molecules

Article
p53 Antibodies as a Diagnostic Marker for Cancer:
A Meta-Analysis
Navid Sobhani 1, * , Giandomenico Roviello 2 , Alberto D’Angelo 3 , Raheleh Roudi 4 , Praveen Kumar Neeli 1
and Daniele Generali 5, *

1 Department of Medicine, Section of Epidemiology and Population Sciences, Baylor College of Medicine,
Houston, TX 77030, USA; [email protected]
2 Department of Health Sciences, University of Florence, 50121 Florence, Italy; [email protected]
3 Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK; [email protected]
4 Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA;
[email protected]
5 Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital,
Strada Di Fiume 447, 34149 Trieste, Italy
* Correspondence: [email protected] (N.S.); [email protected] (D.G.)

Abstract: Importance: The protein p53 is an unequivocal tumor suppressor that is altered in half of
all cancers. The immune system produces systemic p53 autoantibodies (p53 Abs) in many cancer
patients. Objective: This systemic review and meta-analysis focuses on the prognostic value of
p53 Abs expressed in the serum of patients with solid tumors. Data Sources: All the clinical
investigations were searched on PubMed from the first study dated 1993 until May 2021 (date of
submission of the manuscript). Study Selection: Studies were included that met the following



criteria: (1) participants with cancer; (2) outcome results expressed in relation to the presence of a p53


antibody; (3) a primary outcome (disease-free survival, overall survival or progression-free survival)
Citation: Sobhani, N.; Roviello, G.; expressed as hazard ratio (HR). The following exclusion criteria were used: (1) insufficient data
D’Angelo, A.; Roudi, R.; Neeli, P.K.;
available to evaluate outcomes; (2) animal studies; (3) studies with less than 10 participants. As a
Generali, D. p53 Antibodies as a
result, 12 studies were included in the analysis. Data Extraction and Synthesis: PRISMA guidelines
Diagnostic Marker for Cancer: A
were used for abstracting and assessing data quality and validity by three independent observers.
Meta-Analysis. Molecules 2021, 26,
6215. https://doi.org/10.3390/
The summary estimates were generated using a fixed-effect model (Mantel–Haenszel method) or
molecules26206215 a random-effect model (DerSimonian–Laird method), depending on the absence or presence of
heterogeneity (I2 ). Main Outcome(s) and Measure(s): The primary study outcome was to determine
Academic Editor: Laura Cerchia the prognostic value of p53 Abs from a large population of patients with solid tumors, as determined
before data collection. Results: In total, 12 clinical studies involving 2094 patients were included
Received: 18 September 2021 in the meta-analysis, and it was determined that p53 Abs expression in the serum significantly
Accepted: 11 October 2021 correlated with poorer survival outcomes of cancer patients (95% CI 1.48 [1.24, 1.77]; p < 0.00001).
Published: 14 October 2021 Conclusions and Relevance: This is the first meta-analysis proving the diagnostic utility of p53-Abs
for cancer patients in predicting poorer outcomes. The serum-p53 value (s-p53-value) may be useful
Publisher’s Note: MDPI stays neutral
for future theranostics.
with regard to jurisdictional claims in
published maps and institutional affil-
Keywords: meta-analysis; p53; serum p53 antibodies; cancer survival prognostic biomarker
iations.

1. Introduction
Copyright: © 2021 by the authors.
The P53 protein is an unequivocal tumor suppressor mutated in almost half of human
Licensee MDPI, Basel, Switzerland.
cancers [1–4]. It is autoregulated by MDM2, an E3 ubiquitin ligase [5,6].
This article is an open access article
Mice lacking MDM2 show embryonic lethality, while the dual presence of p53 and
distributed under the terms and
conditions of the Creative Commons
MDM2 can rescue lethality [7]. The p53 mutation in cancer (p53-mut) does not activate
Attribution (CC BY) license (https://
the expression of the E3 ligase. Consequently, degradation of p53 protein is not down-
creativecommons.org/licenses/by/ modulated [8]. High expression of p53 by cells recapitulates in T-cells the production of
4.0/). antibodies against mutant or wild type p53 [8]. On the other hand, in many cancer patients

