Prognostic and Predictive Value of Aberrant P53 Status in Human Cancers: Systematic Review and Meta-Analysis

Research Article

Austin Med Sci. 2022; 7(3): 1071.

Prognostic and Predictive Value of Aberrant P53 Status in Human Cancers: Systematic Review and Meta-Analysis

Luo X#, Wang HK#, Guan LL, Yang YY#, Meng XR and Wang F*

Department of Oncology, The First Affiliated Hospital of Zhengzhou University, China

#These authors contribute equally to this work and share first authorship

*Corresponding author: Feng Wang Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No.50 Eastern Jianshe Road, Zhengzhou 450052, Henan Province, China

Received: November 14, 2022; Accepted: December 19, 2022; Published: December 25, 2022


Background: Many studies have attempted to correlate p53 abnormality including p53 gene mutation and p53 protein over expression with prognosis or therapeutic response in adjuvant chemotherapy but have yielded controversial results. To investigate whether p53 aberrations have different impacts on survival and outcomes of adjuvant chemotherapy among cancer patients, we conducted a meta-analysis.

Methods: We performed comprehensive search before September 18, 2022. Hazard Ratio (HR) with 95% Confidence Interval (CI) was effective measure, and Stata 16.0 was applied for data analysis.

Results: A total of 14 articles were enrolled in this meta-analysis. p53 protein over expression detected by immunohistochemistry was a risk factor of 5-year Overall Survival (OS) among cancer patients after Radical Surgery (RS). Furthermore, p53 protein over expressed patients displayed inferior response to adjuvant chemotherapy with unfavorable 5-year Disease Free Survival (DFS) (HR = 1.61, 95% CI: 1.12 ~ 2.32, P = 0.011). p53 gene mutation was a negative indicator of OS in adjuvant chemotherapy (HR = 1.41, 95% CI: 1.19 ~ 1.69, P< 0.001). Furthermore, we performed subgroup analysis according to year of publication, the number of patients, detection method of abnormal p53 and tumor types, consistent result was observed.

Conclusion: p53 protein over expression appears to serve as a predictive and prognostic biomarker in adjuvant chemotherapy setting. p53 gene mutation is a potential predictor and could identify high-risk patients who obtain limited overall benefit from adjuvant chemotherapy and support clinical decision-making.

Keywords: p53; Adjuvant chemotherapy; Cancer; Prognosis; Meta-analysis

Abbreviations: OS: Overall Survival; DFS: Disease Free Survival; HR: Hazard Ratio; CI: Confidence Interval; RS: Radical Surgery; MDM2: Murine Double Minute 2; IHC: Immunohistochemical Staining; NSCLC: Non-Small Cell Lung Cancer; CRC: Colorectal Cancer; Wtp53: Wild-Type P53; Mutp53: Mutant P53; GOF: Gain-Of- Function; PCNA: Proliferating Cell Nuclear Antigen; EGFR: Epidermal Growth Factor Receptor; MDR1: Multiple Drug Resistance 1.


Cancer, a worldwide devastating disease with high incidence, poses a great threat to human health and existence. According to data from the International Agency for Research on Cancer, there were 19.3 million new cases and 10 million cancer deaths worldwide in 2020 [1]. In addition, the incidence of cancer is expected to increase in coming years. Treatment regimens for cancers include conventional surgery, chemotherapy, radiotherapy, molecular targeted therapy, immunotherapy, traditional Chinese medicine and their combination [2-7]. Despite impressive progress in tumor therapy, local recurrence and distant metastasis account for the main causes of mortality [8]. Adjuvant chemotherapy, the adjunction of chemotherapy after RS, significantly reduces the risks of relapse and death by killing residual tumor cells. It is often recommended as the best therapeutic option for stage colorectal cancer (TanyN1-2M0) [9,10], hormone- unresponsive breast cancer [11] stage B-A non-small cell lung cancer (NSCLC) [12] after RS. Though the preponderance of adjuvant chemotherapy has been clearly established, the benefit of adjuvant chemotherapy varies widely among patients with the same tumor type and a substantial proportion of patients acquire resistance and relapse. Therefore, it is urgent and critical to develop biomarkers that could accurately assess high-risk patients who mostly respond to adjuvant chemotherapy and determine optimum therapeutic regimen.

