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RESEARCH 

Racial Disparities in Expression of GDF15 
and NFκB in Prostate Cancer and Benign 
Prostatic Epithelium 
Kenneth A Iczkowski1, Oleksandr Kravtsov1, Sudha Sadasivan2, Watchareepohn Palangmonthip1,3, Yalei 
Chen2, M Scott Lucia4, James R Lambert4, Kathleen C Torkko4, Benjamin A Rybicki2 

1Department of Pathology, Medical College of Wisconsin, Pathology, Milwaukee, WI, United States, 
2Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, United States, 3Department 
of Pathology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand, and 4University of 
Colorado, Aurora, CO, United States 

*Corresponding author: Kenneth A. Iczkowski, E-Mail: kaiczkowski@mcw.edu 

ABSTRACT: Prostate cancer (PC) outcomes are more adverse for African-American (AA) than 
white/European American (EA) men. Growth differentiation factor 15 (GDF15, PDF, NAG-1) is a stress-
induced anti-inflammatory cytokine with immunosuppressive and tumor growth-promoting functions. 
GDF15 inversely regulates NFκB, a transcription factor enabling pro-inflammatory gene expression and 
becomes constitutively activated in androgen-independent PC. Tissue microarrays (TMAs), prepared 
from prostatectomy tissue at three institutions, comprised 688 cases (364 EA and 324 AA). Each case 
included ≥3 tumor punches plus ≥3 non-neoplastic punches. TMAs were stained separately for GDF15 
and NFκB and evaluated by two pathologists, using the 0-3+ scale. PC, compared to benign epithelium, 
had elevated median GDF15 expression (1.93 vs. 0.99) and also, NFκB (1.18 vs. 0.96, both P<0.0001). Only 
in AA men did PC show gradewise or stagewise altered expression of these markers. In AA men, GDF15 
expression fell as stage rose in PC (P=0.007) and also in benign epithelium (P =0.003). In EA men, 
GDF15 expression in benign epithelium fell as stage (P=0.01) and grade (P=0.01) rose. NFκB expression 
was higher in AA than EA men only in high-grade PC (P =0.01). NFκB expression rose with increasing 
tumor grade only in AA men (P =0.027) and in the benign prostate component only in EA men 
(P=0.007). Benign and tumor NFκB expression did not vary with stage. PC showed significant alterations 
in GDF15 and NFκB expression in accord with cancer aggressiveness in AA men only: stagewise 
decrease in GDF15, and gradewide increase in NFκB. Findings suggest a racial disparity in cell growth, 
immune response, stress response, or other functions relevant to prostate carcinogenesis. 
KEYWORDS: Racial disparity, prostate cancer, GDF15, NFκB. 

Citation: Iczkowski1 et al (2021) Racial Disparities in Expression of GDF15 and NFκB in Prostate Cancer and 
Benign Prostatic Epithelium. Cancer Health Disparities. 5:e1-e22. doi:10.9777/chd.2020.1010 
 

mailto:kaiczkowski@mcw.edu


 
 
 
 
 

 
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RESEARCH 

Introduction 

African-American (AA) men generally have worse 
prostate cancer (PC) outcomes than 
white/European American (EA) men or other 
races. The role of chronic inflammation in 
development of prostate cancer is well 
documented (Puhr et al., 2016). Lymphocytic 
infiltration is normal in the prostate (Bostwick et al., 
2003), but whether there are racial differences in 
the level of prostatic inflammation is unclear. 
Immune response-associated gene expression 
differs between AA and EA prostate cancers 
(Wallace et al., 2008); and some studies have 
found chronic inflammation to be more frequent in 
AA men (Eastham et al., 1998) while others have 
noted no difference (Bostwick et al., 2003; Vidal et 
al., 2016) although the studies reporting no 
difference did not distinguish types of 
inflammatory cells and digital quantification was 
not used. Observed differences were not 
accounted for by race-related differences in 
patients' age, serum testosterone level, or prostate 
volume (Eastham et al., 1998). Although many 
studies have shown that interaction of 
inflammatory cytokines with inflammatory 
pathways greatly influence prostate cancer risk, the 
role of some cytokines such as growth 
differentiation factor 15 (GDF15) in prostate cancer 
is ambiguous (Vaňhara et al., 2012). GDF15, also 
called prostate-derived factor or PDF, NAG-1, or 
MIC-1, is a stress-induced anti-inflammatory 
cytokine possessing immunomodulatory functions. 
It is known to interact with Nuclear Factor of kappa 
B (NFκB) which regulates genes involved in cellular 
proliferation, apoptosis, migration and 
angiogenesis (Bennett et al., 2018). GDF15 is known 
to have both pro-tumorigenic and tumor-
suppressing functions. GDF15 is a divergent 
member of the TGF-β and bone morphogenic 

protein family. It directly induces p53, and its high 
expression is associated with progression of 
several cancers, including PC (Iczkowski and 
Pantazis, 2003). GDF15 was found to be up-
regulated in situ and in primary cultures of cancer-
associated fibroblasts from prostate cancer. 
Ectopic expression of GDF15 in fibroblasts 
produced prominent paracrine effects on PC cell 
migration, invasion, and tumor growth (Bruzzese 
et al., 2014) and the same effects were noted in 
cervical cancer (Li et al., 2018). Consistent with an 
anti-inflammatory role, inflammatory lesions in the 
prostate correlated with decreased prostatic 
GDF15 expression (Lambert et al., 2015). Moreover, 
an inverse correlation was demonstrated between 
GDF15 and CD3+, CD4+, CD8+, CD68+, and iNOS 
(NO Synthase)+ leukocytes (Bennett et al., 2018); 
and GDF15 exerts immunosuppressive effects 
(Zhang et al., 2018). 

Nuclear factor kappa-light-chain-enhancer of 
activated B cells, NFκB is a transcription factor (also 
called p65(RelA)) that regulates pro-inflammatory 
gene expression and is constitutively activated in 
androgen-independent prostate cancer, increasing 
anti-apoptotic bcl-2 and angiogenesis (Jin et al., 
2008). GDF15 expression was shown to correlate 
inversely with inflammatory lesions in the prostate 
and acts through the PI3K pathway to suppress 
NFκB activity (Lambert et al., 2015); cervical cancer 
demonstrated this same inverse relationship (Li et al., 
2018). Expression of the NFκB target, interleukin 8 
(IL-8), was downregulated by GDF15 in PC3 cells 
(Lambert et al., 2015). 

Whether these pro-tumorigenic factors show a racial 
disparity in PC is uncertain. In this study we examined 
immunoexpression of GDF15 and NFκB in tissue 
from African-American and white cancerous and 
benign prostate. 



