Concordance between p53 protein overexpression and gene mutation in a large series of common human carcinomas

Soong, Richie; Robbins, Peter; Dix, Brett R.; Grieu, Fabienne; Lim, Berenice; Knowles, S.; Williams, Kate; Turbett, Gavin R.; House, A. K.; Iacopetta, Barry

doi:10.1016/s0046-8177(96)90282-8

Cited by 143 publications

(99 citation statements)

References 27 publications

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“…Accumulation of p53 protein is usually interpreted as a surrogate marker for a missense mutation in the gene, which is the most common mechanism of p53 inactivation in breast cancer (9). However, elevated levels of wild type p53 may also result in a positive immunohistochemical reaction, while non-missense mutations are usually not detectable by immunohistochemistry (8,9). Thus, it is well established that this methodology can only be regarded as a first approximation of p53 dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…Accumulation of p53, which occurs in 10 to 60% of breast cancers, is usually taken as a surrogate marker of a mutation in the gene. However, it is well recognized that the concordance between level of the protein and abnormalities at the DNA level is by no means perfect (7)(8)(9). We wished to correlate the expression patterns of cyclin D1 and p53 in breast cancer with important pathological features and with DNA ploidy, which is a weak but significant prognostic indicator, particularly in nodenegative disease (10).…”

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confidence: 99%

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Abnormal Expression of Cell Cycle Regulatory Proteins in Ductal and Lobular Carcinomas of the Breast

Geradts

Ingram

2000

Modern Pathology

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In a previous study, we demonstrated that the G1 cell cycle checkpoint in carcinomas of the breast is frequently abrogated by loss of p16, the product of the CDKN2/INK4A gene, and, to a lesser extent, by loss of pRB, the product of the retinoblastoma gene. The purpose of the present study was to determine whether other mechanisms of cell cycle deregulation exist in breast cancers which have retained RB and p16 function. Paraffin sections of 81 invasive breast carcinomas (49 ductal, 26 lobular, 6 mixed) were reacted with monoclonal antibodies against cyclin D1 and p53, using optimized immunohistochemical staining protocols. The staining results were correlated with the expression of p16 and pRB, and with a variety of pathological parameters and DNA ploidy. Twenty-five tumors (31%) accumulated (presumably mutant) p53 and 28 (35%) overexpressed cyclin D1; 7 carcinomas (not including any pure lobular cancers) abnormally expressed both proteins. p53 accumulation correlated with nuclear, mitotic, and overall grade, but not with tumor size, lymph node involvement, or DNA ploidy. Overexpression of cyclin D1 was not associated with any of the patho-biological variables. There was an inverse correlation between loss of p16 and high levels of p53, but not cyclin D1. The G1 cell cycle checkpoint, which is controlled by RB, cyclin D1, and p16, was abrogated in 65% of carcinomas, and only p53 was abnormal in an additional 17%. The number of abnormally expressed genes correlated with mitotic activity and overall tumor grade, but not with tumor histology, size, or nodal status, suggesting that cell cycle deregulation is an early event in breast tumorigenesis. Only 18% of the carcinomas showed a normal level of expression of the four genes tested, and p16 appeared to be the most common target of cell cycle deregulation. These data point to the importance of cell cycle regulatory protein abnormalities in human breast cancer.KEY WORDS: Breast cancer, Cell cycle, Cyclin D1, Immunohistochemistry, p16, p53, Pathology. Mod Pathol 2000;13(9):945-953It is generally accepted that several pathways need to be abrogated in the genesis of a malignant neoplasm. There is an increasing body of evidence that deregulation of one or more of the cell cycle checkpoints is among the most common abnormalities in human neoplasia. We have been particularly interested in the genes controlling the late G1 restriction point. Possibly the most critical component of the latter is pRB, the product of the retinoblastoma gene. Hyperphosphorylation, and hence inactivation of pRB is catalyzed by cyclin dependent kinases (CDKs), most notably CDK4 and 6. The CDKs are activated by binding to their respective cyclins, including cyclin D1 (1). They are inhibited by CDK inhibitors including p15 INK4B and p16 INK4A (specific for CDK4/6) and p21 WAF1 . The latter, in turn, is partially under the transcriptional control of p53 (2). We recently demonstrated that abnormal expression of the genes controlling the G1 restriction point is a very common occurrence in carcinomas ...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Abnormal Expression of Cell Cycle Regulatory Proteins in Ductal and Lobular Carcinomas of the Breast

