Expression of cyclin Ds in relation to p53 status in human breast carcinomas

 Cyclin D1 has been reported to be overexpressed in many tumours, including breast carcinomas. Cyclin D1 was first identified as a protooncogene (BCL1/PRAD1), and its overexpression was related to tumour proliferation. The product has also recently been identified as important in mediating cell cycle growth arrest via the p53 pathway in murin fibroblast cell lines. Ninety breast carcinomas previously analysed for p53 status were analysed for amplification of cyclin D1, D2 and D3 genes by Southern blot analysis and for protein expression by immunhistochemistry. In 10 samples gene amplification was detected at the cyclin D1 locus. No gene amplification was detected at the cyclin D2 and D3 loci. Immunoreactivity for cyclin D1 was detected in 38 (42.2%) tumour tissue samples. Fifty samples were immunostained for cyclin D2 and D3. Only 2 samples (4%) showed immunoreactivty for cyclin D2, and 9 samples (18%) for cyclin D3. Cyclin D1 protein overexpression was significantly more often found in tumours with wild type p53 and in tumours with higher grades of differentiation expressing ER. No association was seen between gene amplification of the cyclin D1 gene and p53 status. We conclude there is a relationship between wild type p53 and cyclin D1 protein overexpression in clinical material, indicating that cyclin D1 may be another downstream effector of p53. Received: 25 November 1997 / Accepted: 30 March 1998     

Immunohistochemical analysis of p53 protein overexpression in normal,premalignant, and malignant tissues of the cervix uteri

Two hundred and thirty-eight cervical lesions ranging from normal to malignant were examined for overexpression of p53 protein. Whereas p53 protein was identified in 62 per cent of invasive squamous cell carcinomas, 11 per cent of invasive adenocarcinomas, and 7 per cent of squamous cell carcinomas in situ, no staining was found in adenocarcinoma in situ, dysplastic tissue, condyloma, and normal tissue. In 9 per cent of the positive cases of invasive squamous cell carcinomas. 5-50 per cent of the tumour ceiis were immunoreactive for p53 protein, whereas the other positive specimens were characterized by only rare p53-positive cells. We conclude that in invasive cervical carcinomas widespread overexpression of p53 protein is unusual, but occasional positive nuclei can be found frequently. Furthermore, our results indicate that altered expression of p53 protein may be involved in the progression of cervical carcinomas.     

Relationship between abnormal p53 protein and failure to express p21 protein in human breast carcinomas

Alterations in the p53 protein are a common feature in most malignancies, including breast carcinomas. p53 protein alterations contribute to malignant transformation in several ways, through genomic instability and accumulation of additional genetic alterations in other genes, through alteration of the p53-dependent apoptotic pathway, and through downregulation of downstream effector proteins such as p21 (WAF1/CIP1), necessary for cell-cycle growth arrest. Cell-cycle arrest is needed to allow DNA repair after injury. This study examines the relationship between abnormalities in p53 protein and expression of p21 protein in 70 cases selected from a series of 212 sporadic human breast carcinomas. Immunohistochemistry (IHC) was used for detection of p53 and p21 protein expression. Constant denaturant gel electrophoresis (CDGE) was used for detection of mutations in exons 5–8 of the TP53 gene. A highly significant association was found between abnormalities in p53, scored as protein accumulation and/or mutations, and lack of p21 expression. p21 was also shown to be downregulated in samples without p53 alterations, indicating that other mechanisms are also involved in turning off this gene. © 1997 John Wiley & Sons, Ltd.     