Molecules 2021, 26, 6215. https://doi.org/10.3390/molecules26206215 https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 6215 2 of 10

the p53-wt region is exposed and serum antibodies are generated against p53-wt. These can
be detected by ELISA method. The roles of these antibodies are not yet clearly understood.
Prognostic biomarkers have a crucial role in measuring the progression of diseases
from samples of patients, such as metastasis in cancer, and they can aid clinicians in
intervening with more precise medical interventions. In addition to the common theory
that in humans the loss of p53 increases genomic instability, this loss has been linked to the
proliferation of the stem-cell characteristic that ultimately leads to highly aggressive cancers
with invasive and metastatic properties. p53 antibodies (s-p53-Abs) are stably expressed
in the sera of cancer patients, and could have an important prognostic application. Many
clinical studies have assessed in cancer patients the correlation between the expression of
s-p53-Abs with tumor invasiveness grades, metastasis and prognosis [9].
In our review, we performed a meta-analysis of the current literature, investigating
the prognostic role of serum p53-Abs in cancer patients.

2. Results
After screening the article according to flow chart in Figure 1, 12 studies were se-
lected [10–21]. A total of 2094 patients were included from these studies. The solid cancer
patients were treated with adjuvant chemotherapy (such as cyclophosphamide, docetaxel,
fluorouracil, epirubicin, methotrexate, and vinorelbine), anti-HER2 (trastuzumab, per-
tuzumab or lapatinib), endocrine therapy (such as goserelin, and tamoxifen), or combined
treatment with Herceptin, chemotherapy, and the nonsteroidal anti-inflammatory drug cele-
coxib, also including radiotherapy or a surgical component in some cases (Tables 1 and 2).
The pooled analysis revealed that s-p53-Abs is a negative prognostic factor (HR: 148
[1.24, 1.77]; p < 0.0001, Figure 2) in cancers. The analysis was performed using a random-
effects model (accounting for effect size heterogeneity; I2 = 19%).

Figure 1. Flowchart of literature research strategy.

Molecules 2021, 26, 6215 3 of 10

Table 1. Clinical investigations of p53-wt antibodies in cancer. Main characteristics of clinical investigations for prognostic evaluation of serum p53-wt antibodies in cancer patients.

Study
Patients Methods Inclusion/Exclusion Criteria Intervention Follow-Up Time Prognostic Value of s-p53-Abs Type of Study
Reference
Inclusion: transitional cell
Surgery (TUR)
76 patients with S-p53-Abs urinary bladder cancer
Surgery + There was an association between the
transitional urinary ELISA. Antibodies for Exclusion: secondary organ
[10] chemotherapy + 34 months presence of s-p53-Abs and tumor p53 gene Prospective
bladder cell p53-wt cancer; immunodeficiency state;
radiotherapy overexpression (p = 0.001).
carcinoma 184 CRC patients ages over 90; other urinary
(advanced stage)
bladder tumors.
184 CRC patients. S-p53-Abs
Dukes’ stage: ELISA. Antibodies for Routine Biopsy p53-Abs correlated with shorter survival
[11] Inclusion: primary colon cancer 96 months Retrospective
A (n = 31); B (n = 84); p53-wt Surgery (p = 0.02).
C (n = 41); D (n = 28) 184 CRC patients
Positivity for s-p53Ab in CRC did not
correlate with overall survival.
S-p53Ab, CEA Inclusion: primary colon cancer Kaplan–Meier analysis revealed significant
Surgery (resected tumor 93.6 months
[12] 170 CRC patients ELISA. Antibody for Exclusion: previous differences between patients with elevated Retrospective
specimen) (median value)
p53-wt radiotherapy or chemotherapy s-p53Ab and CEA and those with elevated
levels of either one or neither of these
factors (p < 0.001).
Did not observe any significant correlation
between S-p53Ab in GC and overall
S-p53Ab Inclusion: Histologically survival (hazard ratio (HR) = 2.052; 95%
Detected with confirmed GC confidence interval CI) = 0.891–4.726;
anti-p53 detection kit Exclusion: previously p = 0.091).
[13] 208 GC patients Surgery 34 months Retrospective
MESACUP anti-p53 chemotherapy, radiotherapy Conversely, Cox regression analysis
Test and those who died within 30 revealed that a high level of CA19-9 was
Antibody for p53-wt days after surgery an independent prognostic factor for GC
(hazard ratio (HR) = 3.864; 95% confidence
interval (CI) = 1.248–11.959; p = 0.019).
High levels of p53-Abs correlated with
S-p53-Abs Surgery
3 months worse survival prospects compared to
[14] 231 SCLC patients ELISA. Antibodies for Inclusion: primary SCLC Chemotherapy (227 out Retrospective
(at least) patients with lower levels of the antibodies
p53-wt of 231 patients)
(p = 0.02).
Molecules 2021, 26, 6215 4 of 10

