Table 4.
Prognostic hypoxia gene signatures in pancreatic cancer.
| Signature and Cohort Characteristics | Survival Analysis a | Immune Analysis b | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Genes | Derivation | Scoring | Cohort | Groups (Patient Number) c | End Point | KM (p-Value) | Univariate Cox PH | Multivariate Cox PH | Method | High-Risk Group (Hypoxia-High) | Low-Risk Group (Hypoxia-Low) | Ref. |
| 30 d | Overlap between 200 genes of the hallmark HYPOXIA gene-set and microarray data of two pancreatic cancer cohorts (GSE15471 and GSE16515)—30 DEGs |
Gene score: +1 if gene expression > median expression in entire cohort; −1 if < median expression in entire cohort. Hypoxia score is sum of 30 genes | PAAD TCGA | High (79) vs. Low (98) |
OS PFS |
0.0062 0.0024 |
NA | NA | NA | NA | NA | [141] |
| 8 (DDIT4, LDHA, MXI1, NDRG1, P4HA1, PGK1, SLC2A1, VEGFA) | Expression of 15 genes selected from 398 hypoxia genes collected from published prognostic or predictive signatures tested in 14 cancer cell lines exposed to 1% oxygen | Gene score: +1 if gene expression > median expression in entire cohort; −1 if <median expression in entire cohort. Hypoxia score is sum of 8 genes | PAAD TCGA | High (66) vs. Low (98) |
OS DSS PFS |
0.0035 0.0047 0.01 |
1.9 (1.2–2.9) p = 0.004 2 (1.2–3.2) p = 0.005 1.7 (1.1–2.5) p = 0.011 |
1.7 (1.10–2.7) p = 0.016 1.6 (0.99–2.6) p = 0.056 1.5 (0.97–2.2) p = 0.067 |
CIBERSORTx Immune score Cytolytic index 4-chemokine signature |
M0 macrophages, low cytolytic index, low immune score and low chemokine score |
CD8+ T cells, high cytolytic index, high immune score and high chemokine score |
[23] |
| E-MTAB-6134 | High (136) vs. Low (173) |
OS DFS |
<0.0001 <0.0001 |
2.1 (1.6–2.8) p < 0.001 1.8 (1.3–2.3) p < 0.001 |
2.19 (1.60–3.0) p < 0.001 1.8 (1.39–2.5) p < 0.001 |
|||||||
| 9 (ARNTL1, DCBLD2, DSG3, FAM83A, FOXM1, GZMK, IGF2BP2, SLC38A11, TPX2) | 15 overexpressed HIF-1 related genes in meta-PDAC cohort (GSE62452 and PAAD TCGA)—nine showed critical prognosis association using LASSO regression analysis | Multiplying expression of nine genes with their corresponding multivariable Cox regression coefficient—classification into high-, medium- and low-score based on cutoffs determined by X-tile 3.6.1 software | Meta-PDAC cohort | High (22) vs. Medium (73) vs. Low (110) |
OS | 5.584 × 10−14 | 2.276 (1.741–2.975) p < 0.001 | 2.162 (1.632–2.865) p < 0.001 | Enrichment scores of 25 immune-related terms determined from previous studies in the meta-PDAC cohort only immunostaining for CD8+ T cells in 28 PDACs sorted into low- and high-HIF-1 scores based on median cutoff of HIF-1 scores determined using RT-qPCR |
TIL, activated CD8+ T cells, cytolytic activity, activated B cell, immature B cell and Type 1 T-helper cells significantly more enriched in low-score group. High-HIF-1 score inversely correlated with CD8+ T cell density |
[24] | |
| PDAC ICGC | High vs. Medium vs. Low |
OS | 2.436 × 10−05 | NA | NA | |||||||
| GSE79668 | High-risk vs. Low-risk |
OS | 1.246 × 10−04 | NA | NA | |||||||
| 4 (ENO3, LDHA, PGK1, PGM1) | Network analysis of protein interactions of 200 genes of hallmark HYPOXIA gene-set—50 DEGs with highest interaction- 4 DEGs maintained association with survival following multivariate Cox regression analysis |