TP53 protein accumulation and gene mutation in relation to overexpression of MDM2 protein in ovarian borderline tumours and stage I carcinomas

Three hundred and seventy-four early-stage ovarian tumours, including 27 borderline tumours and 347 stage I carcinomas, were investigated immunohistochemically for overexpression of the TP53 and MDM2 proteins. TP53 (p53) and MDM2 alterations were detected in 15 and 4 per cent of borderline tumours, and in 50 and 13 per cent of stage I carcinomas, respectively. Mutations in the TP53 gene (exons 5–8) were demonstrated in 29 of the 50 stage I carcinomas studied, using denaturing gel electrophoresis followed by direct sequencing. TP53 overexpression was seen less often in tumours of mucinous and endometrioid type than in tumours of other histological types and more often in moderately and poorly differentiated than in well differentiated tumours. MDM2 protein overexpression was seen more often in clear cell carcinoma than in tumours of other histological types. These results indicate that TP53 abnormalities play a crucial role, and MDM2 abnormalities a minor role, in the development of early-stage ovarian carcinoma. There was no significant association between TP53 or MDM2 alterations and survival in multivariate analysis. © 1997 John Wiley & Sons, Ltd.     

TP53 alterations in relation to the cell cycle-associated proteins p21, cyclin D1, CDK4, RB,MDM2, and EGFR in cancers of the uterine corpus

In the present study, TP53 alterations have been analysed and compared with the expression of the proteins p21, cyclin D1, cdk4, RB, EGFR, and MDM2 in 53 cancers of the uterine corpus. TP53 gene mutations analysed by CDGE/DGGE and direct sequencing showed a TP53 gene mutation in 18 per cent of the cases. TP53 gene mutations were not significantly related to overexpression or down-regulation of any of the proteins. Immunohistochemically, there was an increased protein level of TP53 in 77 per cent, p21 in 36 per cent, cyclin D1 in 45 per cent, cdk4 in 77 per cent, EGFR in 8 per cent, and MDM2 in 32 per cent of the cases. Expression of RB protein was normal in all cancers. Significant association of protein expression was seen between TP53 and MDM2 (p = 0·005) and p21 and MDM2 (p = 0·001). Furthermore, there may be an association between TP53 and p21 (p = 0·038) and cyclin D1 and cdk4 (p = 0·045). The results revealed increased levels of TP53 protein in all MDM2-positive cases that did not show TP53 mutations, indicating TP53 protein stabilization and inactivation by complex formation with MDM2. In summary, the high number of cases showing an increased level of TP53 and cdk4 proteins suggests that these proteins play an important role in the neoplastic process in cancers of the uterine corpus. Copyright © 1999 John Wiley & Sons, Ltd.     

Distinctive patterns of p53 protein expression and microsatellite instability in human colorectal cancer

Although evidence suggests an inverse relationship between microsatellite instability and p53 alterations in colorectal cancer, no study has thoroughly examined the use of p53 immunohistochemistry in phenotyping colorectal cancers. We investigated the value of p53 immunohistochemistry in microsatellite instability–positive colorectal cancers prescreening and attempted to clarify the relationship between DNA mismatch repair system and p53 pathway. In a series of 104 consecutive colorectal cancers, we performed p53 immunohistochemistry, TP53 mutational analysis, DNA mismatch repair system efficiency evaluation (DNA mismatch repair system immunohistochemistry, microsatellite instability status, MLH1/MSH2 germ line, and BRAF, murine double minute 2, and p21 immunohistochemistry. Microsatellite instability high was observed in 25 of 104 colorectal cancers, with DNA mismatch repair system protein loss (24/25) and germ line (8/25) or BRAF mutations (8/25). p53 immunohistochemistry revealed 3 distinct patterns of expression: complete negative immunostaining associated with truncating TP53 mutations (P < .0001), diffuse overexpression associated with missense TP53 mutations (P < .0001), and restricted overexpression characterized by a limited number of homogenously scattered strongly positive tumor cells in 36.5% of colorectal cancers. This latest pattern was associated with wild-type TP53 and microsatellite instability high colorectal cancers (P < .0001) including all Lynch tumors (8/8), but its presence among 22% of DNA mismatch repair system–competent colorectal cancers decreased its positive predictive value (55.2% [95% confidence interval, 45%-65%]). It was also correlated with murine double minute 2 overexpression (P < .0001) and inversely with p21 loss (P = .0002), independently of microsatellite instability status. In conclusion, a restricted pattern of p53 overexpression is preferentially associated with microsatellite instability high phenotype and could, therefore, be of clinical use as signal for microsatellite instability analysis in a large-scale tumor screening. Its association with concomitant murine double minute 2 overexpression suggests an alternative mechanism of p53 pathway deregulation.     

