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Laboratoire de génotoxicologie des tumeurs, Institut Curie, 75248 Paris, France
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ABSTRACT |
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 Top ABSTRACT IntroductionThe p53 ProteinThe Specificity of p53...Relationship between p53...Specificity of p53 Antibodiesp53 Antibodies and Clinical...p53 and Follow-Up of...p53 Antibodies and Populations...p53 Protein in SeraAntibodies toward Other...p53 Antibodies: Future...REFERENCES |
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Introduction |
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TopABSTRACTIntroductionThe p53 ProteinThe Specificity of p53...Relationship between p53...Specificity of p53 Antibodiesp53 Antibodies and Clinical...p53 and Follow-Up of...p53 Antibodies and Populations...p53 Protein in SeraAntibodies toward Other...p53 Antibodies: Future...REFERENCES |
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Those studies, performed in the early 1980s, were virtually ignored for more than 10 years because of a lack of interest in p53 during that period. In the early 1990s, it was discovered that the p53 gene is the most common target for molecular alteration in every type of human cancer (10) . This provoked considerable interest in the study of the p53 protein and its function in normal and transformed cells. It also led to the rediscovery of this humoral response, which had been found in cancer patients. Since 1992, more than 150 papers have been published on p53-Abs. This review will summarize this literature and focus on the future applications of this assay.
For a comprehensive view of the p53 discovery, the reader is referred to the excellent review published by Crawford (11) . More reviews on p53 have recently been published (12, 13, 14, 15) .
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The p53 Protein |
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TopABSTRACTIntroductionThe p53 ProteinThe Specificity of p53...Relationship between p53...Specificity of p53 Antibodiesp53 Antibodies and Clinical...p53 and Follow-Up of...p53 Antibodies and Populations...p53 Protein in SeraAntibodies toward Other...p53 Antibodies: Future...REFERENCES |
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The Specificity of p53 Antibodies in Cancer Patients |
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TopABSTRACTIntroductionThe p53 ProteinThe Specificity of p53...Relationship between p53...Specificity of p53 Antibodiesp53 Antibodies and Clinical...p53 and Follow-Up of...p53 Antibodies and Populations...p53 Protein in SeraAntibodies toward Other...p53 Antibodies: Future...REFERENCES |
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p53 is heavily phosphorylated at the NH2 and COOH termini. Such phosphorylation can have an important influence on the reactivity of p53-Abs toward the protein, which suggests that p53 expressed in mammalian cell is a better antigen than those expressed in Escherichia coli. Recently, it has been shown that IgA p53-Abs are found as the only isotype in some patients with head and neck cancers. The fact that a majority of ELISAs use a secondary antibody specific for IgG may eventually lead to false-negative sera.4
p53-Abs have also been found in other body fluids such as the ascites of women with ovarian cancer, the pleural effusions of patients with pancreatic, colon, and lung tumors, and the saliva of patients with oral cancer (27, 28, 29) . Such antibodies are correlated with serum p53-Abs (27 , 28) .
p53 Antibodies and p53 Mutation Frequency.
Eighty serological analyses of p53 status in 18 cancer types that were
published before August 1999 have been compiled (Table 1
). Control experiments were performed in 36 studies, involving 2404
individuals who were either healthy or had nonmalignant diseases.
Studies involving 9489 patients with various types of cancer were
analyzed. Statistical analysis demonstrated that p53 antibodies are a
specific marker of patients with neoplasia (P < 10-4; Table 2
). An analysis of p53-Abs in each type of cancer also showed a
significant correlation with malignant diseases for most types of
cancer except for testicular carcinoma, melanoma, hepatoma, and glioma,
in which the frequency of p53-Abs was very similar to that of the
control group (Table 2)
. Fig. 1
shows the correlation between the frequency of p53-Abs and the
frequency of p53 mutations published in the literature. There is a very
strong correlation between the two rates, again arguing that p53
mutations are involved in the appearance of these antibodies. Apart
from the healthy control, it is striking to observe that three cancers,
well-known to be devoid of p53 mutations, hepatoma (30)
,
testicular carcinoma (31
, 32)
, and melanoma (33
, 34)
, are also negative for p53-Abs. However, cancers such as
esophageal carcinoma and oral squamous cell carcinoma, which
have a high rate of p53 mutations, also have a high frequency of
p53-Abs. The only exception is glioma, with a very low rate of p53-Abs
(35
, 36)
despite a high frequency of p53 mutations
(37)
. In a complete study involving both molecular and
serological analyses, Rainov et al. (35)
found
p53 mutations in 24 of 60 glioblastomas, but none of these patients had
p53-Abs. Several explanations can account for the lack of a p53 immune
response in this type of cancer. It is possible that the immune
privilege of the brain does not allow the induction of this humoral
response. It is also possible that there is inefficient antigen
presentation if p53 cannot cross the brain barrier, or if no immune
response can be elicited in the brain. Furthermore, we should keep in
mind that, in one series, 70% of the patients were treated with
dexamethasone before serum collection (35)
, which can
induce perturbation in the immune response. In the other studies, such
information was not available.
