Immunohistochemical analysis of p53 and MIB-1 in tissue specimens obtained from endoscopic ultrasonography-guided fine needle aspiration biopsy for the diagnosis of solid pancreatic masses

Endoscopic ultrasonography-guided fine-needle aspiration biopsy (EUS-FNAB) has been shown to be a highly accurate technique for distinguishing benign from malignant pancreatic masses. In this study, we examined p53 immunohistochemical analysis in FNAB specimens obtained from solid pancreatic diseases, and prospectively evaluated clinical applications for the diagnosis of malignancy in combination routine histological examination. Tissue specimens obtained from 62 pancreatic masses (51 pancreatic cancers and 11 chronic pancreatitis) by EUS-FNAB were evaluated by routine histological examination and p53 immunostaining. The conventional EUS-FNA diagnostic test statistics for the pancreatic masses were as follows: 76% sensitivity, 91% specificity and 79% accuracy. p53 protein overexpression was observed in 67% patients with pancreatic cancer, but not in patients with chronic pancreatitis. If the diagnosis of malignancy was made using the combination of p53 protein overexpression and conventional histological examination, the diagnostic test statistics changed as follows: 90% sensitivity, 91% specificity and 92% accuracy. p53 immunostaining in combination with routine histological examination of EUS-FNAB may improve the diagnostic accuracy for pancreatic cancer.     

Overexpression of p53 protein in gallbladder carcinoma in North India.

AIMS: p53 mutations are one of the most frequent genetic alterations in human cancers and are thought to play a role in pathogenesis of several malignancies. Overexpression of p53 in gallbladder cancer has not previously been reported from North India which has one of the highest incidence of this malignancy in the world. The present work is aimed at studying the overexpression of p53 in gallbladder carcinoma occurring in North India. METHODS: p53 overexpression by immunohistochemistry was studied in 20 operative specimens of gallbladder carcinoma. The clinico-pathological observations of these patients were correlated with the extent of p53 overexpression. RESULTS: Seventy per cent (14/20) of specimens of gallbladder carcinoma overexpressed p53 protein. There was a significant correlation between presence of gallstones, T stage, grade of tumour and liver invasion with p53 overexpression. There was no significant correlation with other factors studied viz. age, sex, nodal status and histological type. CONCLUSIONS: The results show a strong association between gallstones and p53 protein overexpression in gallbladder carcinoma. The causal relationship in this association, however, still remains unproven.     

Overexpression of p53 in prostate carcinoma is associated with improved overall survival but not predictive of response to radiotherapy

p53 gene mutations are among the most common specific genetic alterations in human cancer. Inactivation of p53 and subsequent protein accumulation has been implicated in a variety of human malignancies and associated with prostate cancer progression. In this study, we assessed p53 protein overexpression and gene mutations in prostate carcinoma and investigated associations between p53 alterations and clinicopathological parameters, survival, and response to radiotherapy. We evaluated 58 archival formalin-fixed, paraffin-embedded prostate carcinomas to detect abnormal p53 nuclear protein accumulation using immunohistochemistry. p53 mutational status of tumor DNA was evaluated using polymerase chain reaction-single-strand conformation polymorphism analysis of exons 5-9 and confirmed by direct DNA sequencing. Univariate and multivariate statistical analysis was used to determine the association of p53 status with clinical characteristics and response to radiotherapy. Overexpression of p53 was detected in 42 (72%) of 58 primary prostate carcinomas, but was undetectable in 7 samples of benign prostatic hyperplasias or 5 samples of normal prostate tissue. p53 exon 5-9 mutations were detected in 8 (14%) of 58 patient specimens. p53 mutational status, but not overexpression, was associated with higher Gleason scores (p=0.0145). Neither p53 overexpression nor mutation was associated with clinical stage, biochemical disease-free probability, or predictive of response to radiotherapy. p53 protein accumulation was inversely associated with improved overall survival (p=0.0108). Our studies demonstrate that p53 protein accumulation is a frequent alteration in prostate cancer. The disparity between p53 protein overexpression and p53 exon 5-9 mutations suggests the possibility of mutations outside this region or stabilization of wild-type p53 by alternative mechanisms. In our patient population, p53 protein overexpression or mutational status was not predictive of outcome in patients treated with radiation therapy. Additional studies are needed to further evaluate the association between p53 protein overexpression and improved overall survival.     