宫颈癌中COX-2与p53、E-cadherin蛋白表达的关系

目的　探讨宫颈癌组织中环氧合酶 2 (COX 2 )的表达与 p5 3、E cadherin蛋白表达的关系。 方法　采用免疫组织化学S P法检测 4 1例宫颈癌和 10例正常宫颈上皮组织中COX 2、p5 3、E cadherin蛋白的表达水平。结果　宫颈癌组织中COX 2、p5 3表达水平明显高于正常宫颈上皮 (P <0 .0 1) ,而E cadherin蛋白的表达水平明显低于正常宫颈上皮 (P <0 .0 1) ;COX 2的高表达与宫颈癌淋巴结转移和浸润深度有关 (P <0 .0 5 ) ,与患者年龄、临床分期、组织学类型、分化程度无关 (P >0 0 5 ) ;COX 2表达阳性组 p5 3的表达水平明显高于COX 2表达阴性组 (P <0 0 5 ) ,COX 2表达阳性组的E cadherin蛋白的表达水平则低于相对应阴性组 ,差异有显著性 (P <0 0 5 )。结论　在宫颈癌的发生发展中COX 2、p5 3、E cadherin可能起重要作用。COX 2通过使抑癌基因p5 3失活 ,降低细胞黏附分子E cadherin的水平促进宫颈癌的发生。     

Expression of p53 protein in benign epithelial hyperplasia,atypical ductal hyperplasia,non-invasive and invasive mammary carcinoma: an immunohistochemical study

To clarify whether p53 protein expression is involved in multistep carcinogenesis or the progression of mammary ductal carcinoma, we investigated p53 protein expression in 83 invasive ductal carcinomas (IDC), 10 IDC with a predominant intraductal component, 13 non-invasive ductal carcinoma (NIDC), 16 atypical ductal hyperplasia (ADH) and 39 benign epithelial hyperplasia (EH), using immunohistochemistry. Expression of p53 protein was detected in 24 (28.9%) cases of IDC, 5 (50%) cases of IDC with a predominant intraductal component and 1 (7.6%) case of NIDC. No expression was observed in either ADH or EH. In IDC, including cases with a predominant intraductal component, p53 protein expression was associated with a higher histological grade (P<0.0001) or mitotic index (P<0.0005). Although overexpression of c-erbB-2 protein has also shown a similar association with these prognostic indicators, expression of p53 protein correlated regardless of the status of c-erbB-2 overexpression. Completely coordinated expression of p53 protein was seen in both intraductal and invasive components. The intraductal component in IDC including cases with a predominant intraductal component which expresses p53 protein had significantly higher histological grade (P<0.0005) or more comedo-subtypes (P<0.0001). These results suggested that p53 protein expression occurs at a stage of NIDC with high histological grade or in comedo-subtypes. Its expression is maintained throughout invasion.     

Absence of TP53 alterations in pheochromocytomas and medullary thyroid carcinomas

The role of the TP53 gene in the development of inherited and sporadic pheochromocytomas and medullary thyroid carcinomas (MTC) has not been clarified because of conflicting reports and limitations in the assays used to detect mutations. To determine the frequency of TP53 alterations in these tumors, 22 pheochromocytomas and 29 MTCs were screened for loss of heterozygosity (LOH) on 17p with four markers. Single-strand-conformation-variant (SSCV) analysis of exons 4–9 of the TP53 gene was performed in 20 of the pheochromocytomas and in 22 of the MTCs. The expression of p53 was determined by immunohistochemistry in 19 pheochromocytomas and in 17 MTCs using two antibodies (D01 and D07) on frozen and paraffin-embedded tissues. Four of the 22 pheochromocytomas and none of the MTCs showed LOH on 17p. No mutations were detected in any of the tumors screened by SSCV analysis. Immunohistochemical staining of frozen and paraffin-embedded tumor sections did not show p53 overexpression in any of the tumors examined. Our findings indicate that mutations in the TP53 gene are an uncommon event in the tumorigenesis of pheochromocytomas and medullary thyroid carcinomas. Genes Chromosom. Cancer 20:24–29, 1997. © 1997 Wiley-Liss, Inc.     

