P53 Autoantibodies and Cancer Speciiicity Diagnosis and Monitoring

Heiko T. Flammann1 and Hella-Monika Kuhn2

1 Institute of Immunology, Pathology and Molecular Biology, Hamburg, Germany; 2 Israelitic Hospital, Hamburg, Germany

1. INTRODUCTION TO p53

p53 has been rightfully called the "guardian of the genome" [1], This tumor suppressor gene plays a critical cellular role with major implications in clinical oncology (for a review, see [2]). In brief, its protein participates in the regulation of the cell-cycle, acts as transcriptional transactivator/repressor, helps in DNA repair, suppresses cell growth, induces apoptosis, and functions in numerous other ways [3-11].

The loss of normal p53 functions during carcinogenesis occurs in several ways. In about 50% of human cancers, the p53 gene is mutated [12]. Cancerous cells that harbor an altered p53 gene carry mainly a missense point mutation with dominant-negative effects. The wild-type allele may then be lost. Ninety-five percent of these missense mutations fall within the evolutionary conserved DNA-binding domain of the gene [13]; some of them, however, may lead to a gain of new function [14]. Germline mutations of p53 (Li-Fraumeni syndrome [15]) pose a high risk for cancer and predispose individuals at an early age to various mesenchymal and epithelial neoplasms at multiple sites. Nonmutational mechanisms leading to a p53 functional loss include complex formation with viral oncoproteins in virus-induced carcinogenesis [16, 17], overexpression of the mdm2 protein in sarcoma [18] as well as inactivation of the dislocated nuclear p53 protein [19] in the cytoplasm (some human breast cancers [20]). Generally, it is the stabilization of an otherwise rapidly turned-over p53 protein which leads to its intracellular (mainly nuclear) accumulation.

A p53 mutation is usually a preinvasive event; both the frequency and the timing vary with the type of cancer [21], In lung cancer, for example, p53 alter ations represent a very early genetic change [22, 23]. However, in colorectal carcinoma (model of Fearon and Vogelstein [24]), p53 mutations are a late event [25] and mark the transition between a dysplastic adenoma and an invasive adenocarcinoma. The fraction of tumors with a mutated p53 gene is typically higher in late-stage neoplasms.

2. ANTI-p53 HUMORAL RESPONSE AND CLINICAL SIGNIFICANCE OF p53 AUTOANTIBODIES

Almost 17 years ago, human p53 autoantibodies (p53AAb) were detected for the first time in sera of patients with breast cancer [26], Since then, p53AAb were found to be associated mainly with solid tumors of the epithelias (carcinoma) or, at reduced frequencies, the lymphatic system (for a review, see [27]). In general, 30-40% of patients with a somatically mutated p53 gene develop specific autoantibodies (overall prevalence: 18-25%). Still, what triggers an anti-p53 immune response remains unclear. It has been suggested that loss of tolerance via p53 protein accumulation is an essential element for the induction of p53AAb [28], In cells of healthy adults, the nuclear p53 protein is present only in very low copy numbers [29] and p53AAb are rare (among blood donors, less than 0.5%). For their frequency in cancer patients, it was assumed to be proportional to the occurence of p53 mutations [30]. Thus, the accumulation of p53 protein may be due to the mutational event and prolonged half-life seems to be one important prerequisite of the humoral response. However, accumulation is not always associated with a mutation [20, 31]. In some cases, p53AAb are elicited without a detectable p53 gene alteration [32, 33]. Moreover, p53AAb were reported for patients with no overexpression of p53 in the tumor [34, 35]. In this context, however, the presence of a second yet occult cancer eliciting p53AAb should also be taken into consideration.

Davidoff et al. [36] have suggested that the site of the p53 mutation might influence the generation of p53AAb. Other studies, however, gave no support to this hypothesis [33, 37], In lung cancer, immunogeni-city seems to depend on the type of the p53 mutation (missense); no p53AAb were detected in patients who had stop, splice or frameshift mutations in their tumors [38]. As another prerequisite, complex formation with heat shock protein Hsp70 has been linked to an immunogenic p53 protein [36]; only tumor tissue from seropositive patients contained such aggregates. Generally, human sera react equally well with mutant and wild-type p53 protein exposing conformational and denaturation-resistent epitopes [39], These epitopes are located in the amino and in the carboxy-terminal regions of the protein outside the central mutational hotspots [28] and are also detected by sera of animals hyperimmunized with wild-type p53 [40]. Ninety-eight percent of p53AAb-positive sera from patients with various cancer types recognize the epitopes in the amino-terminus of the p53 protein while only 48% react with those of the carboxy-terminus [41], The anti-p53 humoral response mainly generates immunoglobulins of the IgGl and IgG2 subclasses [30]; few patients develop predominantly IgA.

As with p53 mutations, the clinical significance of p53AAb varies with cancer type. Furthermore, different investigators come to contradictory conclusions. In cancer of the head and neck, for example, shorter relapse-free and overall survival of the patients were reported for carcinoma harboring p53 mutations [42, 43]. Other studies, however, found no association between mutation, protein accumulation and poor clinical outcome [44,45], Bosari et al. [46] pointed out for colorectal carcinoma that p53 mutations were not correlated with clinical parameters and not related to patient survival. Moreover, 30% of colorectal tumors may have p53 accumulation without the gene mutation [47], This conflicts with three studies [48-50] in which a prognostic significance for the altered gene was found. Likewise, in an early study on p53AAb in lung cancer (NSCLC and SCLC) patients, the humoral response was not correlated with clinical data or survival

[38]. Later, however, clinical relevance of p53AAb was clearly shown for two patients in whom the antibodies predated a lung cancer diagnosis by several months [51] (see below). It should also be noted that the presence of p53AAb in patients with small-cell lung carcinoma may indicate a favorable prognosis with an improved survival [52]. Patients with breast cancer who develop p53AAb, on the other hand, face a shorter overall survival; the humoral response is negatively correlated with oestrogen and progesterone receptors [53]. With respect to colorectal cancer, the prognostic value of p53AAb is still unclear. Houbiers et al. [54] see a decreased survival for patients with p53AAb as do Kressner et al. [55], Angelopoulou et al. [56], however, ascribe no prognostic value to a p53AAb test.

To date, only a few reports turned their focus from the qualitative p53AAb evaluation in cancer diagnosis and prognosis to its usefulness in patient monitoring. With the recent arrival of quantitative ELISA kits, trailing serum levels during therapy or in post-treatment cancer patients will soon provide additional information on the clinical usefulness of p53AAb. This short compilation aims to review some aspects of p53AAb in early diagnosis, patient follow-up, and specificity for malignant diseases.

3. p53 AUTOANTIBODIES: NONTUMOROUS DISEASES AND HEALTHY INDIVIDUALS

The presence of p53AAb is generally indicative of malignancy. Nevertheless, rare exceptions become known. In autoimmune diseases (AID), p53AAb can be detected in patients with systemic lupus erythematosus (SLE) [57, 58], Sjogren's syndrome and systemic sclerosis (scleroderma) [57], Additionally, we found seropositive individuals among patients with Graves' disease, Wegener's granulomatosis, and other vasculitis [58], The role of p53AAb in AID is yet unknown. Furthermore, is there an association between p53AAb generation and p53 protein accumulation in patients with AID? Recently, extensive apoptosis was demonstrated in most of the epidermis of cutaneous lupus erythematosus; lesional skin showed a marked increase in p53 protein-positive keratinocytes [59]. Skin samples from 44 patients with scleroderma, however, revealed no abnormal expression of p53 [59] although Kovacs et al. [57] found a p53AAb-positive patient.

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