 
 
 
 
 

 
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RESEARCH 

Materials and Methods 

Retrospective study in prostatectomy tissue 

Tissue microarrays (TMAs), prepared at three 
different institutions, comprised prostatectomy tissue 
from 697 cases. Each TMA contained at least 3 
individual 0.6 mm punches of the dominant tumor 
nodule plus at least 3 punches of non-neoplastic 
epithelium. Sources were Medical College of 
Wisconsin (57 cases), Prostate Cancer Biorepository 
Network (PCBN, via Johns Hopkins) (153 cases), 
PCBN High-Grade Racial Disparity (120 cases), and 
Henry Ford Hospital (up to 12 evaluable cores each 
of tumor and benign, 367 cases). Each study set 
contained an approximate 1:1 match of AA to white 
cases, based on grade and stage, for a total of 364 
EA and 324 AA men. Gleason score according to 
current consensus (Epstein et al., 2016) and tumor 
pathologic stage (pT) were available for all groups; 
for analysis, grade was expressed according to the 5-
tier International Society of Urological Pathology 
(ISUP) Grade Group system (Epstein et al., 2016). 
Patient ages were available only for the Henry Ford 
and Medical College of Wisconsin cases. The results 
from two Hopkins study sets were combined in all 
analyses going forward. 

Separate slides were stained with polyclonal antibody 
to GDF15 or monoclonal antibody to NFκB. Slides 
were dried 30 min at 60°C, then deparaffinized down 
to deionized water. Antigen retrieval was performed 
on a PT Link (Dako) by preheating Target Retrieval 
Solution to 65°C and heating for 20 min at 97°C in 
pH=6 (Dako). Slides were washed with buffer for 5 
minutes. All IHC staining was performed on the Dako 
Autostainer Plus (Agilent) using the Dako EnVision™ 
FLEX High pH Detection Kit (catalog K8010) with 3 
drop zones at 100 µl each and Dako Protein Block 
(Agilent). Antibodies used were goat polyclonal 
antibody to GDF15 (1:150, 20 min incubation, catalog 

AF957, R&D Systems, Minneapolis) or rabbit 
monoclonal antibody to NFκB (1:2000, 10 min 
incubation, clone D14E12, Cell Signaling 
Technologies, Beverly, MA). Background was stained 
with hematoxylin Dako FLEX. Slides were rinsed with 
deionized water and oven dried 15 min. 

Evaluation of Immunostaining 

TMA cores of tumor and benign prostatic tissue for 
each case were evaluated by two pathologists. 
(Digital evaluation of the TMAs was not feasible 
because the frequent admixture of tumor glands and 
benign glands in many spots required assessment by 
pathologists. Moreover, occasional spots that were 
sampled as benign were actually cancer and vice 
versa, and again pathologists’ interpretations were 
needed to visually dissect out the admixture and 
evaluate the tumor or benign epithelium separately.) 
Immunoreactivity (Figures 1-2) was scored on a scale 
of 0 (negative) to 3+ (strong and diffuse), including 
half-steps (0.5). Disagreements ≥1 were resolved by 
consensus. 

 

Figure 1. Example of strong GDF reactivity in cancer. 
Non-neoplastic glands at lower left are negative. 10x 
objective. 



 
 
 
 
 

 
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RESEARCH 

 

Figure 2. Example of strong NFκB reactivity in 
cancer. Non-neoplastic glands at lower left are 
negative. 10x objective. 

Statistical analysis 

To adjust for potential batch effects from TMAs 
from 3 sites, we first digitally measured the 
expression of both markers in the benign tissue 
spots corresponding to Gleason grade group 2 
tumors from all sites using the QuPath software 
(Bankhead et al., 2017). In QuPath, the stained 
color for a marker (brown) is separated from 
counter stain (blue) using stain vectors auto-
estimated by the software. Percentage of positive 
expression area (PPEA) is determined as the ratio 
of the number of positive brown stained pixels 
(brown optical density (OD) > 0.2) over total 
number of tissue pixels (overall OD > 0.05). The 
average expression intensity (AEI) is calculated as 
the mean brown OD of positively stained pixels. 
The log transformed product of PPEA and AEI, 
log(PPEA*AEI), is used as the marker expression 
level of a subject. Under the assumption that the 
marker expression in benign regions of Gleason 

grade group 2 tumors should be the same across 
the 3 study sites, the batch correction factor for a 
study site with respect to the reference Henry Ford 
study site was defined as the ratio of median 
marker expression level for the benign prostate 
spots evaluated for the study site over median 
marker expression level of benign prostate spots 
of the Henry Ford study site. Subsequently, all 
pathologist-assessed data for each study site were 
adjusted by dividing original measures over the 
batch correction factor (the reference Henry Ford 
site had a batch correction factor of 1). 

Mean age difference between races was tested by 
Wilcoxon signed rank test. Comparisons of 
expression in PC vs. benign prostate were done by 
Wilcoxon signed rank test. 

The non-parametric Mann-Whitney test was used 
for testing expression differences between two 
races. Kruskal-Wallis test was applied for testing 
expression differences across tumor stages (pT2, 
pT3a, or pT3b) and Gleason grade groups (ISUP 
groups 1-5). Correlation of the two markers with 
each other (in benign or tumor) was examined by 
Pearson and Spearman correlation tests. Statistical 
significance was set at P< 0.05. 

Results 

The racial distribution of cases did not differ by 
grade (P=0.9) or pT stage (2, 3a, or 3b) (P=0.9). 
The mean age of AA men was 60.7; this was less 
than for EA men at 62.2 (P=0.03). GDF15 reactivity 
was cytoplasmic, while NFκB reactivity was both 
cytoplasmic and nuclear, as expected (Domingo-
Domenech et al., 2005). 

Between mean reactivities of the TMAs from 3 
study sites—in both cancer and benign spots, 
some batch effect was noted in both normal and 



 
 
 
 
 

 
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RESEARCH 

tumor regions. This was attributed to differences in 
tissue processing across institutions, different lots 
of antibodies used, and other technical 
procedures. Therefore, the above-described 
normalization was applied to all benign and tumor 
results. The degrees of deviation in expression 
before and after batch correction are shown in 
normal and tumor spots of prostate tissue from 
men from all sites for GDF15 expression and NFκB 
expression (Supplementary Figure 1). 

Representative marker reactivity is shown (Figure 
3). Median GDF15 (1.93 vs. 0.19, P<0.0001) and 
NFκB (1.18 vs. 0.96, P<0.0001) expression was 
elevated in PC compared to benign prostate 
(Table 1). Median GDF15 expression for EA men 
was 2.06 in tumor versus 0.87 in benign 
(P<0.0001); comparable values for AA men were 
2.06 vs. 0.83 (P<0.0001). Median NFκB expression 
for EA men was 1.04 in tumor versus 0.88 in 
benign (P<0.0001); comparable values for AA men 
were 1.04 vs. 0.96 (P<0.0001). Tumor-tumor and 
benign-benign comparisons of expression levels 
for both proteins by race were not significant 
except that NFκB was borderline-higher in the 
prostate benign epithelium of AA men (P=0.06). 
(NFκB expression in prostate benign epithelium 
was also significantly higher in AA than EA men 
when we separately analyzed the PCBN High-
Grade TMA set (P=0.01) but not in the other cases; 
namely 41.4% of AA men had reactivity >1 in 
benign glands but 30.2% of EA did (P=0.03); for 
further analysis, however, both PCBN cohorts were 
combined.) 