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Relationship between p53 Antibodies, p53 Mutations, and p53 Accumulation |
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TopABSTRACTIntroductionThe p53 ProteinThe Specificity of p53...Relationship between p53...Specificity of p53 Antibodiesp53 Antibodies and Clinical...p53 and Follow-Up of...p53 Antibodies and Populations...p53 Protein in SeraAntibodies toward Other...p53 Antibodies: Future...REFERENCES |
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, this
finding was confirmed by numerous studies.
Only a subset of patients with p53 mutations will have p53 antibodies
in their tumor. As shown in Fig. 1
, about 20–40% of patients with a
p53 mutation will have p53-Abs in their sera. These results are not due
to a lack of sensitivity of the current methods of detection but to a
real absence of p53-Abs. It had been suggested that only p53 mutations
that are localized in exons 5 and 6 with an altered protein
conformation and that bind to hsp 70 are associated with p53-Abs
(39
, 40)
. These analyses, performed on a small
number of patients, were not confirmed in larger series of patients.
Indeed, a compilation of all of the serological analyses performed in
conjunction with molecular analyses indicates that the repartition of
p53 mutations in patients with p53-Abs is similar to that in patients
without antibodies (Fig. 2
). Several studies have shown that, despite similar types of cancer,
identical p53 mutation, and p53 accumulation, some patients could be
either positive or negative for p53-Abs (41, 42, 43, 44)
. These
observations demonstrate that other factors contribute to this humoral
response. Examination of p53-Abs during follow-up of patients during
therapy indicates that the level of p53-Abs can vary depending
on the tumor burden (see below). Follow-up of patients who were
devoid of p53-Abs at the time of diagnosis failed to detect any
de novo antibody production after therapy failure or relapse
despite p53 accumulation in the tumor and a long follow-up. This
suggests that the capacity to elicit this humoral response is linked to
the biological background of the patients. It is possible that, for an
identical mutation, the immune response is dependent on the specific
combination of MHC class I and II molecules expressed by each
individual.
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Specificity of p53 Antibodies |
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TopABSTRACTIntroductionThe p53 ProteinThe Specificity of p53...Relationship between p53...Specificity of p53 Antibodiesp53 Antibodies and Clinical...p53 and Follow-Up of...p53 Antibodies and Populations...p53 Protein in SeraAntibodies toward Other...p53 Antibodies: Future...REFERENCES |
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Such a finding is totally in accordance with the work performed in mice on the production of p53 monoclonal antibodies. Immunization of mice with murine, xenopus, or human wild-type p53 led to the production of monoclonal antibodies directed to linear epitopes localized in the NH2 and COOH termini of p53 (49, 50, 51, 52) . The analysis of mouse sera immunized with these proteins indicates that it is due to a specific immune response of the mouse toward this region of the protein and not to a bias in the selection of the hybridoma (49) . Monoclonal antibodies specific for the central region of the protein were obtained only after a special immunization or selection procedure (53 , 54) .
Taken together (a) the presence of immunodominant epitopes outside the hot spot region of the p53 mutation; (b) the correlation between p53 accumulation (and p53 gene mutation) in tumor cells and p53-Abs responses; (c) the similarity of humoral responses in patients independent of the cancer type; and (d) the similarity of antigenic site profiles in patients and hyperimmunized animals—all suggest that p53 accumulation is the major component of the humoral response in patients with cancer. This accumulation could lead to a self-immunization process culminating in the appearance of p53-Abs. As stated above, the level of p53 proteins in a normal organism is very low, which suggests very weak (if any) tolerance to endogenous p53. Isotyping of p53-Abs has shown that they correspond mainly to IgG1 and IgG2 subclasses, although some patients exhibit a predominant IgA response (25) . Some patients also had IgM, although none had p53 IgM as the only isotype. No IgG3 or IgG4 was detected. Again, this result strengthens the hypothesis of an active humoral response to p53.
It is not clear whether p53 mutation is really required for the production of p53-Abs or whether the sole accumulation of p53 protein can lead to this humoral response. This question is difficult to answer because there is no normal situation of wild-type p53 accumulation in humans that could be used to test this hypothesis. On the other hand, such a situation occurs in animals. p53-Abs have been discovered in the sera of animals that bear tumors induced by SV40 (1 , 5) . In such tumors, wild-type p53 is stabilized through its interaction with SV40 large T antigen. These observations indicate that p53 accumulation alone is the main component of this autoimmunization.
The mechanism by which p53 is presented to the immune system is unknown. It is possible that it is released after cell necrosis, but thus far, p53 has not been found reproducibly in human sera (see below; 55 , 56 ). Either the p53 protein is very rapidly eliminated from sera, or else other mechanisms of p53 presentation are involved.
