Background
Methods
Gene expression datasets
Gene expression data analysis
Statistical analysis
Results
Patient population
Characteristics | All (n = 601) |
---|---|
Age at diagnosis, years | |
≤ 60 | 118 (32%) |
> 60 | 246 (68%) |
Sex | |
Female | 170 (46%) |
Male | 197 (54%) |
AJCC Stage | |
1 | 62 (12%) |
2 | 431 (84%) |
3 | 10 (2%) |
4 | 12 (2%) |
Pathological type | |
Ductal | 537 (98%) |
Othera
| 11 (2%) |
Pathological grade | |
1 | 33 (12%) |
2 | 154 (55%) |
3 | 91 (32%) |
4 | 2 (1%) |
Pathological tumor size (pT) | |
pT1 | 18 (5%) |
pT2 | 62 (16%) |
pT3 | 302 (77%) |
pT4 | 11 (3%) |
Pathological lymph node status (pN) | |
Negative | 141 (31%) |
Positive | 310 (69%) |
Collisson subtypes | |
Classical | 234 (39%) |
Exocrine-like | 211 (35%) |
Quasi-mesenchymal | 156 (26%) |
Moffitt subtypes, ‘type’ | |
Basal-like | 232 (39%) |
Classical | 369 (61%) |
Bailey subtypes | |
ADEX | 140 (23%) |
Immunogenic | 104 (17%) |
Pancreatic progenitor | 142 (24%) |
Squamous | 215 (36%) |
Deceased | 354 (59%) |
2-year OS (95% CI) | 40% (36–45) |
Median OS, months (range) | 20 (1–156.4) |
Identification of a prognostic expression signature
GO:BP TermsID | GO:BP Terms |
N
|
P value | Status STS vs. LTS |
---|---|---|---|---|
GO:0030198 | Extracellular matrix organization | 70 | 9.15 × 10–26
| Up |
GO:0007155 | Cell adhesion | 75 | 2.46 × 10–22
| Up |
GO:0022617 | Extracellular matrix disassembly | 35 | 2.70 × 10–18
| Up |
GO:0008544 | Epidermis development | 25 | 1.04 × 10–17
| Up |
GO:0030574 | Collagen catabolic process | 26 | 2.78 × 10–17
| Up |
GO:0006955 | Immune response | 50 | 1.44 × 10–16
| Up |
GO:0006954 | Inflammatory response | 52 | 2.34 × 10–16
| Up |
GO:0030199 | Collagen fibril organization | 19 | 6.76 × 10–16
| Up |
GO:0018149 | Peptide cross-linking | 10 | 1.23 × 10–10
| Up |
GO:0006935 | Chemotaxis | 22 | 2.34 × 10–10
| Up |
GO:0010951 | Negative regulation of endopeptidase activity | 23 | 6.65 × 10–10
| Up |
GO:0030216 | Keratinocyte differentiation | 14 | 3.24 × 10–9
| Up |
GO:0010466 | Negative regulation of peptidase activity | 8 | 1.47 × 10–8
| Up |
GO:0001501 | Skeletal system development | 22 | 2.51 × 10–8
| Up |
GO:0007160 | Cell-matrix adhesion | 19 | 1.30 × 10–7
| Up |
GO:0000278 | Mitotic cell cycle | 50 | 1.71 × 10–7
| Up |
GO:0008283 | Cell proliferation | 42 | 1.86 × 10–7
| Up |
GO:0031124 | Mrna 3-end processing | 600 | 2.19 × 10–7
| Up |
GO:0008284 | Positive regulation of cell proliferation | 45 | 3.26 × 10–7
| Up |
GO:0001525 | Angiogenesis | 32 | 3.31 × 10–7
| Up |
GO:0019228 | Neuronal action potential | 6 | 1.26 × 10–6
| Down |
GO:0007409 | Axonogenesis | 12 | 1.13 × 10–6
| Down |
GO:0007628 | Adult walking behavior | 7 | 1.09 × 10–6
| Down |
GO:0007212 | Dopamine receptor signaling pathway | 5 | 7.83 × 10–7
| Down |
GO:0006906 | Vesicle fusion | 10 | 4.63 × 10–7
| Down |
GO:0030073 | Insulin secretion | 9 | 5.27 × 10–8
| Down |
GO:0007274 | Neuromuscular synaptic transmission | 6 | 5.20 × 10–8
| Down |
GO:0007399 | Nervous system development | 27 | 1.44 × 10–8
| Down |
GO:0014047 | Glutamate secretion | 9 | 5.89 × 10–9
| Down |
GO:0007626 | Locomotory behavior | 15 | 4.46 × 10–9
| Down |