Table 1. Cont.

Study
Patients Methods Inclusion/Exclusion Criteria Intervention Follow-Up Time Prognostic Value of s-p53-Abs Type of Study
Reference
Percutaneous injection
(21)
Surgery (15)
Radiofrequency
S-p53-Abs Inclusion: Cytohistological of
interstitial ablation (10) Anti-p53 was not useful as a
[15] 80 HCC patients ELISA. Antibodies for AFP level-based diagnosis of 36 months Retrospective
Chemotherapy (4) prognostic factor.
p53-wt HCC
TACE (8)
Combinational
treatment (5)
No treatment (17)
S-P53Ab had no power to predict the
Surgery (colectomy plus
CEA, CA19-9, Inclusion: preoperative CEA, prognosis (p = 0.786).
lymph nodes dissection) 33.8 months
[16] 244 CRC patients S-P53Ab CA-19 and S-P53Ab. Primary Combined CEA and CA19-9 positivity was Retrospective
Chemotherapy (in case (median)
Antibody for p53-wt tumor diagnosis an exclusive independent prognostic factor
of CRC recurrence)
(p = 0.034).
Bronchial biopsy
Chemotherapy Patients with limited-stage SCLC and
S-p53-Abs (cisplatin, etoposide, p53-Ab had a median survival time of 10
Inclusion: newly and proven 18.1 months
[17] 97 SCLC patients ELISA. Antibodies for doxorubicin, months, whereas limited-stage SCLC Prospective
diagnosed lung cancer (median)
p53-wt cyclophosphamide) patients without p53-Ab had a 17-month
Radiotherapy for those median survival time (p = 0.014).
with brain metastasis
Inclusion: histologically
133 esophageal confirmed ESCC S-p53Ab was detected in 39.1% (52 out of
S-p53Ab, SCC-Ag,
squamous cell Exclusion: patients who died 36 months 133) of patients with ESCC, including
[18] CEA Surgery Retrospective
carcinoma (ESCC) after 30 days after treatment and (median) 40.0% (20 out of 50) of patients with
Antibody for p53-wt
patients those who had preoperative early-stage ESCC (p = 0.009)
radiotherapy
Surgery
Chemotherapy (Stage Patients with lower levels of p53Abs
201 lung cancer S-p53 antibodies by
[22] Inclusion: Primary lung cancer IIIB and IV) 63 months survived significantly longer than patients Retrospective
patients ELISA
Radiotherapy (if with higher levels of p53Abs (p = 0.049).
required)
1487 esophageal s-p53-Ab positive status was not
S-p53 antibodies by Inclusion: radical surgery with 42 months
[19] squamous cell Esophagectomy significantly associated with poor overall Retrospective
ELISA no neoadjuvant treatment (median)
carcinoma survival
Molecules 2021, 26, 6215 5 of 10

Table 1. Cont.