 

Figure 3. Representative TMA spots illustrating 
trends in AA patients. (a) GDF15 in stage 2 tumor, 
(b) GDF15 in stage 3b tumor, (c) NFκB in low grade 
(group 1) tumor with a few stronger-staining 
benign glands at bottom, (d) NFκB in high grade 
(group 5) tumor. 

Gradewise GDF15 in tumor showed changes of 
indeterminate direction (P=0.010), while NFκB 
expression was increased in Gleason grade groups 3, 
4, and 5 in tumor (P=0.009) and benign (P=0.003) 
(Table 2). By pathologic stage (Table 3), GDF15 
expression markedly decreased in tumor (P=0.001) 
and benign epithelium (P<0.001) with increasing 
stage. NFκB expression rose in tumor (P=0.02) with 
increasing stage. Results for each site-specific 
sampling generally followed similar trends as the 
combined sample (Supplementary Tables 1-5). 

Racial disparities of GDF15 and NFκB expression 
emerged, according to tumor grade and stage, in 
both tumor and non-neoplastic prostate. The only 
expression trend by grade in tumor was for 
increasing NFκB expression with grade in AA 
(P=0.03) (Table 4). GDF15 significantly increased with 
grade only in EA men (P=0.01). By stage (Table 5), 



 
 
 
 
 

 
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RESEARCH 

GDF15 significantly decreased in AA men in prostate 
tumor (P=0.007), compared to a non-significant 
trend in the same direction observed in EA men 
(P=0.07); thus the significant decrease in the overall 
study group was driven by AA men. GDF15 
expression in benign epithelium decreased in EA 
men with increasing stage (P=0.01), as well as in AA 
men (P=0.003). NFκB showed no race-specific trends 
according to stage in either tumor or benign 
epithelium. Finally, the two markers did not correlate 
with each other in normal (Supplementary Figure 1A-
1C) or tumor samples (Supplementary Figure 1D-1F), 
either overall or in EA or AA cohorts, shown as 
scatter plots. Trends are summarized (Table 6). 

Discussion 

The current study shows a newly-described, 
significant stagewise decline in GDF15 expression in 
prostate tumors of African-American (AA) men not 
observed in European American (EA) men, and a 
grade-proportional rise of NFκB expression in AA 
tumors. Also, NFκB expression was higher in benign 
epithelium of AA men than EA men in the PCBN 
High-Grade Disparity cohort. Although AA men have 
shown higher Gleason scores in other series (P = 
0.037) (Powell et al., 2013) the lack of significant 
differences between our AA and EA men groups 
rules out differing average grades as a cause of the 
differences observed. Since GDF15 is considered to 
repress NFκB, this may explain the increase in NFκB 
expression in tumor (although the latter was 
gradewise, not stagewise) that was noted in AA men 
but not EA, a finding possibly related to androgen 
independence (Jin et al., 2008). These findings 
suggest racially differing effects of these molecules 
on biologic functions including immune response. 

GDF15 is widely associated with inflammation, 
regulating apoptosis, cell repair, growth, and 

tumorigenesis. GDF15 expression is normally 
relatively high in the prostate, and GDF15 
immunoreactivity in human prostatectomy 
specimens had shown an inverse relationship to 
inflammatory cells (Bruzzese et al., 2014). The 
lowering of GDF15 expression in AA tumor 
progression may be consistent with the known effect 
of vitamin D to upregulate GDF15 (Lambert et al., 
2015). That is, higher prevalence of vitamin D 
deficiency in AA men (Hollis et al., 2013) could explain 
our finding that AA men have lower tumor GDF15 
expression as the stage progresses. Stated differently, 
whereas white men do not show a lowering of 
GDF15 expression as tumor spreads outside the 
prostate, such a reduction occurs in AA men. 
Whether this highly significant (P=0.003) lowering of 
GDF15 expression in benign epithelium in AA men 
predicts future cancer detection will require a 
prospective trial, based on repeated biopsies. 
Notably, increased circulating GDF15 was significantly 
correlated with AA race, smoking, and hypertension 
(Powell et al., 2013), suggesting that some GDF15 
originates from extraprostatic sources. This finding 
supports a role for GDF15 in tumor development; for 
example, increased GDF15 targets p53 and acts 
through the PI3K/AKT and MAPK/ERK signaling 
pathways, with upregulation of cyclins D1 and E1, to 
promote proliferation in cervical carcinogenesis (Li et 
al., 2018). 

Recent evidence supports the concept that the 
greater modulation of GDF15 in AA men is related to 
higher risk of PC progression. A racial disparity was 
found in the link between PSA velocity and eventual 
PC diagnosis such that NSAID use was associated 
with increased PC risk only in AA men but not EA 
men (Wallace et al., 2008; Kryvenko et al., 2019). 
Since NSAID use induces GDF15 expression (Wang et 
al., 2013), this aligns with astronger role of immune-
related genes in tumor development in AA men than 



 
 
 
 
 

 
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RESEARCH 

in EA men (Wallace et al., 2008), and may relate to 
the current study where a greater stagewise 
modulation of GDF15 was found in AA men than in 
EA men (Table 5). 

NFκB is the most important transcription factor for 
oxidative susceptibility in the body. After activation, 
NFκB can activate and regulate the expression of 
many inflammatory factors, which makes it the key 
promoter of the inflammatory response. Infection or 
hypoxia activates NFκB, which is inactive in cells, and 
activates inflammatory genes, induces the up-
regulation of cytokines, adhesion molecules, and 
vasoactive regulators and increases the 
concentration of further downstream cytokines such 
as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-
6), interleukin-8 (IL-8) and others (Moresco et al., 
2011). Our finding of more pronounced rises in NFκB 
in cancer glands in AA tumor development may 
correlate with the more frequent prostatic 
inflammation reported by some (Eastham et al., 1998) 
(but not all) studies in AA men (Bostwick et al., 2003). 

Previous studies suggested NFκB to have a 
reciprocal interaction with GDF15 (Lambert et al., 
2015; Zhang et al., 2018). Thus, a firefly luciferase 
construct was used to show that expression of the 
NFκB target, interleukin 8 (IL-8), was downregulated 
by GDF15 in PC3 cells (Lambert et al., 2015). GDF15 
also inactivates NFκB signaling in dendritic cells, 
enabling induction of immune tolerance after heart 
transplantation (Zhang et al., 2018). On this basis, 
upregulation of NFκB with tumor stage might be 
expected, but this was noted in the tumor only in AA 
men (with stagewise upregulation in benign glands 
in EA men). This could be explained by lower GDF15 
in progression of AA men’s tumors, allowing a 
greater rise in NFκB expression in response to tumor. 
The altered NFκB in AA men could correlate with 
inflammatory response to the cancer tissue, but the 

non-neoplastic cells also have a greater rise in EA 
men which may cause localization of inflammatory 
cells to the tumor. 