X-ray crystallography of human p53 was an important step in the
understanding of the structure of this protein. The central region
(amino acids 102–292) was crystallized in the form of a protein-DNA
complex (57)
. This core region has been shown to include
the following motifs: (a) two antiparallel ß sheets
composed of four and five ß-strands, respectively. These two sheets
form a kind of compact sandwich that holds the other elements;
(b) a LSH containing three ß-strands, an
-helix, and the L1 loop; (c) an L2 loop containing
a small helix; and (d) an L3 loop composed mainly of turns.
It is quite remarkable to note the striking correspondence between
these various structural elements and the four evolutionarily conserved
blocks (II to V). The LSH motif and the L3 helix are involved in direct
DNA interaction (LSH with the major groove and L3 with the minor
groove). The L2 loop is presumed to provide stabilization by
associating with the L3 loop. These two loops are held together by a
zinc atom tetracoordinated to Cys176 and His179 on the L2 loop and to
Cys278 and Cys242 on the L3 loop.
Furthermore, the conformational changes in p53 were dissected by a new battery of monoclonal antibodies directed against the central region of the protein (53) . None of these antibodies was able to recognize native, wild-type p53. On the other hand, regardless of the location of their epitopes, they were all able to recognize p53 mutants that had undergone conformational changes (53) . This result indicates that the central region of wild-type p53 protein has a very compact structure that is held in place by the two antiparallel B sheets. Such conformation and the observation that this region is highly hydrophobic explain its poor immunogenicity.
A recent study (58) indicates that critical residues of epitopes recognized by several anti-p53 monoclonal antibodies correspond to key residues of p53 involved in interaction of the mdm2 protein with the NH2 terminus of the p53 protein. This can explain why such a region is at the surface of the molecule. It should also be mentioned that the p53 protein, whatever its phylogenetic origin, is an incredibly potent antigen. Immunization of mice with p53 requires only a small amount of protein, and adjuvant is not necessary to obtain a high titer of antibodies.5
Recently, several p53 homologues have been identified (59, 60, 61, 62) . Although, the conservation of the sequence is only partial, it is conceivable that p53-Abs could either cross-react with such proteins or were produced toward one of the homologues. Extensive assays of sera with or without p53-Abs indicate that most sera are specific for p53. Nevertheless, specific antibodies toward p73 have been detected.6
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p53 Antibodies and Clinical Parameters |
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TopABSTRACTIntroductionThe p53 ProteinThe Specificity of p53...Relationship between p53...Specificity of p53 Antibodiesp53 Antibodies and Clinical...p53 and Follow-Up of...p53 Antibodies and Populations...p53 Protein in SeraAntibodies toward Other...p53 Antibodies: Future...REFERENCES |
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. As for p53 mutation and p53 immunohistochemical
analysis, these studies have reported contradictory results. Before
examining them, one should bear in mind one question that has not been
assessed thus far, i.e., the role of such antibodies in the
neoplastic process. This question has never been thoroughly discussed
or experimentally tested. During our lifetime, it is quite possible
that we experience several unknown precancers that arise after a
genetic variation in an oncogene or a tumor suppressor gene. Such
preneoplastic cancers could be quickly eliminated either because the
mechanisms that control cellular proliferation have been able to
overcome these tumoral cells or because they have been eliminated from
the organism through various surveillance mechanisms including the
immune system. It is plausible that early p53 accumulation, such as
that seen in lung or oral cancer, can lead to the production of a
humoral and cellular response that participates in the elimination of
the tumor. Such a hypothesis is supported by the work of Roth et
al. (63)
. Immunization with canarypox virus
recombinants that expressed human or murine p53 protected BALB/c mice
from a challenge with a highly tumorigenic mouse fibroblast tumor cell
line that express high levels of mutant p53. This tumor
protection was equally effective regardless of whether wild-type or
mutant p53 was used for the immunization, which indicated that the
immunological response was not dependent on any particular p53 mutation
and that immunization with this live virus vaccine works effectively
against mutant p53 protein expressed in a tumor cell (63)
.
Although there is no formal proof that a natural response toward p53
can protect from precancerous tumor, it is not possible to exclude such
a hypothesis. However, it is quite possible that such an immune
response is totally neutral toward the organism and is simply the
consequence of self-immunization toward a self-protein. In that case,
any clinical correlation with p53-Abs would be due to the presence of
p53 inactivation via mutation.
In breast cancer, several studies indicate that p53-Abs are found in
patients with tumors that have high grades and/or that are negative for
steroid hormone receptors (8
, 24
, 45
, 64
, 65) , two
clinical parameters already known to be associated with p53 mutations
and bad prognosis. Two studies, on 353 and 165 patients, found an
association between p53-Abs and short survival (64
, 66)
,
whereas one study (82 patients) did not find any association
(67)
, and another study (50 patients) found an association
with good survival (68)
. In gastric cancer, three of four
studies found an association between p53-Abs and poorly differentiated
tumors and short survival (69, 70, 71)
. In colon cancer, two
of three studies also found an association between p53-Abs and short
survival (72, 73, 74)
. In lung cancer, as for p53 mutations,
controversies exist concerning the clinical value of p53-Abs (Table 1)
.