P53蛋白在胰腺癌与癌旁组织中表达的临床意义

目的：了解胰腺癌及其癌旁组织的ｐ５３蛋白表达，并分析其临床意义。方法：作者对３６例胰腺导管癌、２５例胰腺癌旁组织、１０例慢性胰腺炎和１２例正常胰腺组织石蜡标本进行ｐ５３单抗的免疫组化染色。结果：３６例胰腺癌和２５例癌旁组织中呈ｐ５３蛋白阳性染色分别为２１例（５８％）和１１例（４４％），且其阳性率间有显著相关性。（Ｐ＜０．０１）。而慢性胰腺炎和正常胰腺组织均未见ｐ５３蛋白阳性染色，与胰腺癌和癌旁组织ｐ５３阳性率间均有显著差异（Ｐ＜０．０１）。不同临床分期及组织学分型胰腺癌，ｐ５３蛋白阳性染色率间无显著差异。结论：ｐ５３蛋白的表达与胰腺癌的发生有关；胰腺癌旁组织中某些细胞呈ｐ５３阳性染色，这些细胞可能较易发生癌变，使胰腺癌呈多中心性发生。     

Association of overexpression of tumor suppressor protein p53 with rapid cell proliferation and poor prognosis in node-negative breast cancer patients.

BACKGROUND: Recent evidence indicates that a subset of axillary node-negative (ANN) breast cancer patients can benefit from adjuvant therapy. Reliable prognostic markers are needed, however, to help clinicians identify these patients and arrive at more rational treatment decisions. PURPOSE: Mutations of the p53 tumor suppressor gene often result in overexpression of the p53 protein. In this study, we evaluated the prognostic significance of p53 protein overexpression in patients with ANN breast cancer. We also studied the association between the tumor cell proliferation rate and overexpression of the p53 and c-erbB-2 proteins, both of which have been implicated in cell cycle control. The c-erbB-2 protein is the product of the ERBB2 gene. METHODS: Two hundred eighty-nine ANN cases were randomly selected from a population-based cohort of patients who had not received any kind of adjuvant chemotherapy or endocrine therapy. Overexpression of the p53 and c-erbB-2 proteins was studied immunohistochemically in archival paraffin-embedded tumor samples, using the CM-1 polyclonal and the TAb 250 monoclonal antibodies, respectively. The tumor cell proliferation rate was measured as the S-phase fraction by DNA flow cytometry. Statistical analyses were performed using BMDP software. RESULTS: High-level p53 protein overexpression, found in 41 of the 289 tumors, was most common in tumors with high histologic grade, negative estrogen receptor status, c-erbB-2 protein overexpression, DNA index greater than 1.3, or high S-phase fraction. The lowest S-phase levels were found in tumors with neither p53 nor c-erbB-2 protein overexpression; the highest levels were seen in tumors showing overexpression of both proteins (P less than .0001). Both p53 and c-erbB-2 overexpression, as well as tumor size, had independent prognostic value in multivariate analysis. Eight-year survival of patients with p53 protein overexpression was 56% compared with 81% in patients with no overexpression (relative risk, 3.7; P less than .0001). If the S-phase fraction was included in a Cox regression analysis, however, only the tumor size and the S-phase fraction emerged as independent predictors of survival. CONCLUSIONS: Overexpression of the p53 and c-erbB-2 proteins indicates a high malignant potential in ANN breast cancer, but it is not a significant prognostic factor independent of the cell proliferation rate. The correlation between overexpression of these proteins and an increased S-phase fraction suggests that they may confer a proliferative advantage to cancer cells in vivo.     

