Systems Biology (Methods in Molecular Biology)

Based on the integrative co-expression network analysis, sur-

vival analysis and literature review STAT3 may be the most signifi-

cant key signature in the metastatic prostate cancer. The metastatic

integrative co-expression analysis also reveals many genes that

involve in TGFβsignaling pathway (SMAD4,SMAD9,TGFBR2,

GDF15,JUN,FOS,JUNB,FOSB,andATF3). All of these genes

were downregulated in metastatic prostate tumor. As mentioned

before, malfunction of TGFβsignaling pathway results in aggressive

phenotypes of prostate cancer [109]. JUN and JUNB are the other

Primary prostate cancer signatures Metastatic prostate cancer signatures

0 20 40 60 80 100 120 140

0.0

0.2

0.4

0.6

0.8

1.0

PGR_H (NO: 75; BCR: 13; MST: 62.61)

PGR_L (NO: 68; BCR: 22; MST: 45.62)

0 20406080100120140

0.0

0.2

0.4

0.6

0.8

1.0

BCL2_H (NO: 74; BCR: 19; MST: 56.61)

BCL2_L (NO: 69; BCR: 16; MST: 52.29)

0 20406080100120140

0.0

0.2

0.4

0.6

0.8

1.0

HOXD10_H (NO: 74; BCR: 13; MST: 60.72)

HOXD10_L (NO: 69; BCR: 22; MST: 47.89)

time (month)

BCR−Free survival probability

BCR−Free surviv

al probability

BCR−Free survival probability

P=0.00931

P=0.873

P=0.0245

0 20 40 60 80 100 120 140

time (month)

0.0

0.2

0.4

0.6

0.8

1.0

BCR−Free survival probability

JUNB_H (NO: 73; BCR: 13; MST: 45.26)

JUNB_L (NO: 70; BCR: 23; MST: 43.34)

0 20 40 60 80 100 120 140

time (month)

0 20 40 60 80 100 120 140

time (month)

STAT3_H (NO: 74; BCR: 10; MST: 65.71)

STAT3_L (NO: 69; BCR: 25; MST: 42.54)

0.0

0.2

0.4

0.6

0.8

1.0

BCR−Free survival probability

JUN_H (NO: 73; BCR: 12; MST: 62.48)

JUN_L (NO: 70; BCR: 23; MST: 46.24)

0.0

0.2

0.4

0.6

0.8

1.0

BCR−Free survival probability

P=0.000136

P=0.00296

P=0.00409

time (month)

time (month)

Fig. 11Kaplan-Meier survival curves of BCR-free survival probability for key molecular signatures in primary
(left panel) and metastatic (right panel) states of prostate cancer. High expression ofSTAT3is associated with
the highest mean survival time (MST¼65.71 months) and lowest BCR event (10 BCR events) among all of
genes. NO: number of samples in the group, BCR: biochemical recurrence,MSTmean survival time

270 Faiz M. Khan et al.