Geradts

Ingram

2000

Modern Pathology

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“…1 The involvement of p53 at this crucial checkpoint in the cell division is probably reflected by the fact that inactivating mutations in the p53 genome are found in the majority of human cancer diseases. 2,3 The rationale behind a broadly applicable vaccination immunotherapy of human cancer disease with HLA-A2 binding p53 peptides is based on the high levels of wild-type p53 demonstrated in p53-mutated tumor cells 4,5 and the presence of peptide residues in the p53 protein that bind to the common HLA class I molecule HLA-A2. 6 A vaccination protocol based on wild-type peptides allows one to circumvent the limitations of strategies focused on the specific nonself peptides that arise through the variable p53 mutations found in single individuals.…”

Section: Abstract: P53; Cytotoxic T-lymphocytes; Hla-a2; Dendritic Cmentioning

confidence: 99%

“…DISCUSSION The high proportion of p53 mutations in human cancers leads to p53 protein accumulation, a phenomenon not observed in nonmalignant cells. 3 This upregulation or accumulation of p53 protein makes it a possible immunologic target for the use in cancer immunotherapy and characterization of human p53-specific CTL reactivity, a highly relevant topic. Here we demonstrate that a CTL line induced by in vitro activation with DC maturated in the presence of soluble CD40L and pulsed with a pool of 4 HLA-A2-binding p53 peptides exhibit cross-reactivity at the clonal level towards 2 nonhomologous p53 peptides, G11V and R9V, present in the peptide pool.…”

Section: Ctl Killing Of Natural Targetsmentioning

confidence: 99%

Specific killing of P53 mutated tumor cell lines by a cross-reactive human HLA-A2-restricted P53-specific CTL line

et al. 2001

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p53 is upregulated in the majority of spontaneous tumors and the HLA class I molecule HLA-A2 is expressed by approximately 50% of the caucasians. Potentially, these facts make HLA-A2-binding p53 peptides for CTL-inducing immunotherapy applicable to a broad range of cancer patients. In our study, we investigated the CTL-inducing capacity of autologous monocyte-derived dendritic cells (DC) maturated by exposure to CD40L and pulsed with a pool of 4 wild-type, HLA-A2-binding p53 peptides, and the p53-specific CD8 ؉ CTL lines established from healthy HLA-A2-positive donors were characterized. Reactivity to p53 65-73 and p53 [187][188][189][190][191][192][193][194][195][196][197] peptides was obtained in the T-cell lines. Interestingly, cold target inhibition experiments demonstrated that the simultaneous recognition of the 2 peptides was the result of crossreactivity, which was confirmed by killing experiments at the clonal CTL level. Furthermore, 4 HLA-A2 ؉ p53-mutated tumor cell lines were lysed by the CTL line, indicating that these peptides are endogenously processed and presented on HLA-A2 molecule. Thus, monocyte-derived DC pulsed with a pool of peptides are able to induce CTL reactivity to wildtype p53 peptides presented by several cancer cell lines. In addition, the recognition of 2 different p53 peptides by the same CTL clone suggests a promiscuous peptide recognition by the TCR involved. Taken together, these in vitro results suggest that vaccination with autologous DC pulsed with multiple p53 epitopes may induce an effective tumor-specific CTL response in vivo with the potential to eradicate p53-upregulated spontaneously occurring tumors. © 2001 Wiley-Liss, Inc. Key words: p53; cytotoxic T-lymphocytes; HLA-A2; dendritic cellsThe cell cycle regulating protein p53 binds to DNA with coincidental nucleotide misincorporations and leads to cell cycle arrest and DNA repair. 1 The involvement of p53 at this crucial checkpoint in the cell division is probably reflected by the fact that inactivating mutations in the p53 genome are found in the majority of human cancer diseases. 2,3 The rationale behind a broadly applicable vaccination immunotherapy of human cancer disease with HLA-A2 binding p53 peptides is based on the high levels of wild-type p53 demonstrated in p53-mutated tumor cells 4,5 and the presence of peptide residues in the p53 protein that bind to the common HLA class I molecule HLA-A2. 6 A vaccination protocol based on wild-type peptides allows one to circumvent the limitations of strategies focused on the specific nonself peptides that arise through the variable p53 mutations found in single individuals.Recently, several clinical studies on cancer immunotherapy using different approaches to activate cytotoxic T cells in vivo [7][8][9] or ex vivo 10 recognizing individual tumor antigens have been highly successful. These results underscore the efficiency of the immune system in controlling tumor growth and emphasize the importance of characterizing CTL specific to general tumor antigens. Four studies on...