p53 Mutation and overexpression in hepatocellular carcinoma and dysplastic nodules in the liver

 In hepatocarcinogenesis, both de novo and multistep pathways have been suggested and in the latter a dysplastic nodule is the proposed precancerous lesion. In this study, we tried to ascertain whether or not the p53 gene is altered in low-grade/high-grade dysplastic nodules (LDN/HDN) and to determine the role of p53 alteration in multistep hepatocarcinogenesis. Eight hepatocellular carcinomas (HCCs), 9 HDNs, 17 LDNs and 25 cirrhotic nodules (LCs) were examined by polymerase chain reaction-single strand conformation polymorphism/direct sequencing and immunohistochemical staining for p53. Four of the 8 HCCs (50%) revealed p53 overexpression and 2 (25%) had missense mutations. Four of the 9 HDNs (44%) showed weak and/or focal p53 overexpression but none had mutation in the exons examined. Neither p53 overexpression nor mutation was found in 17 LDNs and 25 LCs. These results suggest that p53 mutation might be an unusual event in precancerous lesions of multistep hepatocarcinogenesis (DN-HCC sequence) and may play a less crucial part than in colorectal carcinogenesis. Received: 8 April 1997 / Accepted: 2 July 1997     

Relationship between human papillomavirus infection and overexpression of p53 protein in cervical carcinomas and lymph node metastases

Overexpression of p53 protein is common in cervical carcinoma. We investigated archival biopsies from 26 cervical cancer patients (24 with available lymph nodes) to determine the relationship between p53 overexpression and HPV infection at the cervix and lymph nodes. Twelve cervical carcinoma patients had p53 protein in cervical biopsies detectable by immunohistochemistry using monoclonal antibody DO-1, and 22 were positive for HPV DNA in polymerase chain reaction assays (16 contained HPV-16; 3, HPV-18; and, 3 HPV-X). Seven cervical cancer patients had one or more lymph nodes positive for p53 protein, and all but one of these were concordantly p53 positive at the cervix. However, detection of p53 protein in cervical biopsies was predictive neither of the expression of p53 at draining lymph nodes (P > 0.1) nor of the occurrence of metastases (P > 0.1). Fourteen patients were positive at one or more lymph nodes for HPV DNA. Cervical positivity for HPV DNA was associated significantly with concordant HPV positivity at the lymph nodes (P = 0.039) and was predictive of metastases (P = 0.019). There was no association between positivity for p53 and for HPV DNA at primary cervical carcinomas or at the lymph nodes (all P > 0.1). We conclude that, although detectable p53 protein is a common feature of cervical carcinomas, it is not predictive of metastases and is independent of HPV infection. J. Med. Virol. 53:111–117, 1997. © 1997 Wiley-Liss, Inc.     

In vivo patterns of Bcl-2 family protein expression in breast carcinomas in relation to apoptosis

The expression of the pro-apoptotic proteins (Bax, Bak) and anti-apoptotic proteins (Bcl-2, Bcl-X, Mcl-1) was studied by immunohistochemistry in 110 invasive ductal breast carcinomas. The results were correlated with tumour grade, expression of oestrogen receptor (ER) and p53 protein, and the apoptotic index by combined morphology, immunohistochemistry, and a terminal UTP nick end labelling (TUNEL) procedure. Overall, Bcl-2, Bcl-X, Mcl-1, Bax, Bak, ER, and p53 were detected in 62, 75, 68, 75, 60, 68 and 26 per cent of the cases respectively, but at different levels in each case. A high apoptotic index was correlated with high tumour grade (p < 0·001), overexpression of p53 (p < 0·001), Bak expression (p < 0·001), and low expression of Bcl-2 (p < 0·001) and ER (p < 0·001). No correlation was found between the apoptotic index and Bax, Bcl-X, and Mcl-1 immunostaining results. The expression of Bcl-2 and Bcl-X was correlated to that of ER. Overall, the results of this study strongly suggest that Bcl-2 and Bak expression is critical in regulating apoptosis in breast carcinomas. Copyright © 1999 John Wiley & Sons, Ltd.     