In NSCLC, p53-Abs seem to be associated with poor survival,
especially in squamous cell carcinoma (75, 76, 77)
,
whereas in SCLC, the studies are very divergent (78
, 79) . In oral cancer, two studies have also demonstrated an
association between p53-Abs and short survival (80
, 81)
.
Taken together, in all of the these studies, there is a trend toward an association between p53-Abs and tumors with poor differentiation, a feature already observed with p53 mutations. The value of p53-Abs in terms of survival is promising, but additional studies are necessary before this can be clearly established.
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p53 and Follow-Up of Patients during Therapy |
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TopABSTRACTIntroductionThe p53 ProteinThe Specificity of p53...Relationship between p53...Specificity of p53 Antibodiesp53 Antibodies and Clinical...p53 and Follow-Up of...p53 Antibodies and Populations...p53 Protein in SeraAntibodies toward Other...p53 Antibodies: Future...REFERENCES |
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In breast cancer, it is possible to detect the reappearance of p53-Abs 2 years after initial therapy. This increase in p53-Abs has been detected 3 months before the detection of a relapse (5) . Thus, in such tumor types, p53-Abs could be a useful tool for controlling the response to therapy and for monitoring certain early relapses before they are clinically detectable. As indicated above, several studies have demonstrated that sera that score negative at the time of diagnosis never turn positive during follow-up (82 , 83 , 86) .
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p53 Antibodies and Populations at High Risk of Cancer |
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TopABSTRACTIntroductionThe p53 ProteinThe Specificity of p53...Relationship between p53...Specificity of p53 Antibodiesp53 Antibodies and Clinical...p53 and Follow-Up of...p53 Antibodies and Populations...p53 Protein in SeraAntibodies toward Other...p53 Antibodies: Future...REFERENCES |
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. One good model for testing this hypothesis is that of lung cancer and
heavy smokers. It is well established that p53 accumulation is an early
event in lung cancer and that such cancer is strongly associated with
tobacco smoking. Indeed, in 1994, p53-Abs were found in two heavy
smoker who were negative for any detectable lung cancer
(48)
. One of the patients could not be followed but died 8
months later from a rapidly growing lung tumor. The second
patient, PT37, was placed under surveillance, with regular assay for
p53-Abs and thoracic X-rays. Two years later, lung cancer was detected
in this patient before any clinical manifestations of the disease
(88)
. The patient showed good response to therapy that
paralleled the total disappearance of p53-Abs (83
, 88)
.
Since 1996, this patient has been tumor-free, and a recent check-up
indicated that neither the tumor nor p53-Abs had reappeared. To our
knowledge, this is the only prospective study that addressed the
importance of p53-Abs in individuals at high risk for cancer, and that
used such assays for clinical management of the patient. Since that
work, several studies have demonstrated that p53-Abs can be found in
the sera of high-risk individuals.
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; Ref. 42
). This work
is of importance because it is known that p53 mutations are frequent in
individuals exposed to various carcinogens, and such mutations usually
occur early in the transforming process (89)
. Therefore,
this assay could be useful for early identification of cancer in
individuals occupationally exposed to carcinogens. Similarly, p53-Abs
have been detected in the sera of patients with chronic obstructive
pulmonary disease and in heavy smokers (Table 3
; Ref.
90
).
There exist certain clinical situations in which nonmalignant lesions
can predate their progression toward cancer. This is the case in
Barrett’s esophagus. The histopathological sequence for (Barrett’s)
metaplasia, which develops—as a consequence of chronic reflux—to
dysplasia and then to carcinoma is well established for these tumors.
In Barrett’s esophagus, a variety of molecular changes have been
characterized and correlated with tumor initiation and progression.
Mutations and accumulation of p53 are found mainly in the transition
from low- to high-grade dysplasia and are associated with an increased
risk of cancer. The finding of p53-Abs in patients with Barrett’s
esophagus may be promising if confirmed in a larger population because
it may predate clinical diagnosis of esophageal ADC
(91)
. A similar situation occurs in individuals with
premalignant oral lesions (leukoplakia) due to tobacco or betel nut
chewing. Such individuals are at high risk of developing oral cancer
(5–10%). p53-Abs have been found at high frequency in patients with
premalignant and malignant lesions, which suggests that such antibodies
could be used for early detection of cancer (Table 3
;
Ref.92
). Unfortunately, no follow-up has been performed on
these patients. Due to the high frequency of this type of cancer in
countries such as India or Pakistan, this kind of diagnosis could be of
importance. The recent discovery that p53-Abs can be found in saliva
indicates that easy screening could be organized to verify the value of
these antibodies (27)
.