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“…9,[15][16][17] Tp53 gene mutations are a common genetic event in cancers 18,19 and immunohistochemistry has been shown to be an effective means for their detection. 20,21 Most Tp53 mutations in uterine serous carcinomas are missense, which results in an altered p53 protein that can be shown by immunohistochemistry because of a prolonged half life. 22 Variable amounts and staining intensity (from any staining to 50%) for p53 have been interpreted as evidence of p53 overexpression in the published literature, 16,[23][24][25] but the presence of strong nuclear staining in 475% of tumor cells has been shown, more specifically, to correlate with the presence of Tp53 mutations.…”

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confidence: 99%

p53 overexpression in morphologically ambiguous endometrial carcinomas correlates with adverse clinical outcomes

et al. 2010

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The distinction between uterine serous and endometrioid carcinomas can usually be achieved by morphologic examination alone. However, there are occasional 'morphologically ambiguous endometrial carcinomas' that show overlapping serous and endometrioid features and defy histologic classification. The primary aim of this study was to assess the clinical significance of p53 overexpression using immunohistochemistry in such tumors. Related aims included (1) assessing interobserver diagnostic concordance for histologic subclassification of these tumors using a panel of pathologists with and without gynecologic pathology expertise and (2) elucidating the histologic features that correlate with p53 status. Thirty-five such cases were identified during the study period. p53 overexpression was seen in 17 of 35 cases. Tumors with p53 overexpression were associated with a significantly inferior progression-free survival and disease-specific survival compared with those that lacked p53 overexpression (3-year progression-free survival and disease-specific survival were 94 and 100% in patients with no p53 overexpression, and 52 and 54% in patients with p53 overexpression; P ¼ 0.02 and 0.003, respectively). The consensus diagnosis rendered by gynecologic pathologists was predictive of disease-specific survival (P ¼ 0.002), but not progression-free survival (P ¼ 0.11). Although the interobserver diagnostic concordance (kappa ¼ 0.70) was substantial for gynecologic pathologists, and highly associated with p53 status (77% of 'favor serous' cases showed p53 overexpression, whereas only 25% of 'favor endometrioid' cases showed p53 overexpression; P ¼ 0.005), the concordance between the consensus diagnosis of the two specialized pathologists versus each of three non-specialized pathologists was poor (kappa ¼ 0.13-0.25). The histologic feature that correlated most with p53 overexpression was the presence of diffuse high nuclear grade. p53 immunohistochemistry assays in morphologically ambiguous endometrial carcinomas are roughly as clinically informative as gynecologic pathology consultation and can be helpful for prognostic assessment and therapeutic decision making in difficult endometrial carcinomas.

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Concordance between p53 protein overexpression and gene mutation in a large series of common human carcinomas

Cited by 143 publications

References 27 publications

Abnormal Expression of Cell Cycle Regulatory Proteins in Ductal and Lobular Carcinomas of the Breast

Abnormal Expression of Cell Cycle Regulatory Proteins in Ductal and Lobular Carcinomas of the Breast

Specific killing of P53 mutated tumor cell lines by a cross-reactive human HLA-A2-restricted P53-specific CTL line

p53 overexpression in morphologically ambiguous endometrial carcinomas correlates with adverse clinical outcomes

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