Detection Of A Malignant Disease

From all the reports on p53 autoantibodies it seems to come up that p53 autoantibodies are in general associated with a malignant disease, whereas, healthy blood donors are rarely positive for p53 autoantibodies. Two individuals were found to express p53 autoantibodies although no tumor was detected. Both individuals were heavy smokers and diagnosed for chronic cough or a benign obstructive tracheal tumor. Both developed lung cancer within 5 or 15 months, respectively [27]. In a study of patients with prostate carcinoma, a "healthy" control patient was also positive for p53 autoantibodies [28], Later, it turned out that this patient died from an undetected lung cancer. Thus, these studies might indicate that p53 autoantibodies may be early markers for malignancy and that this type of analysis allows for the detection of an unknown cancerous malignancies. However, there are also reports that p53 autoantibodies were found in patients with nontumorous diseases such as autoimmune diseases. p53 autoantibodies were found in 32% of patients with systemic lupus erythematosus (SLE) in 15% of non-SLE control patients but in none of the healthy control sera [29]. Out of the non-SLE antibody-positive sera, two were from patients with Sjogren's syndrome and one from a patient with systemic sclerosis. It is interesting to note that this study was performed with an ELISA and the data were confirmed by Western Blot analysis. Furthermore, it turned out that p53 from T cells established from SLE patients was wild-type as detected by sequencing.

People infected with viruses were also analyzed for the presence of p53 autoantibodies. It was found that 2% of asymtomatic HTLV-I infected individuals, 4% of HTLV-I-associated T-cell leukemia and 6% of HTLV-I-associated myelopathy/tropical spastic paraparesis patients carried antibodies against p53. However, the low number of positive case might indicate that p53 autoantibodies are not a useful serological marker for the analysis of HTLV-I infected individuals [30], p53 autoantibodies were described to be present in patients with a hepatocellular carcinoma [31-33], Since at least in Western countries a hepatitis C virus infection is the major etiologic agent in the development of hepatocellular carcinomas (HCC) one might be interested to analyze whether, or not, p53 autoantibodies might be already present in hepatitis C virus infected individuals. Raedle et al. [34] found that the sensitivity to detect hepatitis C virus infected patients with hepatocellular carcinoma was about 43% and that the immune response against p53 was highly specific (100%) for a malignancy [34], p53 autoantibodies were also detected although with a low frequency (4%) in patients with chronic liver diseases and in patients with liver cirrhosis. All of these patients were free of a hepatocellular carcinoma and they were carefully investigated for another underlying malignancy which was not found. Thus, these results might suggest that p53 autoantibodies are not exclusively detectable in patients with a malignant disease [35].

Unexpectedly, p53 autoantibodies were also found in multiparous women. However, there is ample evidence that the fetal p53 protein is distinct from wild-type p53 because it exhibits enhanced stability, structurally differences and it is unable to bind DNA and these features may be responsible for the immune response of the mother against the fetal p53 protein [36],

In a study of patients with pancreatic diseases, p53 autoantibodies were also found in individuals with benign pancreatic disease [37], These patients had a long history of chronic pancreatitis. Other authors found that none of the patients with chronic pancreatitis were positive for p53 autoantibodies. In the course of the later study the serum from one patient with a stone in the common bile duct was found to have p53 autoantibodies. The relevance of this observation is unclear. This finding may be explained by the presence of an undetected other malignant disease or it may be an early marker for malignancy as it may be the case for lung cancer [27, 39],

Since the presence of p53 autoantibodies may help to detect an otherwise undetected cancerous malignancy or be an early marker for the development of cancer, it seems to be attractive to screen individuals occupationally exposed to carcinogens for the presence of p53 autoantibodies. Angiosarcoma of the liver (ASL) is a rare cancer in humans, except in instances of exposure to carcinogens. Molecular epidemiology studies of vinyl chloride exposed workers found p53 mutations in liver tissue of ASL patients. Using an enzyme linked immunoassay 9 out of 92 individuals were found to have p53 autoantibodies. Among these 9 individuals, 5 had already developed angiosarcoma of the liver, whereas 4 had no clinically evident cancer. In one case the person had p53 autoantibodies 11 years in another case 4 months before the diagnosis of ASL. Thus, p53 autoantibodies can predate clinical diagnosis of ASL and may be useful in identifying individuals at high cancer risks.

In addition to these studies there is some indication that the presence of p53 autoantibodies can predate the clinical diagnosis of esophageal cancer although these patients might be classified as healthy individuals according to conventional diagnosis [26],

5. FREQUENCY OF p53 AUTOANTIBODIES IN SERA OF PATIENTS WITH DIFFERENT CANCERS

Studying sera from patients with various cancers revealed that p53 autoantibodies were found with high frequency in patients with solid tumors and with reduced rates in patients with tumors of the lymphatic system. Moreover, in initial studies it was shown that lung and pancreas carcinoma patients have high incidences for p53 autoantibodies. These two cancer types are known to have a high frequency for p53 gene mutation. Low incidences for p53 autoantibodies were found for patients with leukemia and prostate carcinoma, cancers where mutations in the p53 gene are rare. Meanwhile patients with a lot more tumor types were analyzed for the presence of p53 autoantibodies and the correlation between the presence of p53 autoantibodies and p53 gene mutation is not that strict.

Table 1 shows the frequency of p53 autoantibodies found in patients with different tumor entities. Between 8^10% of lung cancer patients, 16-25% of patients with colorectal cancer, 6-27% of patients with pancreas carcinoma, 25-36% patients with hepatocellular carcinoma, 17-44% of patients with head and neck cancer, 9-26% of breast cancer patients and 11-41% of patients with ovarian cancer have p53 autoantibodies. Low incidences for p53 autoantibodies were found for patients with leukemia [63], non-Hodgkin's lymphoma and multiple myeloma [81], for prostate carcinoma and for patients with endometrial

Table 1. Frequency of p53 autoantibodies in patients with different tumor entities

Cancer

p53 autoantibodies (%)

Ref.

Lung

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