Determination of p53 autoantibodies is becoming increasingly important in oncology diagnostics. In approximately 60% of all tumors, there is a mutation in the p53 tumor suppressor gene, which is associated with a loss of the inhibitory effect of the p53 protein on cell proliferation. p53 autoantibodies are directed against the mutated p53 protein and can be used as an independent tumor marker with high specificity for the early diagnosis of suspected tumors, the monitoring of high-risk patients, and the monitoring of patients after tumor removal or chemotherapy.
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The p53 gene is located on the distal band of the short arm of chromosome 17. It has since been established that it has a critical role as a tumor-suppressor gene. p53 inactivation predisposes cells to malignant transformation. The tumor suppressive role of p53 is so crucial that it is referred to as “the guardian of the genome”. It is the most common mutation found in cancers and is present in half of all solid tumors thus emphasizing its importance in protecting cells from carcinogenesis. The frequency of mutation varies in individual cancers ranging from 5%-12% in cervical and hemopoietic malignancies to 40%-50% in colorectal and ovarian cancer. Additionally, the remaining cancers with no detectable p53 mutation are still thought to have dysfunctional p53 caused by mechanisms other than mutation.
p53 acts as a tumor suppressor by preventing the propagation of defective cells. It is upregulated by various upstream factors in response to cellular stress or damage such as DNA damage, hypoxia, telomere shortening, and oncogenic stimulation or radiation. The p53 gene encodes for a 393 amino-acid, 53 kDa, phospho-protein which is divided into 3 domains-an amino (-NH2) terminal region (approximately amino acids 1-100), a central “core” domain (amino acids 100-300) and a terminal carboxyl (-COOH) region (amino acids 320-360). Almost all mutations are harbored in the central “core” which contains the DNA-binding regions. Thus, p53 dysfunction is most likely caused by mutations that alter DNA binding behavior. Wild-type p53 protein expression is intra-nuclear with a half-life of 5-30 min and is subject to complex regulation. Active p53 has tumor suppressive activity by causing cell cycle arrest, apoptosis, and autophagy. Cell cycle arrest initially provides additional time for the cell to repair damaged DNA.
Disruption of p53 gene transcription function and subsequent production of an inactive mutant p53 protein allows cells to escape the cellular arrest/apoptosis controls. This allows unregulated propagation of abnormal cells and a predisposition to malignant transformation.
An anti-p53 auto-antibody response was first reported by Crawford in 1982 in 9% of patients with breast cancer. Research into the autoantibody was invigorated in the 1990s when the critical role of the p53 gene in carcinogenesis was recognized. The exact cause of induction of anti-p53 auto-antibody production is unknown but is thought to be associated with the presence of p53 mutation and p53 protein over-expression.
The prevalence of anti-p53 antibodies correlates with the degree of cancer malignancy. The increased incidence of anti-p53 antibodies statistically is also associated with a higher frequency of mutations in gene p53.
- Asbestosis: There is statistical evidence for the relationship between p53 autoantibodies and the subsequent development of malignancy with a positive predictive value and an average lead-time to diagnosis up to 4 years.
- Prostate cancer: Patients with prostate cancer have significantly higher total prostate-specific antigen and p53-Abs than patients with benign prostatic disease (BPD), but serum p53-antibodies may not be related to the clinical stage.
- Ovarian cancer: There is only low sensitivity for serum p53 antibodies in ovarian carcinomas alone, and no major additional effect of the detection rate of CA125 was reported (but CA125 correlates with serum p53 antibodies). No associations are reported between p53 antibodies and clinical stage, age, and histology.
- Carcinoma of the uterus: Up to 23% of patients with carcinoma of the uterus have been reported with serum p53 antibody.
- Breast cancer: Between 8% and 11% are positive for p53 antibodies in screening assays.
- Pleural mesotheliomas: Up to 7% of patients with pleural malignant mesothelioma are positive for p53 antibodies, for lung cancer the sensitivity is 15 - 17%.
- Esophageal squamous cell carcinoma: Up to 27 - 30% of the patients are positive for serum p53 antibodies. A high concentration after tumor resection is a predictive marker for recurrence. A high concentration of p53 is an independent prognostic factor, a high concentration also indicates an advanced stage of esophageal carcinoma. The positive rate for serum-p53 antibodies may be higher as compared to CEA in patients with squamous cell carcinoma.
- Adenocarcinoma: Serum p53 antibodies are detected in up to 18 - 63% of patients with adenocarcinoma but only in 3% of patients with adenoma. As compared to the two other markers for adenocarcinoma, carcinoembryonic antigen (CEA) and carbohydrate antigen CA19-9, which showed no significant difference between superficial colorectal adenocarcinoma and adenoma, p53 can differentiate between the two dysplasias.
False positive in normal human serum is less than 1.1% and up to 3.6% in respiratory diseases.
No false positives in systemic lupous erythematosus or Sjogren’s syndrome or during pregnancy so far reported.