Cytology vs molecular analysis for the detection of head and neck squamous cell carcinoma in oesopharyngeal brush samples: a prospective study in 56 patients

Oesopharyngeal brush (OPB) sampling with cytological analysis can yield exfoliated cells from asymptomatic tumours of the upper aero-digestive tract and the oesophagus. In this study, we compared cytological evaluation and molecular analysis for the detection of exfoliated cancer cells sampled with an OPB. A total of 56 patients with a known unique head and neck squamous cell carcinoma (HNSCC) and five healthy controls were enrolled prospectively. Exfoliated cells from these 61 patients were collected with an OPB before initial endoscopy. p53 mutations and UT 5085 microsatellite instability (MI) were analysed in the HNSCC tumour, lymphocytes and the corresponding OPB DNA samples. p53 mutations and UT5085 MI were detected in 31 out of 56 and 14 out of 56 HNSCC, respectively, but not in any of the five controls. Direct sequencing of p53 was able to detect mutations in OPB DNA in only two out of 29 patients harbouring a p53-mutated primary tumour. Microsatellite instability was detected in OPB DNA of 11 out of 13 informative (bandshift detected in tumour) patients, whereas cytological analysis detected abnormal cells in only six of the same 13 patients (P=0.03). In informative patients, all positive OPB samples at cytological analysis were also positive at molecular analysis of UT5085, and both analyses confirmed the two negative samples. Molecular analysis of OPB from eight uninformative patients and from five healthy controls were all negative. OPB sampling with MI-based molecular analysis could be efficient for early detection of recurrent HNSCC. This result prompts us to use other microsatellite markers in order to maximise the percentage of informative patients.     

Correlation p53 expression and human papilloma virus deoxyribonucleic acid with clinical outcome in early uterine cervical carcinoma

BACKGROUND: In the present study we assessed whether expression of p53 protein or HPV DNA correlates with recurrence as well as several known prognostic factors in uterine cervical carcinoma. METHODS: Forty-nine patients with FIGO stage IA-IIB who underwent hysterectomy between 1998 and 2002 were retrospectively studied. All 49 cancer tissue samples were used for immunohistochemical study. Twenty-five of 49 cases were also examined by PCR-RFLP for detection and typing of HPV DNA. RESULTS: Twenty of 49 (40.8%) specimens demonstrated nuclear staining for p53. A significant association between p53 overexpression and age, hormonal status, FIGO stage, or recurrence was observed (p=0.02, 0.01, 0.03, 0.01). However, no significant association was found between p53 overexpression and lymph node metastases, parametrium involvement, or risk of death (p=0.18, 0.06, 0.14). Nineteen of 25 (76%) were HPV DNA-positive and 6 (24%) were negative. Discussion: There was no relation between HPV DNA positivity and age, FIGO stage, lymph node metastases, parametrium involvement, recurrence, or risk of death. CONCLUSION: p53 overexpression is associated with age, hormonal status, FIGO stage, and recurrence in uterine cervical carcinoma.     

Detection of serum p53 protein in patients with different gastrointestinal cancers

Overexpression of p53 has been found in many types of human malignancy. The present study aimed to detect preoperative serum p53 among 158 patients with different gastrointestinal cancers using ELISA technique based on mouse anti-p53 DO-7 monoclonal antibody and anti-p53 rabbit polyclonal antibody. A single band of 53kDa was detected in nuclear protein tissue extracts of selected cancer patients and in 96% of the corresponding sera using Western blot assay. The ELISA technique revealed that the serum p53 was detected in 100% of patients with cholangiocarcinoma, 76% of pancreatic carcinoma, 75% of hepatocellular carcinoma, 70% of colon cancer, 60% of esophagus carcinoma, and 35% of gastric carcinoma. The serum p53 concentrations of the positive patients were highly elevated (P<0.001) compared with healthy individuals. These results suggest that immunodetection of serum p53 could be valuable for post-operative monitoring during follow up in preoperatively positive patients with gastrointestinal cancers.     