In cancer, NFκB becomes constitutively activated in a 
high proportion of androgen-independent prostate 
cancers (Jin et al., 2008; Nadiminty et al., 2008). 
Apparently, the ability of NFκB to promote 
transcription of the prominent anti-apoptotic protein 
Bcl-2 and cyclin D1, cyclooxygenase-2, matrix 
metalloproteinase 9, nitric oxide synthase-2 (NOS-2), 
and vascular endothelial growth factor aids the 
survival of cells that would otherwise die owing to 
loss of androgen activity (Shukla et al., 2004). We 
observed a gradewise increase of tumor expression 
of NFκB in AA men but not EA men, a finding 
possibly related to greater attainment of androgen 
independence in AA men. Signaling linked to NFκB 
and inflammatory cytokine factors was preferentially 
upregulated in PC from AA race (Powell et al., 2013). 
In the face of lower NFκB expression by the tumor, 
this suggests a greater sensitivity of the post-NFκB 
cascade in AA men. 

Aside from these two molecules, other signaling 
pathways involved in the immune response have 
also been noted to show a racial disparity in prostate 
cancer. A germline variant called interferon lambda 4 
was twice as common in prostate tumors of AA men 
than white men (42-67% versus 18-33%); this relied 
on pro-tumorigenic JAK-STAT signaling, and was 
associated with decreased survival (Tang et al., 2018). 

It is uncertain whether our results are consistent with 
the current understanding of the prostatic 
inflammatory environment. The normal prostate 
contains lymphocytes, of which >90% are T cells; and 
those in the epithelium are predominantly 
cytotoxic/suppressor (CD8+) (Bostwick et al., 2003; 
Eastham et al., 1998). Studying just tumor-infiltrating 
T-cell density with three immunohistochemical 



 
 
 
 
 

 
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markers and image analysis, Kaur et al. found no 
association with EA or AA racial ancestry (Kaur et al., 
2018) although increased T-cell density was 
associated with ERG positivity and PTEN loss in both 
races. The REDUCE study, a 4-year, multicenter, 
placebo-controlled study in which a negative 
prostate biopsy was criterion for enrollment, involved 
7,982 men: 7,271 white and 180 AA men. No 
differences were noted in chronic inflammation, but 
AA men were less likely (OR = 0.65, 95%CI: 0.41-1.03, 
P= 0.07) and Asian men (OR = 1.74, 95%CI: 1.14-
2.65, P= 0.001) more likely, to have acute 
inflammation (Vidal et al., 2016). Inflammation in 
biopsies was associated with decreased cancer risk in 
other case-control studies (Kryvenko et al., 2012; Yli-
Hemminki et al., 2013). Our topographic/spatial study 
of atrophy had found only a weak association of 
inflammation with cancer provided the inflammation 
was accompanied by atrophy (Iczkowski et al., 2014). 
Acute inflammation has also been linked with lower 
future PC risk (Allott et al., 2018; Moreira et al, 2014). 
Inflammation was not significantly predictive of PC in 
another study (Khani et al., 2014). High BMI was a 
greater risk factor for PC in AA men than in white 
men (Barrington et al., 2015), and adiposity causes 
generalized inflammation. 

One limitation of the study was its exclusion of 
stromal changes. There is increased reactive 
stroma associated with chronic inflammation in 
prostate cancer of AA men, and fibroblasts 
isolated from AA prostate cancer tissues showed 
increased growth response to androgens, 
fibroblast growth factor 2, and platelet-derived 
growth factor. Conditioned media from AA-
derived fibroblasts enhanced the proliferation, 
motility, and in vivo tumorigenicity of prostate 
cancer cells more than European-American-
derived fibroblasts did, and they had elevated 
markers of myofibroblast activation such as 

expression of SMA, vimentin, and tenascin-C. Also, 
proinflammatory paracrine mediators BDNF, C 
HI3L1, DPPIV, FGF7, ILI8BP, IL6, and VEGF were 
comparatively enriched in AA-derived fibroblasts 
(Gillard et al., 2018). It is possible that the high, and 
rather constant level of GDF15 we observed in the 
benign and cancer epithelia is counteracting these 
stromal proinflammatory mediators. A second 
limitation is not knowing the anatomic sites within 
the prostate from which TMA cancer cores were 
derived. Dominant tumor nodules in AA men are 
larger and more often in the anterior peripheral 
zone, making them less amenable to rectal 
palpation than posterior tumors, and this location 
correlates with an adverse outcome (Sundi et al., 
2014). A third limitation was that serum PSA 
measurements were not available for comparison 
to marker expression; this would have given 
further insight into their roles in tumor 
development, although inflammation had been 
shown to be unrelated to the racial disparity in 
serum PSA (Zhang et al., 2000). 

In summary, we report that tumor immunoreactivity 
showed significant alterations with progression in AA 
men only: a stagewise decrease in GDF15 expression, 
and a gradewide increase in NFκB expression. These 
findings have ramifications for tumor development 
and androgen independence, and further work is 
needed to determine whether the racial disparities 
observed in non-neoplastic prostate are influenced 
by the presence of tumor or independent of it. 

Acknowledgements 
This work is supported by NIH grant 5R01ES011126-
14 [BAR] and Department of Defense PCBN, Award 
No. W81XWH-10-2-0056 and W81XWH-10-2-0046 
(tissue microarrays). 

Conflict of interest 



 
 
 
 
 

 
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RESEARCH 

Dr. Iczkowski has no consultancies, stock 
ownership, equity interest, patent-licensing 
agreements, research support, or honoraria from 
companies whose product figures prominently in 
this manuscript. 

Authors’ contributions 
Study design: KAI, MSL, BAR. Immunostain 
protocol and science background: JRL. Data 
acquisition: KAI, OK, SS, WP, BAR. Statistical 
analysis: YC, KCT. 

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18. Kryvenko ON, Wang Y, Sadasivan S, Gupta NS, Rogers C, 
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Immunol 9, 2407. 

 
 
 
 
 
 

 

 



 
 
 
 
 

 
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Table 1. Expression of GDF15 (top) and NFκB (bottom) according to race in benign and tumor, tissue microarray. 
 African-American,  

median (range) 
European American,  

median (range) 
Overall population,  

median 
 Tumor Benign P Tumor Benign P Tumor Benign P 
GDF15 2.06 

(0, 3) 
0.83 
(0, 3) <0.0001 2.06 

(0, 3) 
0.87 
(0, 3) <0.0001 1.93 0.99 <0.0001 

P (AA-EA)    0.96 0.08     
NFκB 1.04 

(0, 3) 
0.96 
(0, 3) <0.0001 1.04 

(0, 3) 
0.88 
(0, 2.83) <0.0001 1.18 0.96 <0.0001 

P (AA-EA)    0.82 0.06     

AA= African-American; EA = European-American White 

Table 2. Expression of GDF15 and NFκB according to Gleason Grade Group. 
Grade group GDF15. Tumor, median 