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p53 Protein in Sera |
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TopABSTRACTIntroductionThe p53 ProteinThe Specificity of p53...Relationship between p53...Specificity of p53 Antibodiesp53 Antibodies and Clinical...p53 and Follow-Up of...p53 Antibodies and Populations...p53 Protein in SeraAntibodies toward Other...p53 Antibodies: Future...REFERENCES |
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; Refs. 55
, 56
, 93, 94, 95, 96, 97, 98
). It should be pointed out that most
assays use a commercial ELISA kit that was developed for the detection
of p53 protein in cell or tumor extracts but that has not been fully
verified on serum samples. Sera have always been tested undiluted,
which can lead to high background and false-positives. Indeed, in
carefully controlled experiments, Levesque et al.
(55)
demonstrated that some false-positive sera were
caused either by the presence of human antibodies with broad
antispecies specificities that can cross-react with some antibodies
used in the assay or by other nonspecific reactants that interfere with
the assay.
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Antibodies toward Other Oncogenes and Tumor Suppressor Genes |
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TopABSTRACTIntroductionThe p53 ProteinThe Specificity of p53...Relationship between p53...Specificity of p53 Antibodiesp53 Antibodies and Clinical...p53 and Follow-Up of...p53 Antibodies and Populations...p53 Protein in SeraAntibodies toward Other...p53 Antibodies: Future...REFERENCES |
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The presence of antibodies to HER-2/neu were detected in 12 (11%) of 107 breast cancer patients versus none (0%) of 200 normal controls (104) . The presence of antibodies to HER-2/neu was also correlated with the accumulation of HER-2/neu protein in the patient’s primary tumor. Such accumulation of HER-2/neu protein is well known to be associated with a poor prognosis. No information concerning the association of such antibodies with clinical data has been published thus far.
The paucity of these data compared with p53 suggests that p53 immunogenicity is a rather specific situation related to the striking immunogenicity of the p53 protein.
This field is advancing, especially with the use of new methodology, such as SEREX, that enables identification of specific antibodies associated with gene overexpression in tumors (106 , 107) . Such methodology can shed light on new tumor antigens, which could lead to the discovery of new cancer genes, repeating the history of the p53 with the identification of the protein prior to cloning the gene.
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p53 Antibodies: Future Directions |
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TopABSTRACTIntroductionThe p53 ProteinThe Specificity of p53...Relationship between p53...Specificity of p53 Antibodiesp53 Antibodies and Clinical...p53 and Follow-Up of...p53 Antibodies and Populations...p53 Protein in SeraAntibodies toward Other...p53 Antibodies: Future...REFERENCES |
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and 2)
clearly
demonstrates the specificity of this serological analysis because such
antibodies are truly rare in the normal population. It is possible to
estimate that the specificity of this assay attains 95%. Such
specificity is supported by our knowledge of p53 that accumulates
specifically in the nucleus of tumor cells after gene mutation. Among
the various TAAs that have been analyzed over the years, the production
of p53-Abs is surely the best studied and most clearly explains humoral
response. One of the disadvantages of this assay is its lack of
sensitivity inasmuch as only 20–40% of patients with p53 mutations
will develop p53-Abs. This lack of sensitivity totally precludes the
use of the assay to evaluate p53 alteration in human tumor.
Nevertheless, if we estimate that there are 8 million patients with
various types of cancer throughout the world, and 50% of them have a
mutation in their p53 gene, then we can deduce that about 1
million of these patients have p53-Abs. There exist several situations in which p53-Abs could have clinical utility. The first is in the monitoring of sera during therapy. Only prospective studies on various types of cancer in which relapses occur several months or years after treatment will enable us to validate this assay. The use of standardized assays that have been validated for quantitative analysis should help in such studies.
The second situation concerns p53-Abs in high-risk individuals. One of the challenges of the next millennium is the early detection of tumors using highly sensitive assays with gene probes specific for tumor genetic alterations (108) . Such approaches are still under development and remain costly. I do believe that there is still room for serological assays of tumors markers such as those described in the present review. In developing countries, there is an increased burden of tumors due to carcinogen exposure. This is the result of an increase in cigarette consumption, higher pollution caused by political laxism, uncontrolled industrial development, and the absence of regulation in waste evacuation. It is possible that p53 mutations in cancer related to such exposure are high (109) . The use of a low-cost assay for the detection of p53-Abs could be of public health benefit in such countries.
Over the past 10 years, a tremendous amount of work has been performed on p53. Such an effort, both in academic and private laboratories has never been made for any other single gene thus far. This work has led to the development of numerous clinical studies including gene therapy protocols, with the aim of achieving more efficient cure of the disease.
Finally, let me dedicate this review to Patient PT37 (88) . I think that this patient is the first to have benefited from significant improvement, and, indeed, whose very life has been saved, thanks to the knowledge we have gained about p53, particularly from the TAA studies published 20 years ago (7) .
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Ligue Nationale contre le Cancer
(Comité de Paris), the Association pour la Recherche contre le
Cancer (ARC), the Mutuelle Générale de l’Éducation
Nationale (MGEN), Direction de la Recherche Clinique (DRC) de
l’Assistance Publique-Hôpitaux de Paris Contract Grant
AOA94084. 
