHHC family (palmitoyl transferases)	Multi-gene signature	OS	Yes	Yes	External	A-	Lu et al[37]
7-gene SASP prognostic signature: ANGPTL4, DKK1, EREG, IGFBP3, IL18, MMP13, PLAU; Plus SASP molecular subtypes	Multi-gene signature	OS	Yes	Yes	Multi-cohort	A	Kuang et al[38]
SEMA3 family genes; 9-gene prognostic signature derived from SEMA3-related DEGs; key driver: SEMA3C	Multi-gene signature	OS	Yes	Yes	External	A-	Jin et al[39]
Six-gene mitophagy-related signature (PAPPA, NBPF12, CXCL11, CKLF-CMTM1, CCDC6, AHNAK)	Multi-gene signature	OS	Yes	Yes	Multi-cohort	A	Cai et al[40]
Six ICD-associated lncRNA prognostic signature: ZEB2-AS1, AC099792.1, LINC01091, LINC02613, AC005304.3, LINC00705	Multi-gene signature	OS	Yes	Yes	External	A-	Zhu et al[41]
11-gene ITH-related prognostic signature	Multi-gene signature	OS	Yes	Yes	Multi-cohort	A	Zhao et al[42]
Ferroptosis-related 3-gene signature (NOTCH2, KRT18, H1-2); key single biomarker: NOTCH2	Multi-gene signature	OS	Yes	Yes	Multi-cohort	A	Zhang et al[43]
16-gene DNA damage and repair-related prognostic risk score model; key experimental gene: LY6D	Multi-gene signature	OS	Yes	Yes	Multi-cohort	A	Zhang et al[44]
STING signalling pathway-derived 6-gene prognostic signature: DTX4, IFI16, MAVS, PRKDC, ZDHHC1, IFIT2	Multi-gene signature	OS	Yes	Yes	External	A	Yu et al[45]
SERPINE1	Single gene	OS	Yes	Yes	External	A	Wang et al[46]
KRAS protein level, KRAS mRNA expression, KRAS mutation status/subtype	Single gene	OS	Yes	Yes	Limited	B	Stålberg et al[47]
RAD51AP1 (DNA repair-associated protein)	Single gene	OS	Yes	Yes	External	A-	Rezagholizadeh et al[48]
Mitochondrial 12-gene prognostic signature; mechanistic emphasis on CAMK2A and THEM4	Multi-gene signature	OS	Yes	Yes	Multi-cohort	A	Nie et al[49]
Innate immune barrier gene signature (84 genes); key genes: UBASH3B, ITGB6, COL17A1, MMP28, DIAPH3 (focus on UBASH3B)	Multi-gene signature	OS	Yes	Yes	Multi-cohort	A	Luo et al[50]
P4HA1, CCDC148, UCA1, TMPRSS11E + tumour stage	Multi-gene signature	OS	Yes	Yes	Multi-cohort	A	Lin et al[51]
KRAS mutational status as key biomarker; integrated molecular classifier of KRAS wild-type vs KRAS-mutant classical vs KRAS-mutant basal-like; exploratory HRD and other somatic mutations	Multi-gene signature	OS	Yes	Yes	Internal	B+	Lansbergen et al[52]
PAUF (ZG16B-related protein product)	Single gene	OS	Yes	Yes	Limited	B	Kim et al[53]
Six BA-related prognostic genes: SERPINB5, CALU, TFRC, LY6D, SFRP1, GBP2	Multi-gene signature	OS	Yes	Yes	External	A-	Kang et al[54]
TIPARP (PARP7) expression	Single gene	OS	Yes	Yes	Limited	B	Jiang et al[55]
Microenvironmental, stromal, and immune markers, including MFAP4, EGR3, KRT8, monocyte infiltration, CD68+ macrophages, CD3/CD4/CD8 T-cell infiltration	Multi-gene signature	OS	Yes	Yes	Limited	B	Han et al[56]
Hypoxia score; 13-gene signature (including LYZ, PLAU, INSIG2, and KRTCAP2)	Multi-gene signature	OS/PFS	Yes	Yes	External	A	Ge et al[57]
CSCLPI genes (SHCBP1, CEP55, GMNN, CDCA5, FAM111B)	Multi-gene signature	OS	Yes	Yes	Limited	B	Fang et al[58]
23 ISGS-based features in risk score model	Multi-gene signature	OS	Yes	Yes	External	A	Fang et al[59]
Cuproptosis-related lncRNA prognostic model; key lncRNAs: LINC00900 and AC078820.1	Multi-gene signature	OS	Yes	Yes	Partial	B+	Duo et al[60]