Mutational spectra of p53 in geographically localized esophageal squamous cell carcinoma groups in China

BACKGROUND: Esophageal carcinoma is a particularly interesting tumor because of the dramatic difference in its incidence and geographic distribution among populations of similar ethnic origin. Epidemiologic data have suggested that many environmental exposures may be associated with an increased risk of its formation. METHODS: In this study, 92 samples of esophageal squamous cell carcinoma (ESCC) were collected from patients who resided in 2 geographic areas in China with different incidences of ESCC: Linxian and Zhejiang. Overexpression and mutations of the p53 tumor-suppressor gene were examined by using immunohistochemistry, single-strand conformation polymorphism analysis, and direct sequencing. RESULTS: The rates of point mutation and overexpression of p53 in the ESCC specimens studied were 30.4% (29 of 92 specimens) and 51.1% (47 of 92 specimens), respectively. The overexpression of p53 was associated with tumor metastasis and with 5-year case fatality. Significant differences were found in the rates of overexpression and mutations in patients with clinical T2 tumors between the specimens from Linxian, which is a high-incidence geographic area, and the specimens from Zhejiang, which is a low-incidence area. Furthermore, different mutational spectra were found in the tumor samples from these two geographic areas: In tumor samples from Linxian, the most common substitution mutation was a transversion in exon 5, whereas the most common mutations in tumor samples from Zhejiang were transitions in exon 7. CONCLUSIONS: The data suggest that the mutation and overexpression of p53 may play important roles in the development of ESCC. The changes in p53 may reflect environmental exposure to the different combinations of mutagenic factors and genetic instability demonstrated by the populations in Linxian and Zhejiang. The overexpression of p53 protein may have significance as a prognostic factor for patients with esophageal carcinoma.     

Mutant p53 protein overexpression in women with ipsilateral breast tumor recurrence following lumpectomy and radiation therapy

BACKGROUND: The p53 tumor suppressor gene encodes a nuclear phosphoprotein that is thought to be important to cell cycle regulation and DNA repair and that also may regulate induction of apoptosis by ionizing radiation. Somatic p53 gene mutations occur in 30-50% of breast carcinomas and are associated with poor prognosis. Mutations in the p53 gene result in prolonged stability of the protein that can be detected by immunohistochemical techniques. In a matched case-control study of breast carcinoma patients with ipsilateral breast tumor recurrence (IBTR) following lumpectomy and radiation therapy, the authors investigated the frequency and prognostic significance of somatic p53 mutations as well as the clinical characteristics of patients with these mutations. METHODS: Between 1973 and 1995, there were 121 breast carcinoma patients with IBTR following lumpectomy and radiation therapy, and the authors identified 47 patients in whom the paraffin embedded tissue blocks from the primary breast tumors were available for further molecular analysis. Forty-seven control breast carcinoma patients from the breast carcinoma data base were individually matched to the index cases who did not have IBTR for age, treatment date, follow-up, histology, margin status, radiation dose, and adjuvant treatment. Immunohistochemistry using a monoclonal antibody to mutant p53 protein was used to determine mutant p53 protein overexpression in breast tumors and appropriately scored. RESULTS: A total of 12 of 47 tumor specimens (26%) from index patients with breast tumor relapses demonstrated mutant p53 protein overexpression, whereas only 4 of 47 specimens from controls (9%) demonstrated high mutant p53 immunoreactivity (P = 0.02). The authors found that 9 of 23 patients (39%) with early breast tumor recurrences (recurrences within 4 years of diagnosis) had overexpression of mutant p53 protein, whereas only 1 of 23 control cases (4%) had high mutant p53 protein immunoreactivity (P = 0.003). In contrast, index cases from patients with late breast tumor relapses (more than 4 years after diagnosis), which are more likely to represent de novo breast tumors, and control cases from the breast carcinoma data base without IBTR had similar levels of mutant p53 protein overexpression (P = not significant). The 10-year distant disease free survival for patients with mutant p53 protein was 48%, compared with 67% for breast carcinoma patients without detection of mutant p53 protein (P = 0. 08). The authors found that 13 of 14 primary breast tumors (93%) with mutant p53 protein overexpression were estrogen receptor negative (P = 0.01) and 11 of 14 (79%) were progesterone receptor negative (P = not significant). CONCLUSIONS: In a matched case-control study, overexpression of mutant p53 protein has prognostic significance with respect to IBTR following lumpectomy and radiation therapy. Breast tumors with p53 mutations are generally estrogen receptor negative and are associated with compromised distant disease free survival.     