Analysis of p53 and mdm2 proteins in malignant fibrous histiocytoma in absence of gene alteration: prognostic significance

TP53 and MDM2 genes and their protein expression were evaluated in frozen and paraffin-embedded tissue from 27 patients with malignant fibrous histiocytoma to elucidate the relationship between them, their implication in tumor progression mechanisms and their possible diagnostic-prognostic value in malignant fibrous histiocytoma. Single-strand conformation polymorphism analysis and direct sequencing of polymerase chain reaction-amplified DNA were used to establish two TP53 mutations (7.4%): a point mutation and a 63-bp duplication. Amplification of the MDM2 gene was observed in two tumors (7.4%) by means of Southern-blot analysis, one of them also carrying the TP53 point mutation. Immunohistochemical and Western-blot techniques were used to study nuclear accumulation of p53 and mdm2 proteins: 11 cases (40.7%) with p53 protein expression and thirteen cases (48.1%) with mdm2 protein expression were detected. We confirmed overexpression of mdm2 protein in eight of ten cases (80%) with p53 protein expression without TP53 gene mutation. Statistical analysis shows that simultaneous co-expression of p53 and mdm2 in malignant fibrous histiocytoma is significantly correlated with survival in absence of gene alteration in contrast to the lack of statistical correlation with survival of p53 protein expression alone. Received: 13 April 1999 / Accepted: 14 July 1999     

p21WAF1/Cip1 is associated with cyclin D1CCND1 expression and tubular differentiation but is independent of p53 overexpression in human breast carcinoma

p21^WAF1/Cip1 is an inhibitor of cdk/cyclin complexes, and thus regulates the cell cycle. p21 is also related to cell differentiation and is regulated by wild-type p53, although p53-independent regulatory pathways have been proposed. In order to analyse p21 expression as well as its relationship with p53 in human breast cancer, an immunohistochemical analysis was undertaken of 77 breast carcinomas, 16 of them with an in situ component; 30 adjacent normal tissue samples; and five non-neoplastic specimens. Forty-four infiltrating carcinomas (57 per cent) were p21-positive. Expression of p21 was also observed in pre-invasive lesions, whereas normal ducts were negative or focally and weakly positive. p21 expression was associated with high histological grade (II+III) (P-0·017) and poor tubule formation (P-0·002), and was significantly less frequent in lobular carcinomas (P-0·0001). p21 positivity also correlated with increased proliferation, but this seemed to be dependent on the histological grade. Twenty carcinomas (26 per cent) showed p53 overexpression, but this was not associated with p21 negativity, suggesting the existence of p53-independent mechanisms for p21 regulation in vivo. Cyclin D1^CCND1 expression was analysed in the same series and an association between p21 and cyclin D1 expression was found, since 23 of 26 cyclin D1-positive carcinomas were p21-positive (P<0·001 …). In conclusion, p21 is frequently overexpressed in breast carcinomas and this occurs in the early stages of neoplastic progression. This overexpression seems to be independent of p53 status and might be involved in cyclin D1 modulation. © 1998 John Wiley & Sons, Ltd.     

P53 overexpression and Epstein-Barr virus infection in undifferentiated and squamous cell nasopharyngeal carcinomas

We have analysed 22 nasopharyngeal carcinomas (NPCs) for expression of the small nuclear Epstein-Barr virus (EBV)-encoded RNAs (EBERs) and for immunohistologically detectable overexpression of p53. in situ hybridization demonstrated expression of the EBERs in 13 undifferentiated NPCs while nine squamous cell NPCs were EBER-negative. These results therefore confirm our previous DNA-DNA in situ hybridization studies and demonstrate that in the nasopharynx EBV is exclusively associated with undifferentiated but not with squamous cell carcinomas. p53 overexpression was demonstrated by immunohistology in 5 of 9 squamous cell NPCs and in 9 of 13 undifferentiated NPCs. Thus, there appears to be no correlation of p53 overexpression with EBV infection. These results are unexpected in the light of previous studies demonstrating that the p53 gene in primary undifferentiated NPC is consistently in the wild-type configuration. By contrast, analyses of squamous cell carcinomas of the head and neck have demonstrated that p53 overexpression in these cases is the result of p53 gene mutation. Whilst more detailed genetic analysis is required, our results suggest that mechanisms other than mutation of the p53 gene may be responsible for the stabilization of the protein in cases of undifferentiated NPC. It is tempting to speculate that an EBV-encoded protein may be involved.     