(range) 
P n= GDF15. Benign, median (range) P n= 

1 2.06 (0, 3) 0.010 221 0.83 (0, 3) 0.9475 250 
2 2.06 (0, 3)  198 0.83 (0, 3)  210 
3 2.06 (0, 3)  87 0.93 (0, 3)  94 
4 2.42 (0.4 ,3)  52 0.95 (0, 3)  59 
5 1.70 (0, 3)  70 0.83 (0, 3)  72 
Grade group NFκB. Tumor, median (range) P n= NFκB. Benign, median (range) P n= 
1 1.00 (0, 3) 0.009 221 0.88(0, 2.7) 0.003 248 
2 0.97 (0, 3)  195 0.85 (0, 2.5)  210 
3 1.17 (0, 3)  87 1.08 (0, 2.3)  94 
4 1.50 (0, 2.9)  57 1.06 (0, 3)  59 
5 1.06 (0, 3)  72 0.96 (0, 2.8)  71 

n= number of informative cases 

Table 3. Expression of GDF15 and NFκB according to pathologic stage. 
Pathologic 

stage 
GDF15. Tumor, median (range) P n= GDF15. Benign, median (range) P n= 

2 2.20 (0, 3) 0.001 462 1.43 (0.188, 2.56) <0.001 514 
3a 1.91 (0, 3)  106 1.82 (0.5, 2.81)  109 
3b 1.65 (0, 3)  56 1.16 (0.25, 2.56)  58 
4 1.33 (0.6, 2.8)  4 1.16 (0.625, 1.69)  4 

Pathologic 
stage 

NFκB. Tumor, median (range) P n= NFκB. Benign, median (range) P n= 

2 1.04 (0, 3) 0.02 466 0.9 (0, 3) 0.10 511 
3a 0.97 (0, 3)  105 0.9 (0, 2.5)  109 
3b 1.20 (0, 3)  57 1.08 (0, 2.1)  58 
4 0.54 (0, 0.7)  4 0.86 (0.7, 1.2)  4 

n= number of informative cases 

 



 
 
 
 
 

 
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Table 4. Racial disparity of expression of GDF15 and NFκB according to Gleason Grade Group. 

 African-American European American 

Grade 
Group 

GDF15. 
Tumor, 
median 
(range) 

P n= GDF15. 
Benign, 
median 
(range) 

P n= GDF15. 
Tumor, 
median 
(range) 

P n= GDF15. 
Benign, 
median 
(range) 

P n= 

1 2.15 (0, 3) 0.08 107 0.83 (0, 3) 0.80 118 2.06 (0, 3) 0.19 114 0.97 (0, 
2.9) 

0.01 132 

2 2.06 (0.4, 
3) 

 93 0.83 (0, 3)  97 2.00 (0, 3)  105 0.83 (0, 
3) 

 113 

3 2.17 (0.2, 3)  42 0.83 (0, 3)  44 2.01 (0, 3)  45 1.1 (0, 
3) 

 50 

4 2.71 (0.4, 3)  22 0.88 (0, 3)  27 2.34 (0.5, 
3) 

 30 1.15 (0, 
3) 

 32 

5 1.63 (0, 3)  36 0.96 (0 ,3)  37 2.03 (0.3, 
3) 

 34 0.69 (0, 
2.5) 

 35 

Grade 
Group 

NFκB. 
Tumor, 
median 
(range) 

P N= NFκB. 
Benign, 
median 
(range) 

P n= NFκB. 
Tumor, 
median 
(range) 

P n= NFκB. 
Benign, 
median 
(range) 

P n= 

1 0.96 (0 ,3) 0.03 107 0.96 (0, 
2.7) 

0.37 117 1.04(0, 3) 0.23 114 0.82 (0, 
2.5) 

0.007 131 

2 1.04 (0 ,3)  89 0.91 (0, 
2.3) 

 97 0.87 (0, 3)  106 0.75 (0, 
2.5) 

 113 

3 1.15 (0, 3)  42 1.08 (0, 
2.3) 

 44 1.25 (0, 3)  45 1.04 (0, 
2.1) 

 50 

4 1.50 (0, 2.9)  25 1.00 (0, 3)  27 1.46 (0, 
2.9) 

 32 1.07 (0, 
2.1) 

 32 

5 1.12 (0, 3)  37 0.96 (0, 1. 
8) 

 36 1.04 (0.2, 
3) 

 35 0.96 (0, 
2.8) 

 35 

n= number of informative cases 

Table 5. Racial disparity of expression of GDF15 and NFκB according to pathologic stage. 

 African-American European American 

Stage GDF15. 
Tumor, 
median 
(range) 

P n= GDF15. 
Benign, 
median 
(range) 

P n= GDF15. 
Tumor, 
median 
(range) 

P n= GDF15. 
Benign, 
median 
(range) 

P n= 

2 2.20 (0, 3) 0.007 221 0.83 (0, 3) 0.003 242 2.08 (0, 3) 0.07 241 1.00 (0, 
3) 

0.01 272 

3a 1.61 (0.4, 3)  49 0.42 (0, 2)  50 2.06 (0, 3)  57 0.80 (0, 
3) 

 59 



 
 
 
 
 

 
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3b 1.63 (0, 3)  28 1.10 (0, 
2.5) 

 29 1.65 (0.3, 
3) 

 28 0.75 (0, 
2.5) 

 29 

4 2.01 (0, 
2.8) 

 2 1.38 (0.8, 
1.9) 

 2 1.02 (0.6, 
1.4) 

 2 0.92 
(0.2, 1.7) 

 2 

Stage NFκB. 
Tumor, 
median 
(range) 

P n= NFκB. 
Benign, 
median 
(range) 

P n= NFκB. 
Tumor, 
median 
(range) 

P n= NFκB. 
Benign, 
median 
(range) 

P n= 

2 1.04 (0, 3) 0.21 222 0.96 (0, 3) 0.96 240 1.08 (0, 3) 0.15 244 0.86 (0, 
2.8) 

0.18 271 

3a 1.06 (0, 3)  48 0.96 (0, 
1.9) 

 48 0.89 (0, 3)  57 0.88 (0, 
2.5) 

 59 

3b 1.23 (0, 
2.8) 

 28 0.96 (0, 
1.8) 

 28 1.12 (0.2, 
3) 

 29 1.12 (0.1, 
2.1) 

 29 

4 0.54 (0.4, 
0.7) 

 2 0.93 (0.7, 
1.2) 

 2 0.36 (0, 
0.7) 

 2 0.86 
(0.8, 1.0) 

 2 

n= number of informative cases 

Note: With only 2 cases for Stage 4, values are probably not representative. 

Table 6. Summary of inflammatory markers in prostate. 

Marker By increasing stageK By increasing gradeK 

GDF15 in EA men Decreases in benign (P=0.01), not in tumor Decreases in benign only (P=0.01) 

GDF15 in AA men Decreases in tumor (P=0.007) as well as 
benign (P=0.003) No change in benign or tumor 

NFκB in EA men No change in benign or tumor Increases in benign (P=0.007) but not tumor 
(P=0.23) 

NFκB in AA men No change in benign or tumor Increases in tumor (P=0.027) but not benign 
(P=0.37) 

AA= African-American; KKruskal-Wallis; wWilcoxon test; EA= European American 

 



 
 
 
 
 

 
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Supplementary Figure 1. Normalization of GDF15 and NFκB expression in normal and tumor regions of 
prostate of men with Gleason Grade group 2 prostate cancer from the three study sites. Box plots showing 
digitally assessed GDF15 (A,B) and NFκB (C,D) expression in normal prostate before (A,C) and after (B,D) 
normalization. Additional Box plots show effect of normalization on pathologically assessed GDF15 (E-H) 
and NFκB (I-L) expression in normal (E,F & I,J) and malignant (G,H & K,L) prostate before (E,G,I,K) and after 
(F,H,J,L) normalization. Ford=Henry Ford, Hopkins=Johns Hopkins, MCW=Medical College of Wisconsin. 