The critical p53 tumor suppressor gene, located on human chromosome 17p13.1, encodes a 375 amino acid nuclear phosphoprotein [13]. p53 protein plays a variety of roles in the prevention and suppression of tumor initiation and progression through cell cycle arrest, cellular apoptosis, cellular senescence, DNA repair, inhibition of angiogenesis, and so on [14,15]. Mutations in the p53 gene are frequently documented in more than half of all human cancers [16-18] and majority of mutations are missense mutations in DNA binding domains, a region that is necessary for wild-type p53 (wtp53) to bind to its target genes and perform its function as a transcription factor [19,20]. While the critical role of wtp53 in tumor suppression has been firmly established, a growing body of evidence has demonstrated that mutant p53 (mutp53) proteins not only lose the tumorsuppressive function of wtp53, but also confers novel activities to promote tumorigenesis independently of wtp53, referred to as gain-of-function (GOF) [21]. One of the characteristics of mutp53 proteins is that mutp53 proteins are prone to more stable and accumulate in tumors which are primarily mediated by dysfunctional murine double minute 2 (MDM2). MDM2 is a key negative regulator for wtp53. MDM2 binds to and degrades wtp53 through ubiquitination. Meanwhile, MDM2 itself is a p53-regulated gene. In this way, MDM2 forms a negative feedback loop with wtp53 p53 to tightly regulate wtp53 p53 protein levels and functions [22-25]. In light of this characteristic of the mutp53 protein, positive Immunohistochemical staining (IHC) of p53 in tumor tissues has been widely used as a surrogate for detection of mutp53. However, p53 protein overexpression is not always equal to p53 gene mutation in several tumors. A plethora of studies reported that p53 protein overexpression occur frequently in a broad range of cancers [26,27]. To date, dozens of studies have focused on the relationship between p53 abnormalities and adjuvant chemosensitivity, but the conclusions are still inconsistent to a great extent. For instance, Popat et al [28] reported that p53 overexpression increases the sensitivity of adjuvant chemotherapy among patients with Colorectal Cancer (CRC), whereas Williams et al [29] suggested that p53 overexpression does not affect the chemosensitivity of patients with CRC in adjuvant setting.

Meta-analysis is generally considered a powerful statistical tool to overcome the limitations of different sample sizes from individual studies to generate the best overall estimation. Therefore, the study aims to elaborate precisely the relationship between the p53 alteration and prognosis, as well as effectiveness of adjuvant chemotherapy among cancer patients. Hoping our study will provide essential and valuable information for clinicians in clinical practice.

Materials and Methods

Search Strategy

The meta-analysis was carried out in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement and methods. A comprehensive search was conducted to identify relevant studies by two independent reviewers (XL, HKW). We retrieved all relevant literature published in English from four online databases consisting of PubMed, Embase, Web of Science and Cochrane Library until September 18, 2022. HR and 95% CI for OS and DFS was extracted. Following keywords were used for the search: (“TP53 Genes” OR “p53 Genes” OR “p53 expression” OR “p53 protein” OR “p53 accumulation” OR “p53 status” OR “p53 overexpression”) AND (“Adjuvant Chemotherapy” OR “Drug Therapy, Adjuvant” OR “Adjuvant Drug Therapy” OR “Postoperative chemotherapy”) AND (“carcinoma” OR “tumor” OR “neoplasia” OR “neoplasm”, “cancer” OR “malignancy” OR “malignant neoplasm”).

Inclusion and Exclusion Criteria

In order to achieve our research objectives, we determined the following inclusion and exclusion criteria. The inclusion criteria were as following: (1) prospective or historical cohort studies; (2) cancer patients receiving adjuvant chemotherapy after RS or only RS; (3) p53 alteration either detected as overexpression in the protein level or as mutation by the DNA level; (4) correlation between p53 and survival indexes, such as 5-year OS and DFS; (5) providing HR with 95% CI or data to calculate. Articles were excluded if one of the following criteria was fulfilled: (1) articles with insufficient sample size (n <30); (2) animal studies, case report, reviews, comments, and editorials; (3) duplicate data or analysis; (4) insufficient data for calculating HR and 95% CI; (5) literature not published in English.

Data Extraction and Quality Evaluation

The following data were extracted from all included studies: (1) name of the first author; (2) the year of publication; (3) the country; (4) tumor types; (5) sample size of study; (6) agents of adjuvant chemotherapy; (7) detection method for p53 gene mutation or p53 protein expression; (8) primary outcome measures including 5-year OS and DFS; (9) HR of OS and DFS. Two investigators (XL, HKW) conducted data extraction independently. An external referee (LLG) was involved in case of disagreements which could not be resolved by both investigators. The data was summarized in extraction table (Table 1) and analyzed manually. The quality of all eligible studies was assessed by two investigators (LLG, YYY) according to the Newcastle-Ottawa Scale (NOS) independently. The NOS consists of three parts: selection (0-4points), comparability (0-2 points), and outcome assessment (0-3 points). NOS scores of ≥ 6 were regarded as highquality studies. The NOS scores of all included articles were ≥ 6, and the scoring details are presented in (Table 2).