Multiplying expression of nine genes with their corresponding multivariable Cox regression coefficient—classification into high- and low-hypoxia risk score based on the median risk score | PAAD TCGA | High-risk (88) vs. Low-risk (89) |
OS | <0.001 | 1.986 (1.579–2.498) p < 0.001 | 1.878 (1.498–2.354) p < 0.001 | CIBERSORT Expression of genes unfavorably regulating immune-related processes. Expression of genes positively regulating T cells, DCs and MDSCs |
Resting NK cells Higher expression of VEGFA, MICB and ICAM1. Higher expression of CXCL5 |
CD8+ T cells, and naive B cells Higher expression of CCL21 and CCR7 |
[142] |
| GSE78229 and GSE57495 | High-risk (58) vs. Low-risk (54) |
OS | 0.024 | 1.410 (1.190–1.670) p < 0.001 | 1.622 (1.050–2.507) p = 0.029 | |||||||
| 8 (ANKZF1, CITED, ENO3, JMJD6, LDHA, NDST1, SIAH2, TES) | Correlation between 200 genes of hallmark HYPOXIA gene-set and RNA-seq data of PAAD TCGA cohort—108 DEGs were correlated—45 DEGs were associated with OS based on univariate Cox regression analysis—eight maintained association based on LASSO regression analysis |
Multiplying expression of eight genes with their corresponding LASSO coefficient—classification into high- and low-hypoxia risk score based on the median risk score | PAAD TCGA | High-risk (81) vs. Low-risk (81) |
OS | <0.0001 | 2.508 (1.575–3.992) p < 0.0001 | 2.503 (1.483–4.226) p < 0.0001 | CIBERSORT (applied only in TCGA cohort) Expression of immune checkpoint genes (applied only in TCGA cohort) |
Neutrophils with higher expression of CD47 |
Treg higher expression of BTLA, CTLA4, LAG3, TNFRSF4 and PDCD1 |
[143] |
| GSE62452 | High-risk (33) vs. Low-risk (32) |
OS | 0.00075 | NA | NA | |||||||
| 3 (ANXA2, LDHA, TES) | Overlap between 200 genes of hallmark HYPOXIA gene-set and RNA seq data of PAAD TCGA cohort—67 DEGs correlated with OS based on univariate Cox regression analysis—three maintained association with survival following multivariate Cox regression analysis |
Multiplying expression of three genes with their corresponding multivariable Cox regression coefficient—classification into high- and low-hypoxia risk score based on the median risk score | PAAD TCGA | High-risk vs. Low-risk |
OS | 0.00061 | 2.5746 (1.6083–4.122) p < 0.001 |
NA | CIBERSORT | M0 macrophages, monocytes (ICGC and GSE57495) | CD8+ T cells (TCGA and ICGC), naïve B cells (TCGA and GSE57495) | [144] |
| PDAC ICGC | High-risk vs. Low-risk |
OS | 0.004 | 3.0760 (1.7135–5.522) p < 0.001 |
NA | |||||||
| GSE57495 | High-risk vs. Low-risk |
OS | 0.031 | NA | NA | |||||||
a Univariate and multivariate Cox PH analysis reporting the hazard ratio, in bold, with the 95% confidence interval in brackets and corresponding p value. b Reported immune cell fractions present in at least two datasets. c Some studies have not reported the exact patient number per group. d Gene list was not reported. KM: Kaplan–Meier; PH: proportional hazard; Ref: reference; DEGs: differentially expressed genes; OS: overall survival; PFS: progression-free survival; DSS: disease-specific survival; DFS: disease-free survival; vs.: versus; NA: not available; Treg: regulatory T cells; TIL: tumor-infiltrating lymphocytes; DCs: dendritic cells; MDSCs: myeloid-derived suppressor cells.