 



 
 
 
 
 

 
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Supplementary Figure 2. Correlation of GDF15 and NFκB expression in normal and tumor regions of 
prostate in European/White American (EA) and African American (AA) men with prostate cancer. Scatter 
plots and associated correlation coefficients are shown for all normal samples (A), normal prostate regions 
in EA (B), Normal prostate regions in AA (C), all tumor samples (D), tumor regions in EA (E), tumor regions 
in AA (F). 

 

 

Supplemental Table 1.  Expression of GDF15 (top) and NFκB (bottom) according to race in benign and tumor, tissue 
microarray stratified by Study Site. 

Henry Ford 
 African-American, median 

(range) 
White American, median (range) Overall population, median 

(range) 
 Tumor Benign P Tumor Benign P Tumor Benign P 
GDF15 2.83 

(0, 3) 
1.14 
(0, 3) 

<0.0001 2.75 
(0, 3) 

1.18 
(0, 3) 

<0.0001 2.75  
(0, 3) 

1.17 
(0, 3) 

<0.0001 

P (AA-W)    0.251 0.931     
NFκB 1.50 

(0, 3) 
1.15 
(0, 3) 

<0.0001 1.42 
(0, 3) 

0.90 
(0, 2.83) 

<0.0001 1.45  
(0, 3) 

1.00 
(0, 3) 

<0.0001 

P (AA-W)    0.992 0.039     
 



 
 
 
 
 

 
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Johns Hopkins 
 African-American, median 

(range) 
White American, median (range) Overall population, median 

 Tumor Benign P Tumor Benign P Tumor Benign P 
GDF15 2.50 

(0.5, 3) 
0.83 
(0, 3) 

<0.0001 2.00 
(0, 3) 

1.00 
(0, 3) 

<0.0001 2.00 
(0, 3) 

1.00 (0, 
2.6) 

<0.0001 

P (AA-W)    <0.0001 0.148     
NFκB 1.25 

(0.2, 
2.94) 

0.60 
(0, 2.52) 

<0.0001 1.56 
(0.38, 3) 

0.67 
(0, 2.5) 

<0.0001 1.47  
(0, 3) 

0.67 
(0, 2.5) 

<0.0001 

P (AA-W)    <0.0001 0.73     
 
Medical College of Wisconsin (MCW) 
 African-American, median 

(range) 
White American, median (range) Overall population, median 

 Tumor Benign P Tumor Benign P Tumor Benign P 
GDF15 2.00 

(0.67, 3) 
0.88 
(0, 2.33) 

<0.0001 1.00 
(0, 3) 

0.67 
(0, 2.5) 

0.082 1.58 
(0, 3) 

0.77 
(0, 2.5) 

<0.0001 

P (AA-W)    0.007 0.454     
NFκB 2.00 

(0.75, 3) 
1.83 
(0.17, 3) 

0.161 2.00 
(0, 3) 

1.67 
(0.5, 3) 

0.943 2.00  
(0, 3) 

1.75  
(0.17, 3) 

0.297 

P (AA-W)    0.283 0.384     

AA= African-American; W= White 

 

Supplemental Table 2. Expression of GDF15 and NFκB according to Gleason Grade Group Stratified by Study Site. 
Henry Ford 
Grade group GDF15. Tumor, median (range) P n= GDF15. Benign, median (range) P n= 

1 2.81 (0, 3) 0.668 103 1.17 (0, 3) 0.268 132 
2 2.75 (0, 3)  101 1.17 (0, 3)  113 
3 2.83 (0.167, 3)  32 1.30 (0.056, 3)  39 
4 2.75 (0.5 ,3)  43 1.11 (0, 3)  50 
5 2.50 (0.75, 3)  20 0.92 (0, 3)  33 
Grade group NFκB. Tumor, median (range) P n= NFκB. Benign, median (range) P n= 

1 1.25 (0, 3) 0.128 106 0.95 (0, 2.67) 0.544 130 
2 1.25 (0, 3)  101 0.90 (0, 2.5)  113 
3 1.47 (0, 3)  32 1.19 (0, 2.33)  39 
4 1.71 (0, 2.92)  48 1.25  (0, 3)  50 
5 1.83 (0.167, 3)  22 1.23 (0, 2.82)  21 
 
Johns Hopkins 
Grade group GDF15. Tumor, median (range) P n= GDF15. Benign, median (range) P n= 
1 2 (0,3) 0.458 112 1 (0,2.56) 0.040 112 



 
 
 
 
 

 
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2 2.12 (0,3)  80 0.91 (0,2.56)  81 
3 2.41 (0.5,3)  26 1.47 (0,2.56)  26 
4 2.44 (2.06,2.83)  9 1.4 (0.67,2.56)  9 
5 2.12 (0.5,3)  45 1.44 (0.25,2.6)  45 
Grade group NFκB. Tumor, median (range) P n= NFκB. Benign, median (range) P n= 

1 1.35 (0,3) 0.001 110 0.40 (0,2.38) <0.00
01 112 

2 1.44 (0,2.88)  80 0.42 (0,2.12)  81 
3 1.5 (0.25,2.69)  26 0.86 (0.1,2.5)  26 
4 1.62 (0.69,2.94)  9 1.06 (0.58,1.69)  9 
5 2 (0.25,2.81)  45 1.31 (0.38,2.52)  45 
 
Medical College of Wisconsin (MCW) 
Grade group GDF15. Tumor, median (range) P n= GDF15. Benign, median (range) P n= 
1 1.25 (0.5,2) 0.085 6 0.75 (0,1) 0.573 6 
2 1.5 (0.5,3)  16 0.5 (0,2.5)  16 
3 2.33 (0,3)  29 1 (0,2.5)  29 
4 ---  0 ---  0 
5 1.67 (0.5,2.17)  5 0.5 (0,2.33)  5 
Grade group NFκB. Tumor, median (range) P n= NFκB. Benign, median (range) P n= 

1 1.5 (0.75,3) 0.049 5 1.5 (0.8,1.8) 0.000
3 6 

2 1.5 (1,2.83)  16 1.4 (0.17,2)  16 
3 2.08 (0,3)  29 2 (0.5,3)  29 
4 ---  0 ---  0 
5 2.5 (2.25,2.62)  5 2 (1.4,2.83)  5 

n= number of informative case 

Supplemental Table 3. Expression of GDF15 and NFκB according to pathologic stage stratified by Study Site. 
Henry Ford 
Pathologic 
stage 