p53 overexpression as a prognostic factor for advanced stage bladder cancer

Overexpression of the TP53 gene protein detected by immunohistochemistry appears to identify those patients with superficial bladder cancer at risk of the development of muscle invasive or metastatic disease. However, the role of p53 overexpression in patients with advanced or metastatic bladder cancer is not yet well established. In the present study, 44 specimens from 44 patients with advanced stage bladder tumours (T₂–T₄) undergoing radical cystectomy were investigated for different biological and clinical characteristics as possible prognostic factors: sex, age, depth of tumour infiltration, T-stage, histological grade, lymph node status, application of adjuvant systemic chemotherapy (MVAC), proliferative activity (staining for proliferating cell nuclear antigen (PCNA) by monoclonal antibody (PC10) as well as overexpression of the p53 oncoprotein (monoclonal antibody pAb 1801)). After a median follow-up of 22 months, 16 of the 23 patients (70%) with more than 40% of tumour cells stained positively for p53 (Group B) died from tumour progression compared with 7 of the 21 patients (33%) with less than 40% of tumour cells positive for p53. During univariate analysis, p53 overexpression (P = 0.008), staining for PCNA (80% of cells positive) (P = 0.01) and tumour stage (P = 0.01) were significant prognostic factors for survival, among which p53 overexpression (P = 0.023) as well as T-stage (P = 0.012) remained independent significant predictors during multivariate analysis. Prospective studies are needed to confirm the independent prognostic potential of p53 overexpression in patients with advanced bladder cancer. The availability of more refined prognostic factors should assist decision making regarding the value of more aggressive treatment options, such as adjuvant or neoadjuvant chemotherapy, for prognostically defined subgroups of patients.     

Is there an epidemiological link between human papillomavirus DNA and basaloid squamous cell carcinoma of the pharynx?

The epidemiological link between human papillomavirus (HPV) DNA and basaloid squamous cell carcinoma (BSCC) of the pharynx was studied. The expression of p53 protein was evaluated by immunohistochemical analysis. The presence of HPV DNA was evaluated by polymerase chain reaction amplification and "in situ" hybridization. The tobacco and alcohol consumption and the clinical outcomes of nine patients with BSCC of the pharynx are compared with site and stage matched 109 conventional squamous cell carcinoma (SCC) patients. The BSCC specimens were analyzed for the presence of HPV DNA and p53 expression. We did not find any significant differences in tobacco and alcohol consumption between patients with BSCC and patients with SCC. No HPV DNA was detected in BSCC, and p53 overexpression was found in five (55%) of the cases. Our results do not support an etiological link between HPV DNA and BSCC.     

Predictive value of Ki-67, p53 protein, and DNA content in the diagnosis of gastric carcinoma.