Correlation of p53 protein expression with apoptotic incidence in colorectal neoplasia

The wild-type p53 gene suppresses cell proliferation and induces apoptosis when it is transfected into human colon cancer cell lines. Therefore, mutation of the p53 gene, which correlates closely with p53 protein overexpression, would be predicted to activate cell proliferation and limit apoptosis. We tested this hypothesis by correlating p53 protein expression with cell proliferation and apoptosis in 70 neoplasms (29 adenomas and 41 carcinomas) using p53 and Ki-67 immunohistochemical staining and DNA nick end labelling. The p53 immunoreactivity was independent of the Ki-67 positivity. The apoptotic incidence was less frequent (P<0.005) in tumours with diffuse p53 protein overexpression than in those with the sporadic overexpression, defined as p53 staining of isolated or scattered expression. In addition, apoptotic incidence only correlated directly (P<0.05) with Ki-67 positivity in tumours with sporadic p53-protein expression. These results indicate that p53 protein that is expressed sporadically in colorectal neoplasms is probably wild-type protein and induces apoptosis in response to active cell proliferation. In contrast, diffusely overexpressed p53 protein in colorectal neoplasms is probably mutant and correlates with a reduction in apoptotic cell death independently of cell proliferation.     

Simultaneous loss of E-cadherin and catenins in invasive lobular breast cancer and lobular carcinoma in situ

Loss of expression of the intercellular adhesion molecule E-cadherin frequently occurs in invasive lobular breast carcinomas as a result of mutational inactivation. Expression patterns of E-cadherin and the molecules comprising the cytoplasmic complex of adherens junctions, α-, β- and γ-catenin, were studied in a series of 38 lobular breast carcinomas with known E-cadherin mutation status. The effect of loss of E-cadherin by mutational inactivation (or other mechanisms) on the expression of catenins was investigated. Complete loss of plasma membrane-associated E-cadherin expression was observed in 32 out of 38 invasive lobular carcinomas, for which in 21 cases a mutation was found in the extracellular domain of E-cadherin. In total, 15 frameshift mutations of small deletions or insertions, ranging from 1 to 41 bp, three non-sense mutations, and three splice mutations were identified. Mutations were scattered over the whole coding region and no hot spots could be detected. In all cases, simultaneous loss of E-cadherin and α- and β-catenin expression was found; in 50 per cent of these cases, additional loss of γ-catenin was observed. In six invasive lobular carcinomas, expression of both E-cadherin and catenins was retained. In none of these carcinomas was an E-cadherin mutation detected. Lobular carcinoma in situ adjacent to invasive lobular carcinoma showed simultaneous loss of E-cadherin and catenins in all the cases studied—remarkably, also, in four cases positive for E-cadherin and catenin expression in the invasive component. These results indicate that simultaneous loss of E-cadherin and α-, β- and γ-catenin may be an important step in the formation of lobular carcinoma in situ, as a precursor of invasive lobular breast cancer. Events additional to E-cadherin inactivation must be involved in the transition of lobular carcinoma in situ to invasive lobular carcinoma. © 1997 John Wiley & Sons, Ltd.     