GDF15. Tumor, median (range) P n= GDF15. Benign, median (range) P n= 

2 2.83 (0,3) .015 243 1.25 (0,3) 0.01 295 
3a 2.71 (0.167,3)  34 0.88 (0,3)  37 
3b 2.2 (0.75,3)  20 1.19 (0.25,2.5)  22 
4 2.1 (1.42,2.79)  2 1.06 (0.19,1.94)  2 
Pathologic 
stage 

NFκB. Tumor, median (range) P n= NFκB. Benign, median (range) P n= 

2 1.42 (0,3) 0.203 253 1.00 (0,3) 0.589 292 
3a 1.42 (0,3)  33 0.88 (0,2.5)  37 
3b 1.62 (0,3)  21 1.25 (0,2.08)  22 
4 0.18 (0,0.36)  2 0.71 (0.67,0.75)  2 
 



 
 
 
 
 

 
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Johns Hopkins 
Pathologic 
stage 

GDF15. Tumor, median (range) P n= GDF15. Benign, median (range) P n= 

2 2.25 (0,3) 0.081 183 1 (0,2.56) 0.900 183 
3a 2 (0.5,3)  57 1 (0,2.6)  58 
3b 2 (0.5,3)  30 1.04 (0.25,2.5)  30 
4 1.41 (1.31,1.5)  2 1.16 (0.63,1.69)  2 
Pathologic 
stage 

NFκB. Tumor, median (range) P n= NFκB. Benign, median (range) P n= 

2 1.38 (0,3) 0.005 181 0.58 (0,2.5) <0.00
01 

183 

3a 1.38 (0,2.88)  57 0.5 (0,1.98)  58 
3b 2.25 (0.25,2.81)  30 1.11 (0.42,2.52)  30 
4 1.68 (1.55,1.81)  2 1.38 (1.25,1.5)  2 
 
Medical College of Wisconsin (MCW) 
Pathologic 
stage 

GDF15. Tumor, median (range) P n= GDF15. Benign, median (range) P n= 

2 1.5 (0.33,3) 0.589 36 1 (0,2.5) 0.101 36 
3a 1.83 (0,3)  14 0.5 (0,2.5)  14 
3b 1.75 (0.5,2.67)  6 0.88 (0,2.33)  6 
4 ---  0 ---  0 
Pathologic 
stage 

NFκB. Tumor, median (range) P n= NFκB. Benign, median (range) P n= 

2 2 (0.75,3) 0.206 35 1.73 (0.75,3) 0.860 36 
3a 1.71 (0,2.83)  14 1.77 (0.17,2.88)  14 
3b 2.42 (1,3)  6 1.92 (1.4,2.83)  6 
4 ---  0 ---  0 
n= number of informative cases



 
 
 
 
 

 
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Supplemental Table 4. Racial disparity of expression of GDF15 and NFκB according to Gleason Grade Group stratified by Study Site. 

Henry Ford 

 African-American White American 

Grade 
Group 

GDF15. Tumor, 
median (range) P n= GDF15. Benign, 

median (range) P n= GDF15. Tumor, 
median (range) P n= GDF15. Benign, 

median (range) P n= 

1 2.69 (0,3) 0.557 48 1.17 (0,3) 0.591 59 2.83 (0,3) 0.585 55 1.18 (0,2.88) 0.104 73 

2 2.75 (0.5,3)  44 1.2 (0,3)  48 2.75 (0,3)  57 1.17 (0,3)  65 

3 2.83 (0.17,3)  15 1.42 (0.06,3)  17 2.75 (1,3)  17 1.27 (0.13,3)  22 

4 2.96 (1,3)  18 0.92 (0,3)  23 2.75 (0.5,3)  25 1.33 (0,3)  27 

5 2.79 (0.75,3)  9 1.17 (0.25,3)  10 2.25 (1.15,3)  11 0.73 (0,2.5)  12 

Grade 
Group 

NFκB. Tumor, 
median (range) P n= NFκB. Benign, 

median (range) P n= NFκB. Tumor, 
median (range) P n= NFκB. Benign, 

median (range) P n= 

1 1.17 (0,3) 0.754 48 1.17 (0,2.67) 0.912 58 1.33 (0,3) 0.122 58 0.81 (0,2.5) 0.511 72 

2 1.33 (0,3)  41 1 (0,2.25)  48 1.21 (0,3)  60 0.75 (0,2.5)  65 

3 1.6 (0,3)  15 1.42 (0,2.33)  17 1.25 (0,3)  17 0.98 (0,2.12)  22 

4 1.75 (0,2.88)  21 1.25 (0,3)  23 1.5 (0,2.92)  27 1.25 (0,2.08)  27 

5 1.25 (0.36,3)  10 1.23 (0,1.8)  9 2.31 (0.17,3)  12 1.12 (0,2.83)  12 

 

Johns Hopkins 

 African-American White American 

Grade 
Group 

GDF15. Tumor, 
median (range) P n= GDF15. Benign, 

median (range) P n= GDF15. Tumor, 
median (range) P n= GDF15. Benign, 

median (range) P n= 

1 2.38 (0.5,3) 0.867 56 1 (0,2.56) 0.872 56 1.81 (0,3) 0.174 56 1 (0,2.5) 0.007 56 

2 2.5 (0.5,3)  41 1.21 (0,2.56)  41 1.5 (0,3)  39 0.63 (0,2.5)  40 



 
 
 
 
 

 
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3 2.5 (0.5,3)  13 1.06 (0,2.56)  13 2.25 (0.5,3)  13 1.5 (0,2.5)  13 

4 2.53 (2.12,2.83)  4 0.74 (0.67,2.35)  4 2.44(2.06,2.81)  5 1.81 (1,2.56)  5 

5 2.38 (0.88,2.94)  23 1.44 (0.38,2.38)  23 1.88 (0.5,3)  22 1.34 (0.25,2.6)  22 

Grade 
Group 

NFκB. Tumor, 
median (range) P n= NFκB. Benign, 

median (range) P n= NFκB. Tumor, 
median (range) P n= NFκB. Benign, 

median (range) P n= 

1 1 (0,2.42) 0.019 55 0.33 (0,2.38) <0.00
01 56 1.5 (0.38,3) 0.034 55 0.5 (0,1.75) <0.000

1 56 

2 1.19 (0,2.81)  41 0.42 (0.08,1.81)  41 1.5 (0.44,2.88)  39 0.44 (0,2.12)  40 

3 1.62 (0.25,2.69)  13 0.75 (0.1,2.08)  13 1.38(0.75,2.69)  13 0.88 (0.25,2.5)  13 

4 1.81 (0.83,2.94)  4 1.24 (0.75,1.62)  4 1.62 (0.69,2)  5 1.06 (0.58,1.69)  5 

5 1.81 (0.25,2.69)  23 1.28 (0.38,2.52)  23 2.12(0.81,2.81)  22 1.31 (0.58,2.25)  22 

 

Medical College of Wisconsin (MCW) 