2 To whom requests for reprints should be
addressed, at Laboratoire de génotoxicologie des tumeurs,
Institut Curie, 26 rue d’Ulm, 75248 Paris, France. Phone:
33-1-44-32-41-60; Fax: 33-1-44-32-42-32; E-mail: thierry.soussi{at}curie.fr
3 The abbreviations used are:
p53-Ab, p53 antibody; TAA, tumor-associated antigen; LSH,
loop-sheet-helix (motif); SCLC, small cell lung cancer; NSCLC,
non-SCLC; ADC, adenocarcinoma.
4 M. Tavassoli and T. Soussi. Expression of p53 in
oral squamous cell carcinoma is associated with the presence of p53
autoantibodies in sera and saliva, manuscript in preparation.
5 Y. Legros and T. Soussi, unpublished
observation; D. Lane, personal communication.
6 O. Tominaga, K. Unzal, and T. Soussi. p73
antibodies are found in the sera of patients with various types of
cancer, manuscript in preparation.
Received 10/25/99. Accepted 2/16/00.
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TopABSTRACTIntroductionThe p53 ProteinThe Specificity of p53...Relationship between p53...Specificity of p53 Antibodiesp53 Antibodies and Clinical...p53 and Follow-Up of...p53 Antibodies and Populations...p53 Protein in SeraAntibodies toward Other...p53 Antibodies: Future...REFERENCES |
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-fetoprotein status. Hepatology, 18: 559-565, 1993.[Medline]
-fetoprotein and p53 autoantibodies in patients with chronic hepatitis C. Dig. Dis. Sci., 40: 2587-2594, 1995.[Medline]
-fetoprotein and p53 antibodies in the diagnosis of hepatocellular carcinoma. Transplant. Proc., 30: 780-781, 1998.[Medline]
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 M. M. Lauwen, S. Zwaveling, L. de Quartel, S. C. Ferreira Mota, J. A.C. Grashorn, C. J.M. Melief, S. H. van der Burg, and R. Offringa Self-Tolerance Does Not Restrict the CD4+ T-Helper Response against the p53 Tumor Antigen Cancer Res., February 1, 2008; 68(3): 893 - 900. [Abstract] [Full Text] [PDF]
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A. Gagnon, J.-H. Kim, J. O. Schorge, B. Ye, B. Liu, K. Hasselblatt, W. R. Welch, C. A. Bandera, and S. C. Mok Use of a Combination of Approaches to Identify and Validate Relevant Tumor-Associated Antigens and Their Corresponding Autoantibodies in Ovarian Cancer Patients Clin. Cancer Res., February 1, 2008; 14(3): 764 - 771. [Abstract] [Full Text] [PDF]
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S. R. Pereira-Faca, R. Kuick, E. Puravs, Q. Zhang, A. L. Krasnoselsky, D. Phanstiel, J. Qiu, D. E. Misek, R. Hinderer, M. Tammemagi, et al. Identification of 14-3-3{theta} as an Antigen that Induces a Humoral Response in Lung Cancer Cancer Res., December 15, 2007; 67(24): 12000 - 12006. [Abstract] [Full Text] [PDF]
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 H.-S. Lin, H. S. Talwar, A. L. Tarca, A. Ionan, M. Chatterjee, B. Ye, J. Wojciechowski, S. Mohapatra, M. D. Basson, G. H. Yoo, et al. Autoantibody Approach for Serum-Based Detection of Head and Neck Cancer Cancer Epidemiol. Biomarkers Prev., November 1, 2007; 16(11): 2396 - 2405. [Abstract] [Full Text] [PDF]
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 M. E. Hudson, I. Pozdnyakova, K. Haines, G. Mor, and M. Snyder Identification of differentially expressed proteins in ovarian cancer using high-density protein microarrays PNAS, October 30, 2007; 104(44): 17494 - 17499. [Abstract] [Full Text] [PDF]
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 P. Das, K. Vaiphei, D. Jain, and Jai Dev Wig p53 and mdm2 Expression in Colorectal Carcinoma: A Correlative Analysis With Clinical Staging and Histological Parameters International Journal of Surgical Pathology, October 1, 2007; 15(4): 335 - 345. [Abstract] [PDF]
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M. Caron, G. Choquet-Kastylevsky, and R. Joubert-Caron Cancer Immunomics Using Autoantibody Signatures for Biomarker Discovery Mol. Cell. Proteomics, July 1, 2007; 6(7): 1115 - 1122. [Abstract] [Full Text] [PDF]
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G. Chen, X. Wang, J. Yu, S. Varambally, J. Yu, D. G. Thomas, M.-Y. Lin, P. Vishnu, Z. Wang, R. Wang, et al. Autoantibody Profiles Reveal Ubiquilin 1 as a Humoral Immune Response Target in Lung Adenocarcinoma Cancer Res., April 1, 2007; 67(7): 3461 - 3467. [Abstract] [Full Text] [PDF]