GO:0086010 | Membrane depolarization during action potential | 8 | 1.71 × 10–9
| Down |
GO:0031018 | Endocrine pancreas development | 12 | 1.16 × 10–9
| Down |
GO:0017158 | Regulation of calcium ion-dependent exocytosis | 10 | 9.94 × 10–10
| Down |
GO:0006112 | Energy reserve metabolic process | 20 | 4.05 × 10–11
| Down |
GO:0017157 | Regulation of exocytosis | 13 | 1.60 × 10–11
| Down |
GO:0006813 | Potassium ion transport | 15 | 3.94 × 10–12
| Down |
GO:0071805 | Potassium ion transmembrane transport | 17 | 1.97 × 10–13
| Down |
GO:0016079 | Synaptic vesicle exocytosis | 17 | 4.00 × 10–15
| Down |
GO:0007269 | Neurotransmitter secretion | 19 | 7.04 × 10–16
| Down |
GO:0007268 | Synaptic transmission | 66 | 2.33 × 10–37
| Down |
Symbol | Description | Cytoband | Expression status |
---|---|---|---|
GPR87 | G protein-coupled receptor 87 | 3q24 | Up STS vs. LTS |
KRT13 | keratin 13, type I | 17q21.2 | Up STS vs. LTS |
RAC2 | ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2) | 22q13.1 | Up STS vs. LTS |
C16orf74 | chromosome 16 open reading frame 74 | 16q24.1 | Up STS vs. LTS |
NAMPT | nicotinamide phosphoribosyltransferase | 7q22.3 | Up STS vs. LTS |
DHRS9 | dehydrogenase/reductase (SDR family) member 9 | 2q31.1 | Up STS vs. LTS |
HIST2H2BF | histone cluster 2, H2bf | 1q21.2 | Up STS vs. LTS |
TREM2 | triggering receptor expressed on myeloid cells 2 | 6p21.1 | Up STS vs. LTS |
ZDHHC20 | zinc finger, DHHC-type containing 20 | 13q12.11 | Up STS vs. LTS |
CD180 | CD180 molecule | 5q12 | Up STS vs. LTS |
ADGRG6 | adhesion G protein-coupled receptor G6 | 6q24.1 | Up STS vs. LTS |
APBB1IP | amyloid beta (A4) precursor protein-binding, family B, member 1 interacting protein | 10p12.1 | Up STS vs. LTS |
EGR3 | early growth response 3 | 8p23-p21 | Down STS vs. LTS |
MACROD2 | MACRO domain containing 2 | 20p12.1 | Down STS vs. LTS |
EPHA7 | EPH receptor A7 | 6q16.1 | Down STS vs. LTS |
RASGEF1A | RasGEF domain family, member 1A | 10q11.21 | Down STS vs. LTS |
SYNM | synemin, intermediate filament protein | 15q26.3 | Down STS vs. LTS |
S100A1 | S100 calcium binding protein A1 | 1q21 | Down STS vs. LTS |
WNK2 | WNK lysine deficient protein kinase 2 | 9q22.3 | Down STS vs. LTS |
RAMP2 | receptor (G protein-coupled) activity modifying protein 2 | 17q12-q21.1 | Down STS vs. LTS |
SOCS2 | suppressor of cytokine signaling 2 | 12q | Down STS vs. LTS |
COL28A1 | collagen, type XXVIII, alpha 1 | 7p21.3 | Down STS vs. LTS |
B4GALT6 | UDP-Gal:betaGlcNAc beta 1,4-galactosyltransferase, polypeptide 6 | 18q11 | Down STS vs. LTS |
PLCB4 | phospholipase C, beta 4 | 20p12 | Down STS vs. LTS |
MTURN | maturin, neural progenitor differentiation regulator homolog (Xenopus) | 7p14.3 | Down STS vs. LTS |
Validation of the 25-gene classifier and clinicopathological associations
Characteristics |
n
| LTS-like (n = 346) | STS-like (n = 216) |
P value |
---|---|---|---|---|
Age at diagnosis | 0.219 | |||
≤ 60 | 108 | 64 (31%) | 44 (38%) | |
> 60 | 217 | 145 (69%) | 72 (62%) | |
Sex | 0.419 | |||
Female | 157 | 105 (50%) | 52 (44%) | |
Male | 171 | 106 (50%) | 65 (56%) | |
AJCC stage | 0.759 | |||
1 | 54 | 35 (12%) | 19 (11%) | |
2 | 403 | 255 (84%) | 148 (85%) | |
3 | 10 | 5 (2%) | 5 (3%) | |
4 | 11 | 8 (3%) | 3 (2%) | |