 African-American White American 

Grade 
Group 

GDF15. Tumor, 
median (range) P n= GDF15. Benign, 

median (range) P n= GDF15. Tumor, 
median (range) P n= GDF15. Benign, 

median (range) P n= 

1 1.5 (1.5,2) 0.512 3 0.5 (0,1) 0.867 3 1 (0.5,1) 0.127 3 1 (0,1) 0.757 3 

2 2 (1,3)  8 0.75 (0,1.5)  8 1 (0.5,1.5)  8 0.5 (0,2.5)  8 

3 2.42 (0.67,3)  14 0.94 (0,1.5)  14 2.17 (0,3)  15 1 (0,2.5)  15 

4 ---  0 ---  0 ---  0 ---  0 

5 1.83 (1.5,2.17)  4 0.56 (0,2.33)  4 0.5 (0.5,0.5)  1 0.5 (0.5,0.5)  1 

Grade 
Group 

NFκB. Tumor, 
median (range) P n= NFκB. Benign, 

median (range) P n= NFκB. Tumor, 
median (range) P n= NFκB. Benign, 

median (range) P n= 

1 1 (0.75,1.5) 0.005 3 1.25 (0.8,1.8) 0.010 3 2.33 (1.67,3) 0.559 2 1.5 (1.5,1.5) 0.078 3 

2 1.5 (1,2.83)  8 1.5 (0.17,2)  8 1.69 (1,2.75)  8 1.23 (0.75,2)  8 



 
 
 
 
 

 
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3 2.17 (1,3)  14 2 (1.4,3)  14 2 (0,2.5)  15 2 (0.5,3)  15 

4 ---  0 ---  0 ---  0 ---  0 

5 2.5 (2.33,2.62)  4 2.17 (1.4,2.83)  4 2.25 (2.25,2.25)  1 1.83 (1.83,1.83)  1 
n= number of informative cases 

Supplemental Table 5. Racial disparity of expression of GDF15 and NFκB according to pathologic stage stratified by Study Site. 

Henry Ford 

 African-American White American 
Stage GDF15. Tumor, 

median (range) 
P n= GDF15. Benign, 

median (range) 
P n= GDF15. Tumor, 

median (range) 
P n= GDF15. Benign, 

median (range) 
P n= 

2 2.83 (0,3) 0.528 113 1.21 (0,3) 0.080 134 2.82 (0,3) 0.009 130 1.25 (0,3) 0.042 161 
3a 2.49 (1.04,3)  12 0.9 (0.06,1.7)  13 2.79 (0.167,3)  22 0.787 (0,3)  24 
3b 2.88 (0.75,3)  8 1.25 (0.25,2.5)  9 2.08 (1.15,3)  12 1.12 (0.35,2.5)  13 
4 2.79 (2.79,2.79)  1 1.94 (1.94,1.94)  1 1.42(1.42,1.42)  1 0.19 (0.19,0.19)  1 
Stage NFκB. Tumor, 

median (range) 
P n= NFκB. Benign, 

median (range) 
P n= NFκB. Tumor, 

median (range) 
P n= NFκB. Benign, 

median (range) 
P n= 

2 1.45 (0,3) 0.545 115 1.16 (0,3) 0.773 114 1.38 (0,3) 0.244 138 0.9 (0,2.83) 0.432 160 
3a 0.92 (0,3)  11 1.32 (0,1.92)  11 1.49 (0,3)  22 0.71 (0,2.5)  24 
3b 1.75 (0,2.83)  8 0.91 (0,1.75)  8 1.62 (0.17,3)  13 1.25 (0.13,2.08)  13 
4 0.36 (0.36,0.36)  1 0.67 (0.67,0.67)  1 0 (0,0)  1 0.75 (0.75,0.75)  1 
Johns Hopkins 

 African-American White American 
Stage GDF15. Tumor, 

median (range) 
P n= GDF15. Benign, 

median (range) 
P n= GDF15. Tumor, 

median (range) 
P n= GDF15. Benign, 

median (range) 
P n= 

2 2.5 (0.5,3) 0.496 92 1 (0,2.56) 0.813 92 2 (0,3) 0.162 91 1 (0,2.56) 0.974 91 
3a 2.5 (0.5,3)  29 1 (0,2.56)  29 1.5 (0.5,2.69)  28 1 (0,2.6)  29 
3b 2.31 (0.88,3)  15 1.06 (0.38,2.5)  15 1.81 (0.5,2.94)  15 1.02 (0.25,2.38)  15 
4 1.31 (1.31,1.31)  1 1.69 (1.69,1.69)  1 1.5 (1.5,1.5)  1 0.63 (0.63,0.63)  1 



 
 
 
 
 

 
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Stage NFκB. Tumor, 
median (range) 

P n= NFκB. Benign, 
median (range) 

P n= NFκB. Tumor, 
median (range) 

P n= NFκB. Benign, 
median (range) 

P n= 

2 1.25 (0,2.94) 0.250 91 0.46 (0,2.38) 0.008 92 1.5 (0.38,3) 0.010 90 0.6 (0,2.5) 0.002 91 
3a 1.12 (0,2.75)  29 0.5 (0,1.98)  29 1.5 (0.5,2.88)  28 0.5 (0,1.94)  29 
3b 1.75 (0.25,2.69)  15 0.94 (0.42,2.52)  15 2.31 (0.83,2.81)  15 1.25 (0.58,2.25)  15 
4 1.81 (1.81,1.81)  1 1.5 (1.5,1.5)  1 1.55 (1.55,1.55)  1 1.25 (1.25,1.25)  1 
 
Medical College of Wisconsin (MCW) 

 African-American White American 
Stage GDF15. Tumor, 

median (range) 
P n= GDF15. Benign, 

median (range) 
P n= GDF15. Tumor, 

median (range) 
P n= GDF15. Benign, 

median (range) 
P n= 

2 2 (1,3) 0.696 16 1 (0,1.5) 0.104 16 1 (0.33,3) 0.435 20 1 (0,2.5) 0.485 20 
3a 2.25 (1,3)  8 0.5 (0,1)  8 1.58 (0,2.67)  6 0.42 (0,2.5)  6 
3b 2 (0.67,2.67)  5 1.12 (0,2.33)  5 0.5 (0.5,0.5)  1 0.5 (0.5,0.5)  1 
4 ---  0 ---  0 ---  0 ---  0 
Stage NFκB. Tumor, 

median (range) 
P n= NFκB. Benign, 

median (range) 
P n= NFκB. Tumor, 

median (range) 
P n= NFκB. Benign, 

median (range) 
P n= 

2 1.56 (0.75,3) 0.589 16 1.68 (0.8,3) 0.546 16 2 (0.83,3) 0.101 19 1.75 (0.75,3) 0.281 20 
3a 1.96 (1.5,2.83)  8 2.12 (0.17,2.88)  8 1.19 (0,2.17)  6 1.45 (0.5,2)  6 
3b 2.5 (1,3)  5 2 (1.4,2.83)  5 2.25 (2.25,2.25)  1 1.83 (1.83,1.83)  1 
4 ---  0 ---  0 ---  0 ---  0 
n= number of informative cases 

Note: With only 1 cases for Stage 4, values are probably not representative. 

 

 

 