BACKGROUND: The ability to make a precise preoperative diagnosis is a valuable and effective method in improving the prognosis of patients with gastric carcinoma. The authors examined retrospectively whether preoperative histopathologic analysis with p53 protein, Ki-67 labeling index, and DNA ploidy along with preoperative radiographic and endoscopic findings led to a precise preoperative diagnosis of patients with gastric carcinoma. METHODS: Histopathologic analysis of p53 protein, Ki-67 labeling index, and DNA content was performed on formalin fixed, paraffin embedded tissue. Tissue sections from endoscopic and surgically resected specimens were stained immunohistochemically for p53 protein and Ki-67 labeling index, and the cell nuclear DNA content of the surgically resected primary lesion was measured using a microspectrophotometer. These analyses were performed on 16 patients with early gastric carcinoma (EGC) who were diagnosed with advanced gastric carcinoma (AGC) based on the preoperative imaging findings and on 15 patients with AGC who were diagnosed preoperatively with EGC. RESULTS: Overexpression of p53 in the AGC group was significantly more frequent compared with that in the EGC group (P = 0.0386). With regard to the correlation between lymph node metastases and p53 overexpression, there was no apparent relation in either the AGC group (P = 0.648) or the EGC group (P = 0.726). The AGC group had significantly higher Ki-67 labeling indices compared with the EGC group (P = 0.0195). There was complete concordance between endoscopic and surgically resected specimens with regard to the p53 and Ki-67 labeling index findings. DNA ploidy in the primary tumor did not differ between the AGC and EGC groups. The survival rates for the EGC group were significantly superior to those for the AGC group (P = 0.0312). CONCLUSIONS: The findings of the current study suggest that in routine clinical practice, the combination of preoperative imaging findings in addition to Ki-67 labeling indexes, and p53 protein analyses may be useful for the accurate diagnosis of EGC; however, DNA ploidy did not appear to reflect the growth potential of gastric carcinoma.     

Frequent overexpression of STK15/Aurora-A/BTAK and chromosomal instability in tumorigenic cell cultures derived from human ovarian cancer

The STK15 (also known as Aurora-A/BTAK) gene localized on chromosome 20q13 and encoding a centrosome-associated serine/threonine kinase is amplified and overexpressed in multiple human tumor cell types. Overexpression of this gene is involved in tumorigenic transformation, induction of centrosome duplication-distribution abnormalities, and aneuploidy in mammalian cells. To examine the potential role of STK15 in ovarian tumorigenesis, its mRNA and protein expression status were examined in cells grown in culture from 15 ovarian cancer specimens using semiquantitative RT-PCR and Western blot analysis. Normal ovarian surface tissues and the near diploid nontumorigenic breast epithelial cell line MCF10 were used as controls. The status of STK15 correlated with transformation-associated cellular phenotypes including tumorigenicity in nude mice, p53 expression level, and chromosomal ploidy. For chromosome ploidy analyses, FISH was carried out with direct fluorescence-labeled a-satellite probes for chromosome 3 and 17. STK15 mRNA was found overexpressed in 10 of the 15 ovarian cancer cell cultures. Five of these cell cultures revealed a truncated form of the STK15 protein with a molecular mass of 36 kDa. When tested for tumorigenicity in nude mice, 9 of the 10 cell cultures that overexpressed STK15 mRNA formed tumors in nude mice, while only one of the five cell cultures with no overexpression did. Cells overexpressing STK15 mRNA showed significant correlation with chromosome 3 polysomy. Six of the 13 (46%) cell cultures analyzed for p53 expression revealed overexpression of p53 and five of these six (83%) also overexpressed STK15. Four of the remaining seven cultures (57%) with overexpression of STK15 revealed minimal or no expression of p53. These results demonstrate that overexpression of STK15 significantly correlates with nude mice tumorigenicity and chromosomal aneuploidy in human ovarian cancer cells grown in vitro. Additionally, cells overexpressing STK15 also revealed frequent coordinate loss of wild-type p53 function manifested either as highly expressed intense staining reflective of a mutant form of p53 or almost complete absence of p53 staining. Overexpression of STK15 with coordinate loss of wild-type p53 function thus appears to play an important role in ovarian tumorigenesis and offers a novel molecular target in designing effective therapy of human ovarian cancer.     

Prevalence of p53 overexpression or mutations, but not k-ras mutations, in recurrent patients affected by colorectal-carcinoma

In order to establish prognostic indicators of poor clinical evolution in colorectal cancer, we have studied p53 abnormalities and K-ras mutations in 65 patients affected by colorectal carcinoma who had undergone radical surgery. A single event of p53 protein overexpression or p53 mutation, but not K-ras mutation, was significantly prevalent in recurrent tumors. A double event of K-ras mutation and p53 protein overexpression was prevalent in patients showing Dukes' stage C, but showed a lack of prevalence in patients who recurred. The presence of p53 protein overexpression does not assure an underlying mutation in colorectal carcinoma.     