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N. J. Nesslinger, R. A. Sahota, B. Stone, K. Johnson, N. Chima, C. King, D. Rasmussen, D. Bishop, P. S. Rennie, M. Gleave, et al. Standard Treatments Induce Antigen-Specific Immune Responses in Prostate Cancer Clin. Cancer Res., March 1, 2007; 13(5): 1493 - 1502. [Abstract] [Full Text] [PDF]
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 D. Ito, A. Albers, Y. X. Zhao, C. Visus, E. Appella, T. L. Whiteside, and A. B. DeLeo The Wild-Type Sequence (wt) p5325-35 Peptide Induces HLA-DR7 and HLA-DR11-Restricted CD4+ Th Cells Capable of Enhancing the Ex Vivo Expansion and Function of Anti-wt p53264-272 Peptide CD8+ T Cells J. Immunol., November 15, 2006; 177(10): 6795 - 6803. [Abstract] [Full Text] [PDF]
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Y. Fujita, T. Nakanishi, M. Hiramatsu, H. Mabuchi, Y. Miyamoto, A. Miyamoto, A. Shimizu, and N. Tanigawa Proteomics-Based Approach Identifying Autoantibody against Peroxiredoxin VI as a Novel Serum Marker in Esophageal Squamous Cell Carcinoma. Clin. Cancer Res., November 1, 2006; 12(21): 6415 - 6420. [Abstract] [Full Text] [PDF]
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C. A. Casiano, M. Mediavilla-Varela, and E. M. Tan Tumor-associated Antigen Arrays for the Serological Diagnosis of Cancer Mol. Cell. Proteomics, October 1, 2006; 5(10): 1745 - 1759. [Abstract] [Full Text] [PDF]
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 M. Robin, J. Andreu-Gallien, M.-H. Schlageter, D. Bengoufa, I. Guillemot, K. Pokorna, C. Robert, J. Larghero, P. Rousselot, E. Raffoux, et al. Frequent antibody production against RAR{alpha} in both APL mice and patients Blood, September 15, 2006; 108(6): 1972 - 1974. [Abstract] [Full Text] [PDF]
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V. Goodell, L. G. Salazar, N. Urban, C. W. Drescher, H. Gray, R. E. Swensen, M. W. McIntosh, and M. L. Disis Antibody Immunity to the p53 Oncogenic Protein Is a Prognostic Indicator in Ovarian Cancer J. Clin. Oncol., February 10, 2006; 24(5): 762 - 768. [Abstract] [Full Text] [PDF]
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A. Erkanli, D. D. Taylor, D. Dean, F. Eksir, D. Egger, J. Geyer, B. H. Nelson, B. Stone, H. A. Fritsche, and R. B.S. Roden Application of Bayesian Modeling of Autologous Antibody Responses against Ovarian Tumor-Associated Antigens to Cancer Detection Cancer Res., February 1, 2006; 66(3): 1792 - 1798. [Abstract] [Full Text] [PDF]
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 X. Wang, J. Yu, A. Sreekumar, S. Varambally, R. Shen, D. Giacherio, R. Mehra, J. E. Montie, K. J. Pienta, M. G. Sanda, et al. Autoantibody Signatures in Prostate Cancer N. Engl. J. Med., September 22, 2005; 353(12): 1224 - 1235. [Abstract] [Full Text] [PDF]
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F. Fernandez-Madrid, N. Tang, H. Alansari, J. L. Granda, L. Tait, K. C. Amirikia, M. Moroianu, X. Wang, and R. L. Karvonen Autoantibodies to Annexin XI-A and Other Autoantigens in the Diagnosis of Breast Cancer Cancer Res., August 1, 2004; 64(15): 5089 - 5096. [Abstract] [Full Text] [PDF]
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 J. T. Chang, F.-H. Wong, C.-T. Liao, I-H. Chen, H.-M. Wang, and A.-J. Cheng Enzyme Immunoassay for Serum Autoantibody to Survivin and Its Findings in Head-and-Neck Cancer Patients Clin. Chem., July 1, 2004; 50(7): 1261 - 1264. [Full Text] [PDF]
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J. A. Koziol, J.-Y. Zhang, C. A. Casiano, X.-X. Peng, F.-D. Shi, A. C. Feng, E. K. L. Chan, and E. M. Tan Recursive Partitioning as an Approach to Selection of Immune Markers for Tumor Diagnosis Clin. Cancer Res., November 1, 2003; 9(14): 5120 - 5126. [Abstract] [Full Text] [PDF]
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K. Chikamatsu, A. Albers, J. Stanson, W. W. Kwok, E. Appella, T. L. Whiteside, and A. B. DeLeo p53110-124-specific Human CD4+ T-helper Cells Enhance in Vitro Generation and Antitumor Function of Tumor-reactive CD8+ T Cells Cancer Res., July 1, 2003; 63(13): 3675 - 3681. [Abstract] [Full Text] [PDF]
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J.-Y. Zhang, C. A. Casiano, X.-X. Peng, J. A. Koziol, E. K. L. Chan, and E. M. Tan Enhancement of Antibody Detection in Cancer Using Panel of Recombinant Tumor-associated Antigens Cancer Epidemiol. Biomarkers Prev., February 1, 2003; 12(2): 136 - 143. [Abstract] [Full Text] [PDF]