ST3GAL2, SLCO1B3, PTGES, PRKACA	Multi-gene signature	OS/PFS	Yes	Yes	External	A-	Deng et al[61]
DCBLD2, OCIAD2, SAMD9	Multi-gene signature	OS	Yes	Yes	External	A	Cui et al[62]
Disulfidptosis-related prognostic signature (8-gene signature: SLC3A2, HMGA1, S100A2, DUSP5, SPRR1B, MET, CREB5, MACROD2)	Multi-gene signature	OS	Yes	Yes	Multi-cohort	A	Cui et al[63]
M2 macrophage-related 6-gene prognostic signature: CCL2, CD9, FBP1, LIMS1, LYZ, TGFBI; M2/TAM biology and TNFRSF12A also highlighted	Multi-gene signature	OS	Yes	Yes	Partial	B+	Chen et al[64]
20-protein diagnostic panel; 4 proteomic prognostic subtypes; 18-protein prognostic risk score (PURB, SDCBP2, CD2BP2, GALM, SERPINA3, OAS3, FAN1, ZPR1, KRT2, NUDT2, SMNDC1, SERPINA4, CUTA, WDR36, POSTN, CLEC11A, PEX14, PI4KA)	Multi-protein signature	OS	Yes	Yes	External	A	Aref et al[65]
Complement pathway genes (C1R, C1S, C3, C4B, C7) in tumour microenvironment	Multi-gene signature	OS	Yes	Yes	Partial	B+	Zhang et al[66]
13-gene autophagy-related signature (EIF4EBP1, HDAC6, GABARAP, CASP4, ATG16 L2, BCL2 L1, BAG3, ATG4B, TNFSF10, PTK6, ITGA3, BIRC5, BAK1)	Multi-gene signature	OS	Yes	Yes	External	A-	Wang et al[67]
Fibroblast-related 14-gene prognostic signature	Multi-gene signature	OS	Yes	Yes	Multi-cohort	A	Wang et al[68]
ANP32E	Single gene	OS	Yes	Yes	External	A-	Liu et al[69]
Cuproptosis-related signature score (MIR3677, AC068620.2, UPK2, LDHAP7, FAM83A)	Multi-gene signature	OS	Yes	Yes	External	A-	Ge et al[70]

The categories below were developed by the authors for this review. Categories were defined as follows: A+: Multivariable significance with robust external validation across multiple independent cohorts and prospective validation; no included study met these criteria, and the category was therefore unawarded. A: Multivariable significance with external validation in more than 1 independent cohort, or in a single independent cohort with no recorded limitations. A-: Multivariable significance with external validation in a single independent cohort where limitations were recorded (e.g., dataset overlap, limited cohort diversity, or methodological concerns). B+: Moderate evidence; multivariable significance with internal validation or partial external validation. B: Multivariable significance without adequate validation. Studies without a statistically significant multivariable result are shown as not applicable because every category presupposes a significant result. MRS: Mitochondrial unfolded protein response-related gene risk score; LMRGS: Lactate metabolism-related gene signature; PCLM-BM: Pancreatic cancer liver metastasis and basement membrane; EFFscore: Efferocytosis-related score; mCAF: Myofibroblastic cancer-associated fibroblast; PCD: Programmed cell death; ICD: Immunogenic cell death; MDRG: Metastatic dissemination-related gene; BM: Basement membrane; TF: Transcription factor; ER: Endoplasmic reticulum; zDHHC: Zinc finger DHHC-type palmitoyl transferase; SASP: Senescence-associated secretory phenotype; DEGs: Differentially expressed genes; lncRNA: Long noncoding RNA; mRNA: Messenger RNA; ITH: Intratumoral heterogeneity; HRD: Homologous recombination deficiency; BA: Brown adipocyte; CD: Cluster of differentiation; ISGS: Immunologic signature gene sets; TAM: Tumor-associated macrophage; OS: Overall survival; PFS: Progression-free survival.