Pathological type | 0.087 | |||
Ductal | 504 | 308 (98%) | 196 (100%) | |
Other | 6 | 6 (2%) | 0 (0%) | |
Pathological grade | 1.50 × 10–3*
| |||
1 | 27 | 24 (16%) | 3 (3%) | |
2 | 138 | 90 (59%) | 48 (54%) | |
3 | 75 | 38 (25%) | 37 (42%) | |
4 | 2 | 1 (1%) | 1 (1%) | |
Pathological tumor size (pT) | 0.879 | |||
pT1 | 15 | 9 (4%) | 6 (5%) | |
pT2 | 57 | 36 (16%) | 21 (16%) | |
pT3 | 281 | 181 (78%) | 100 (76%) | |
pT4 | 11 | 6 (3%) | 5 (4%) | |
Pathological lymph node status (pN) | 0.824 | |||
Negative | 123 | 79 (30%) | 44 (29%) | |
Positive | 291 | 183 (70%) | 108 (71%) | |
Collisson subtypes | 1.00 × 10–6*
| |||
Classical | 223 | 130 (38%) | 93 (43%) | |
Exocrine-like | 194 | 147 (42%) | 47 (22%) | |
Quasi-mesenchymal | 145 | 69 (20%) | 76 (35%) | |
Moffitt subtypes, ‘type’ | 7.80 × 10–15*
| |||
Basal-like | 214 | 88 (25%) | 126 (58%) | |
Classical | 348 | 258 (75%) | 90 (42%) | |
Bailey subtypes | 1.00 × 10–6*
| |||
ADEX | 128 | 114 (33%) | 14 (6%) | |
Immunogenic | 101 | 69 (20%) | 32 (15%) | |
Pancreatic progenitor | 133 | 90 (26%) | 43 (20%) | |
Squamous | 200 | 73 (21%) | 127 (59%) | |
2-year OS (95% CI) | 562 | 48% (42–54) | 25% (0.18–0.33) | 4.33 × 10–9*
|
Median OS, months (range) | 562 | 22.8 (1–156.4) | 15.0 (1–103.92) |
Uni- and multivariate prognostic analyses
Characteristics | Univariate | Multivariate | Multivariate | |||||||
---|---|---|---|---|---|---|---|---|---|---|
N
| HR (95% CI) |
P value |
N
| HR (95% CI) |
P value |
N
| HR (95% CI) |
P value | ||
Age at diagnosis | >60 vs. ≤ 60 | 325 | 1.22 (0.88–1.70) | 0.234 | ||||||
Sex | Male vs. female | 328 | 1.08 (0.80–1.45) | 0.633 | ||||||
AJCC Stage | 2 vs. 1 | 478 | 2.01 (1.32–3.07) | 4.71 × 10–3*
| 408 | 1.57 (0.88–2.82) | 0.128 | |||
3 vs. 1 | 3.11 (1.33–7.23) | 408 | 2.21 (0.82–5.97) | 0.119 | ||||||
4 vs. 1 | 2.85 (1.16–7.05) | 408 | 1.44 (0.19–10.97) | 0.723 | ||||||
Pathological type | Other vs. ductal | 510 | 0.36 (0.09–1.45) | 0.151 | ||||||
Pathological grade | 2 vs. 1 | 242 | 1.52 (0.65– 3.55) | 0.185 | ||||||
3 vs. 1 | 2.15 (0.91– 5.11) | |||||||||
4 vs. 1 | 2.66 (0.53–13.3) | |||||||||
Pathological tumor size (pT) | 2 vs. 1 | 364 | 1.49 (0.62–3.59) | 0.131 | ||||||
3 vs. 1 | 1.95 (0.86–4.42) | |||||||||
4 vs. 1 | 2.93 (1.01–8.48) | |||||||||
Pathological lymph node status (pN) | 1 vs. 0 | 414 | 1.83 (1.34–2.48) | 1.24 × 10–4*
| 408 | 1.50 (1.04–2.16) | 2.95 × 10–2*
| |||
Collisson subtypes | Exocrine-like vs. classical | 562 | 1.00 (0.77–1.29) | 2.32 × 10–3*
| 562 | 0.94 (0.66–1.34) | 0.732 | |||
Quasi-mesenchymal vs. classical | 1.52 (1.17–1.99) | 562 | 1.15 (0.83–1.59) | 0.395 | ||||||
Moffitt subtypes, ‘type’ | Classical vs. basal-like | 562 | 0.64 (0.51–0.80) | 6.29 × 10–5*
| 562 | 1.00 (0.72–1.38) | 0.994 | |||
Bailey subtypes | Immunogenic vs. ADEX | 562 | 0.81 (0.57–1.17) | 8.98 × 10–6*
| 562 | 0.68 (0.43–1.06) | 0.090 | |||
Pancreatic progenitor vs. ADEX | 0.97 (0.70–1.35) | 562 | 0.79 (0.51–1.23) | 0.302 | ||||||
Squamous vs. ADEX | 1.64 (1.22–2.19) | 562 | 1.09 (0.68–1.74) | 0.731 | ||||||
25-gene classifier | STS-like vs. LTS-like | 562 | 1.93 (1.55–2.42) | 7.47 × 10–9*
| 408 | 2.04 (1.54–2.70) | 6.33 × 10–7*
| 562 | 1.77 (1.38–2.26) | 6.33 × 10–6*
|