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M. H. Hansen, H. V. Nielsen, and H. J. Ditzel Translocation of an Intracellular Antigen to the Surface of Medullary Breast Cancer Cells Early in Apoptosis Allows for an Antigen-Driven Antibody Response Elicited by Tumor-Infiltrating B Cells J. Immunol., September 1, 2002; 169(5): 2701 - 2711. [Abstract] [Full Text] [PDF]
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M. J. Scanlan, S. Welt, C. M. Gordon, Y.-T. Chen, A. O. Gure, E. Stockert, A. A. Jungbluth, G. Ritter, D. Jager, E. Jager, et al. Cancer-related Serological Recognition of Human Colon Cancer: Identification of Potential Diagnostic and Immunotherapeutic Targets Cancer Res., July 15, 2002; 62(14): 4041 - 4047. [Abstract] [Full Text] [PDF]
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S. H. van der Burg, A. G Menon, A. Redeker, M.-C. Bonnet, J. W. Drijfhout, R. A. E. M. Tollenaar, C. J. H. van de Velde, P. Moingeon, P. J. K. Kuppen, R. Offringa, et al. Induction of p53-specific Immune Responses in Colorectal Cancer Patients Receiving a Recombinant ALVAC-p53 Candidate Vaccine Clin. Cancer Res., May 1, 2002; 8(5): 1019 - 1027. [Abstract] [Full Text] [PDF]
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O. A. Elisseeva, Y. Oka, A. Tsuboi, K. Ogata, F. Wu, E. H. Kim, T. Soma, H. Tamaki, M. Kawakami, Y. Oji, et al. Humoral immune responses against Wilms tumor gene WT1 product in patients with hematopoietic malignancies Blood, May 1, 2002; 99(9): 3272 - 3279. [Abstract] [Full Text] [PDF]
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F. Le Naour, F. Brichory, D. E. Misek, C. Brechot, S. M. Hanash, and L. Beretta A Distinct Repertoire of Autoantibodies in Hepatocellular Carcinoma Identified by Proteomic Analysis Mol. Cell. Proteomics, March 1, 2002; 1(3): 197 - 203. [Abstract] [Full Text] [PDF]
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F. Brichory, D. Beer, F. LeNaour, T. Giordano, and S. Hanash Proteomics-based Identification of Protein Gene Product 9.5 as a Tumor Antigen That Induces a Humoral Immune Response in Lung Cancer Cancer Res., November 1, 2001; 61(21): 7908 - 7912. [Abstract] [Full Text] [PDF]
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F. Le Naour, D. E. Misek, M. C. Krause, L. Deneux, T. J. Giordano, S. Scholl, and S. M. Hanash Proteomics-based Identification of RS/DJ-1 as a Novel Circulating Tumor Antigen in Breast Cancer Clin. Cancer Res., November 1, 2001; 7(11): 3328 - 3335. [Abstract] [Full Text] [PDF]
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 M. Lu, R. M. Nakamura, E. D. Dent, J.-Y. Zhang, F. C. Nielsen, J. Christiansen, E. K. L. Chan, and E. M. Tan Aberrant Expression of Fetal RNA-Binding Protein p62 in Liver Cancer and Liver Cirrhosis Am. J. Pathol., September 1, 2001; 159(3): 945 - 953. [Abstract] [Full Text] [PDF]
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F. M. Brichory, D. E. Misek, A.-M. Yim, M. C. Krause, T. J. Giordano, D. G. Beer, and S. M. Hanash An immune response manifested by the common occurrence of annexins I and II autoantibodies and high circulating levels of IL-6 in lung cancer PNAS, August 14, 2001; 98(17): 9824 - 9829. [Abstract] [Full Text] [PDF]
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 M Abu-Shakra, D Buskila, M Ehrenfeld, K Conrad, and Y Shoenfeld Cancer and autoimmunity: autoimmune and rheumatic features in patients with malignancies Ann Rheum Dis, May 1, 2001; 60(5): 433 - 441. [Abstract] [Full Text] [PDF]
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H. Naora, Y. Yang, F. J. Montz, J. D. Seidman, R. J. Kurman, and R. B. S. Roden A serologically identified tumor antigen encoded by a homeobox gene promotes growth of ovarian epithelial cells PNAS, March 27, 2001; 98(7): 4060 - 4065. [Abstract] [Full Text] [PDF]
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E. Jager, S. Gnjatic, Y. Nagata, E. Stockert, D. Jager, J. Karbach, A. Neumann, J. Rieckenberg, Y.-T. Chen, G. Ritter, et al. Induction of primary NY-ESO-1 immunity: CD8+ T lymphocyte and antibody responses in peptide-vaccinated patients with NY-ESO-1+ cancers PNAS, October 24, 2000; 97(22): 12198 - 12203. [Abstract] [Full Text] [PDF]
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