TP53 mutations are associated with a particular pattern of genomic imbalances in breast carcinomas

TP53 mutations play an important role in the development of several cancers and are present in 20-40% of all breast carcinomas, contributing to increased genomic instability. In order to address the relationship of mutated TP53 to genomic complexity, the present study analysed 61 breast carcinomas for TP53 mutations and compared mutation status with the pattern of genomic imbalances as assessed by comparative genomic hybridization (CGH). Twenty per cent of the present series of breast carcinomas harboured TP53 mutations. An increasing number of abnormalities, as identified by CGH (higher genomic complexity), correlated significantly with mutant TP53. Among the chromosome arms most commonly altered (in more than 20% of the tumours), loss of 8p and gain of 8q were associated with TP53 mutations, whereas loss of 16q was associated with wild-type TP53. By performing supervised hierarchical clustering analysis of the CGH data, a cluster of chromosome imbalances was observed that showed differences between wild-type and mutant TP53 cases. Among these, loss of chromosome arm 5q revealed the strongest correlation with altered TP53. To investigate further the most commonly deleted region of 5q, gene expression patterns from two publicly available microarray data sets of breast carcinomas were evaluated statistically. The expression data sets identified potential target genes, including genes involved in ubiquitination and the known TP53 target CSPG2. The genomic complexity of breast carcinomas as assessed by CGH is associated with TP53 mutation status; breast cancers with TP53 mutations display more complex genomes than do those with wild-type TP53. The pattern of genomic imbalances associated with mutant TP53 is non-random, with loss of chromosome arm 5q being particularly closely associated with TP53 mutations.     

Abnormalp53 immunoreactivity and prognosis in node-negative breast carcinomas with long-term follow-up

Summary The expression of thep53 gene product was investigated immunocytochemically in a retrospective series of 164 formalin-fixed paraffin-embedded invasive breast carcinomas with pathologically proven negative lymph nodes. Overall, 78 tumors (48%) showed a variable degree ofp53 immunoreactivity. Among these, 38 cases were low expressors (1–10%p53 immunoreactive tumor cells), 21 moderate expressors (10–50% immunoreactive cells) and 19 high expressors (> 50% immunoreactive cells). Abnormalp53 expression correlated significantly with tumor size, histological and nuclear grade, DNA ploidy, mitotic rate and proliferation index, and with the lack of estrogen receptors. Disease-free and adjusted survival analysis of the 124 node-negative patients with long term (more than 10 years) follow-up, however, did not reveal an independent prognostic role for p53 expression. These data suggest that the evaluation ofp53 immunoreactivity may only play a role in a multiparametric prognostic assessment of node-negative breast carcinoma.     

The biological and clinical value of p53 expression in pelvic high‐grade serous carcinomas

Studies on the p53 expression and outcome for women with ovarian carcinoma have produced conflicting results. The observed heterogeneity may be due to the range of cut‐offs used to define overexpression and the mix of histotypes of the study cohorts. We aimed to examine the association between p53 expression and biological properties of tumours as well as outcome in 502 pelvic high‐grade serous carcinomas (HGSCs) derived from two population‐based cohorts from British Columbia representing cases with or without residual tumour after initial surgery, respectively, and one clinical trial cohort from Germany (AGO‐OVAR‐3). p53 expression was assessed on tissue microarrays by immunohistochemistry using the DO‐7 antibody. p53 expression was scored in three tiers as complete loss of expression, focal expression or overexpression (defined as more than 50% positive tumour cell nuclei) and correlated with survival using multivariate Cox regression models. p53 was completely absent in 30.3%, focally expressed in 12.0%, and overexpressed in 57.7% of HGSCs, which was an inverse pattern compared to clear cell and endometrioid types of ovarian carcinomas, where 76% and 69% of cases showed focal expression, respectively (p < 0.001, chi square test). Pelvic HGSCs show either complete absence of p53 expression or p53 overexpression in 88% of cases; thus, aberrant p53 expression is a ubiquitous feature of HGSCs. HGSCs with p53 overexpression were associated with a reduced risk of recurrence compared to cases with complete absence of p53 in the British Columbia cohort with residual tumour (HR = 0.71, 95% CI 0.51–0.99) and for a combination of all three cohorts (HR = 0.70, 95% CI 0.55–0.89) in multivariate analysis including age, stage, residual tumour, and stratification by cohort. The association of complete absence of p53 expression with unfavourable outcome suggests functional differences of TP53 mutations underlying overexpression, compared to those underlying complete absence of expression. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.