Study
Patients Methods Inclusion/Exclusion Criteria Intervention Follow-Up Time Prognostic Value of s-p53-Abs Type of Study
Reference
Six hepatocellular
carcinoma-associated Inclusion: histologically proven
antigens, including HCC The positivity for the TAA panel was
160 hepatocellular
[20] Sui1, p62, RalA, p53, Exclusion: coexisting or Surgery 60 months independently associated with poor Retrospective
carcinoma
NY-ESO-1, and c-myc metachronous cancer within 5 prognosis (p = 0.030)
antibodies by ELISA disease-free years
(TAA Panel)
Inclusion: primary gastric
S-p53 antibodies by cancer 32 months Overall survival was not associated with
[21] 72 gastric cancers Surgery Retrospective
ELISA Exclusion: previous (median) the antibodies
chemotherapy; coexisting cancer
While seropositive patients did not
Inclusion: primary esophageal
105 demonstrate significant poor overall
S-p53 antibodies by squamous cell carcinoma 35 months
[23] esophageal squamous Surgery survival, high-titer patients demonstrated Retrospective
ELISA Exclusion: metastatic disease; (median)
cell carcinoma significant poor overall survival based on
neoadjuvant therapy
the multivariate analysis (p < 0.001).
Abbreviations: CRC, Colorectal Carcinoma; GC, Gastric Cancer; SCLC, Small Cell Lung Carcinoma; HCC, Hepatocellular Carcinoma; TACE, chemoembolization with epidoxorubicin and lipiodol; TUR,
Transurethral Resection of the Tumor.
Molecules 2021, 26, 6215 6 of 10

Table 2. Clinical investigations of p53-mut antibodies in cancer. Main characteristics of clinical investigations for prognostic
evaluation of serum p53-mut antibodies in cancer patients.

Study
Patients Methods Prognostic Value of s-p53-Abs Type of Study Inference
Reference
S-p53-Abs The survival time of serum-positive
Levels of patients was significantly longer than Significant correlation
111 gastric
p53-mut were that of patients with low/negative seen between levels of
[24] carcinoma Retrospective
determined with a serum levels, with a survival rate of S-p53-mut Abs and
patients
selective, quantitative 41.2% and 14.9%, respectively, over 48 patient survival rate
ELISA kit months (p < 0.05).
Overall survival (OS) was OS is significantly
S-p53-Abs
significantly higher for patients with increased in advanced
104 ovarian ELISA. Antibodies
[25] antibodies to mutant p53 when Retrospective stage ovarian cancer
cancer patients against p53K132Q
compared with patients without p53 patients with antibodies
(c.394A > C).
antibodies (p = 0.01). to p53
S-p53-Abs by
Presence of anti-p53 Abs
Immunofluorescence. Presence of anti-p53 autoantibodies is
134 lung cancer had a significant
[17] Antibodies against almost exclusively linked to the Retrospective
patients correlation with shorter
p53 R273H (c.818G > presence of malignant disease.
survival in NSCLC.
A) by ELISA.
S-p53-Abs s-p53-Abs were higher in BC patients
Presence of s-p53-Abs
ELISA. Antibodies with high risk vs. patients with low
[26] 50 BC patients Retrospective showed higher risk for
against p53R273H risk. The difference was not
BC patients.
(c.818G > A). statistically significant (p = 0.15).

Figure 2. Meta-analysis of serum p53-antibodies. The prognostic value of p53 antibodies in the sera of cancer patients from
eight clinical investigations was investigated in this meta-analysis.

The funnel plot (Figure 3) of the included studies showed a symmetric funnel plot
and no significant publication bias was identified.
Molecules 2021, 26, 6215 7 of 10

Figure 3. The funnel plot of included studies.