Prognostic value of overexpression of p53 in human ovarian carcinoma patients receiving cisplatin

A major obstacle to the treatment of ovarian carcinoma is intrinsic/acquired resistance to cisplatin-based chemotherapy. The clinical significance of p53 overexpression in patients with ovarian carcinoma is still controversial. The aim of this study was to investigate the independent prognostic significance of p53 overexpression in patients with ovarian carcinoma who are treated with cisplatin. We retrospectively examined the overexpression of p53 in primary ovarian carcinoma, and its association with chemotherapeutic efficacy. One hundred and thirty four ovarian carcinomas were surgically removed from patients who received adjuvant cisplatin-based chemotherapy. Immunohistochemical analysis of p53 was performed using a DO7 antibody against the p53 protein in 134 ovarian carcinomas. The significance of p53 in the prognosis of patients with ovarian carcinomas was also examined by a survival analysis of mortality follow-up data covering the period from 1988 to 2001. Thirty-three tumors (25%) exhibited p53 overexpression. Overexpression of p53 in grade 2/grade 3 tumors was significantly higher than that seen in grade 1 tumors (P=0.0088, 0.0229). Patients with tumors who also showed overexpression of p53 had a significantly inferior response to chemotherapy compared with the patients with p53-negative tumors (P=0.04). Cox regression analysis revealed that p53 overexpression was prognostic for poor disease outcome after adjustment for FIGO stage, grade and residual tumor. These findings suggest that overexpression of p53 in ovarian carcinoma is associated with unfavorable clinical outcome in patients treated with cisplatin-based chemotherapy. Therefore, detection of p53 overexpression using the DO7 antibody may be considered as a predictive marker of chemoresistance for cisplatin in patients with ovarian carcinoma.     

Analysis of p53 mutation and cyclin d1 expression in breast tumors

P53 and cyclin D1 are interacting regulatory genes and both are frequently altered in breast cancer. We analysed p53 mutation by SSCP and sequencing methods as well as p53 protein accumulation immunohistochemically in 34 consecutively operated breast tumors. None of 4 fibroadenomas revealed p53 mutation or p53 protein accumulation. Mutation of p53 was present in 7 carcinomas. Immunohistochemistry revealed accumulation of p53 protein in 6 carcinomas and there was a significant correlation between p53 mutation and protein accumulation. Overexpression of cyclin D1 protein was observed in 11 carcinomas by immunohistochemistry and no correlation was observed between cyclin D1 overexpression and p53 mutation or accumulation. Our data support the concept that the p53-cyclin D1 signal pathway and the cyclin D1 cascade are disregulated in breast cancer.     

The p53 tumor-suppressor gene is overexpressed but not mutated in human atherosclerotic tissue

Excessive proliferation of smooth muscle cells (SMC) in the arterial intima is thought to be a major contributing factor to the development of atherosclerosis. One of the theories put forward to explain the aberrant growth is that genetic alterations similar to those observed in cancers also occur in the SMC. Since mutations in the p53 tumour suppressor gene and the c-Ki-ras oncogene are the most common genetic alterations observed in a wide variety of tumour types, we searched for evidence of mutation in human atherosclerotic tissue. DNA was extracted from atherosclerotic plaques and screened for p53 and c-Ki-ras gene mutations using polymerase chain reaction-single strand conformation polymorphism analysis. Tissue sections were also examined for overexpression of p53 protein using an immunohistochemical technique. The molecular analysis showed that wild-type p53 and c-Ki-ms gene sequences were present in all 54 specimens examined. Overexpression of p53 protein was found in 61% of samples. Our results do not support the view that genetic alterations similar to those occurring in cancer contribute to the abnormal proliferation of SMC, although we caution that only two cancer-related genes were studied. Epigenetic changes to the gene products could play a role however, as evidenced by overexpression of p53 protein in many of the atherosclerotic specimens.