EURURO Vol. 71 No. 5

781 844

and presentation (PSMB9, TAP1, and HLA-A) in an extended
set of CRPC bone metastasis samples (n = 53), non-treated
PC metastases (n = 11), and non-treated metastases from
other malignancies (n = 13; . Levels in metastases
were compared to levels in paired samples of non-
malignant and malignant prostate tissue from radical
prostatectomies (n = 12). PSMB9 , TAP1, and HLA-A mRNA
levels in bone metastases were significantly lower in PC
patients than in patients with other malignancies A–
C). However, and in accordance with the array data, the
CRPC bone metastases could be classified into two groups
on the basis of their variation in PSMB9 , TAP1, and HLA-A
mRNA levels ), suggesting MHC class I antigen
presentation was downregulated in the majority of CRPC
Table 2 – Canonical pathways predicted by Ingenuity pathway analysis to be upregulated or downmodulated in AR-driven compared to non-
AR-driven castration-resistant prostate cancer bone metastases according to whole-genome array analysis and principal component analysis
Ingenuity canonical
pathway
p value Ratio Category Molecules
Upregulated
Cholesterol biosynthesis
superpathway
0.004 0.26 Sterol biosynthesis DHCR7, ACAT2, MSMO1, HMGCS2, HMGCR,
TM7SF2, SC5D
Methionine degradation
superpathway
0.005 0.23 Methionine degradation CBS/CBSL, DLD, PCCB, CTH, MUT, SUOX, AHCY
Fatty acid b-oxidation I 0.025 0.20 Fatty acid degradation ACSL3, SLC27A2, ECI2, AUH, IVD, HSD17B4
2-Oxobutanoate degradation I 0.025 0.60 2-Oxobutanoate degradation DLD, PCCB, MUT
Cholesterol biosynthesis 0.025 0.31 Sterol biosynthesis DHCR7, MSMO1, TM7SF2, SC5D
Pyrimidine ribonucleotide
interconversion
0.032 0.19 Pyrimidine nucleotide biosynthesis NME3, NME4, ENTPD6, AK4, CANT1
b-Alanine degradation I 0.032 1.0 B-Alanine degradation ABAT, ALDH6A1
Spermine biosynthesis 0.032 1.0 Amine and polyamine biosynthesis SMS, AMD1
Cysteine biosynthesis/
homocysteine degradation
0.032 1.0 Homocysteine degradation,
cysteine biosynthesis
CBS/CBSL, CTH
Pyrimidine ribonucleotide de
novo biosynthesis
0.042 0.18 Pyrimidine nucleotide de novo
biosynthesis
NME3, NME4, ENTPD6, AK4, CANT1
Downregulated
Hepatic fibrosis / hepatic stellate
cell activation
2e-08 0.18 Disease-specific pathways;
ingenuity toxicity list pathways
IGFBP4, FN1, MYH9, SMAD3, KLF6, COL8A1, CCL5,
PDGFC, COL15A1, COL5A1, IL1R2, COL1A2, TIMP1,
PDGFRA, COL22A1, COL18A1, KLF12, TNFRSF1B,
TIMP2, PDGFRB, TNFRSF11B, VCAM1, COL5A2,
MMP2, IFNAR2, COL1A1, TLR4, LY96, COL6A3,
CD40, IL10RA, CD14
Antigen presentation pathway 7e-08 0.38 Cellular immune response; humoral
immune response
HLA-G, B2M, PSMB9, HLA-DRB4, HLA-DRB1, HLA-
DMA, HLA-A, HLA-B, CD74, PSMB8, HLA-F, TAPBP,
HLA-E, MR1
Leukocyte extravasation signaling 1e-07 0.16 Cellular immune response RAC2, CLDN11, MMP16, TIMP1, CYBA, CYBB,
RASSF5, ACTN1, ACTA1, TIMP2, VCAM1, CXCR4,
ACTB, ARHGAP4, ITGA5, THY1, MMP2, NCF4,
GNAI2, BTK, ITGB2, WIPF1, ITGAM, ARHGAP9,
WAS, JAM3, PLCG2, PIK3CD, ACTN4, PRKCB, MSN
Caveolar-mediated Endocytosis
Signaling
1E-06 0.24 Cellular Immune Response;
Organismal Growth and
Development; Pathogen-Influenced
Signaling
B2M, FYN, HLA-A, ACTB, HLA-B, CD48, ITGA5,
ITGB7, ITGB2, ITGAM, FLNC, ITGA11, ITGA9, CAV1,
ITGB4, ACTA1, ITGAX
Crosstalk between Dendritic Cells
and Natural Killer Cells
1E-06 0.21 Cellular Immune Response TYROBP, HLA-A, ACTB, CD69, HLA-B, LTB, HLA-G,
TLR4, PRF1, HLA-DRB1, HLA-DRB4, MICB, CD40,
FSCN1, CD86, TNFRSF1B, HLA-F, ACTA1, HLA-E
Allograft rejection signaling 1e-06 0.29 Cellular immune response;
disease-specific pathways
HLA-G, B2M, PRF1, HLA-DRB4, HLA-DRB1, CD40,
HLA-DMA, GZMB, HLA-A, HLA-B, FCER1G, CD86,
HLA-F, HLA-E
Complement system 2e-06 0.33 Humoral immune response C1R, ITGB2, CFD, ITGAM, C5AR1, CFB, CFI, C1QC,
C1QA, C1QB, C2, ITGAX
Dendritic cell maturation 3e-06 0.15 Cellular immune response;
cytokine signaling; pathogen-
influenced signaling
B2M, PLCB2, TYROBP, FCGR2A, HLA-A, HLA-B, LTB,
PLCL2, FCGR1A, COL1A2, COL1A1, TLR4, HLA-
DRB4, HLA-DRB1, CD40, HLA-DMA, DDR2, FSCN1,
PLCG2, FCER1G, CD86, PIK3CD, IRF8, COL18A1,
TNFRSF1B, TNFRSF11B
Integrin signaling 6e-06 0.14 Cell cycle regulation; cellular
growth, proliferation and
development; intracellular and
second messenger signaling
RAC2, RAP2A, FYN, MPRIP, TSPAN7, ARPC5, ITGB7,
RHOG, ITGA11, ITGA9, CAV1, ITGB4, TSPAN4,
ACTA1, ACTN1, ASAP1, ACTB, ITGA5, RHOJ, GSN,
ITGB2, WIPF1, ITGAM, WAS, PLCG2, PIK3CD,
ACTN4, ITGAX
Phagosome formation 7E-06 0.19 Cellular Immune Response;
Pathogen-Influenced Signaling
PLCB2, FN1, MRC2, FCGR2A, TLR8, ITGA5, RHOJ,
PLCL2, FCGR1A, INPP5D, TLR4, RHOG, SCARA3,
PLCG2, SYK, FCER1G, PIK3CD, MARCO, PRKCB
a P value after FDR correction according to Benjamini-Hochberg.
E U R O P E A N U R O L O G Y 7 1 ( 2 0 1 7 ) 7 7 6 – 7 8 7 781