3. Discussion
The meta-analysis showed that high levels of p53 antibodies significantly correlated
with worse clinical outcomes. However, our study had some limitations. First, the retro-
spective nature of the study was intrinsically susceptible to biases. Second, different forms
of solid tumors were included pre- or post-treatment with various types of therapies, as
the typology requirements were at different stages. Consequently, in our analysis patients
were observed independently of treatment and tumor type because of the relatively low
number of randomized studies at our disposal. Third, there was a lack of follow-up with
patients from different clinical trials. Thus, differences in survival probability may have
been influenced by the durations of the studies. This may have given rise to different
age populations, which could ultimately have affected the data. All these variables may
ultimately have influenced the results.
As medicine advances, studies involving greater numbers of patients could help to
evaluate the impact of our findings and treatment response.
In summary, p53 is a well-established tumor suppressor, and its absence is commonly
found in patients diagnosed with cancer. The p53 protein has been demonstrated to be
absent or mutated in approximately one out of two malignancies. It is known that p53-
wt cancers have a better prognosis compared to p53-mut cancers. Our data are not in
contradiction with this notion. Although both mutated and wild type p53 antibodies can be
detected in cancer patients, their role is still controversial and a matter for debate. Recently,
a few studies have reported that these antibodies are statistically associated with the
survival of patients diagnosed with different malignancies. To the best of our knowledge,
our meta-analysis is original and is the first study gathering p53 (wild type/mutated)
antibody data generated from 1993 thus far. Overall, the investigation includes 12 studies
and a total of 2094 patients.
Molecules 2021, 26, 6215 8 of 10

4. Materials and Methods

The studies were identified according to the following inclusion criteria: (1) partic-
ipants with cancer; (2) outcome results expressed in relation to the presence of a p53
antibody; (3) a primary outcome (disease-free survival, overall survival or progression-free
survival) expressed as hazard ratio (HR). The following exclusion criteria were used: (1)
insufficient data available to evaluate outcomes; (2) animal studies; (3) studies with less
than 10 participants.
Two independent researchers revised the included studies, and all potential disputes
that could have arisen were evaluated with the corresponding author.
The summary estimates were generated using a fixed-effect model (Mantel–Haenszel
method) [27] or a random-effect model (DerSimonian–Laird method) [28] depending on the
absence or presence of heterogeneity (I2 ). A subgroup analysis was performed to highlight
any differences between studies in terms of Overall Survival (OS), Disease-Free Survival
(DFS), Progression-Free Survival (PFS), as summarized in Table 1.
When we used the keywords “p53 antibodies in early cancer“, p53 antibodies in
metastatic cancer”, “p53 antibodies impact on cancer progression”, the PubMed search
yielded 1375 potentially relevant articles. Studies as duplicates, animal studies, cellular
studies, or letters to the editor or reviews were excluded. After viewing the titles and
abstracts, the full texts of 34 studies were retrieved and 12 studies [10–21] were included in
the analysis because they had the hazard ratio available for survivals (Tables 1 and 2) as
summarized in the flow chart of Figure 1.

5. Conclusions
We observed that serum antibodies generated in the blood of cancer patients against
p53 (and mostly p53-wt) were deleterious. Given the straightforward detection in blood of
p53 antibodies as a biomarker for cancer survival, as summarized in a simple workflow in
Figure 4, these antibodies, together with other biomarkers, potentially constitute a valid
method for prediction of cancer patients’ survival outcomes. The correlation could also
play an important role for targeted therapies involving a cancer-suppressing p53 pathway.

Figure 4. Schematic representation of the significance of serological biomarker p53 antibodies (p53Abs) in prediction of
cancer survival.

6. Competing Interests
The authors have no relevant affiliations or financial involvement with any organiza-
tion or entity with a financial interest in, or financial conflict with, the subject matter or
materials discussed in the manuscript. This includes employment, consultancies, honoraria,
stock ownership or options, expert testimony, grants or patents received or pending, or
royalties. No writing assistance was utilized in the production of this manuscript.

Author Contributions: G.R. and N.S. conceived, designed and planned the study. G.R. and N.S.
acquired data and produced original drafts and figures. G.R. conducted statistical analysis of the
data. G.R. and N.S. drafted the manuscript. P.K.N., R.R., D.G. and A.D. revised and improved
Molecules 2021, 26, 6215 9 of 10

the manuscript’s content and visualization. All authors helped interpret the results and draft the
manuscript. All authors revised and reviewed this article. All authors have read and agreed to the
published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable for studies directly not involving humans
or animals. Also as to ethics approval, the article does not contain any direct studies with human
participants or animals performed by any of the authors.
Informed Consent Statement: Not applicable for studies directly not involving humans.
Data Availability Statement: All relevant data are within the paper.
Acknowledgments: This research was supported by Mednote, spin-off–University of Trieste–Mozart Program.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are not available from the authors.

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