Incidence Of P53 Research Articles

Hormone receptor status (estrogen receptor, progesterone receptor), human epidermal growth factor-2 and p53 in South Indian breast cancer patients: A tertiary care center experience.

Breast cancer, in India, is the second commonest cancer in females. Receptor status with ER/PR/Her 2 is now routinely done in patients with invasive carcinoma. The tumour suppressor gene, p53, is also present in most breast cancers. Proteins produced by a mutated p53 gene, accumulate in the nucleus of tumour cells and are detected by immunohistochemistry (IHC). We have undertaken this study with the aim to evaluate the ER, PR, HER-2 and p53 expressions in invasive breast carcinomas by IHC and to compare the HER-2 expression with various clinicopathological parameters.Materials and Methods:In this retrospective single institutional study from January 2001 to December 2010, 389 cases of histopathologically diagnosed infiltrating carcinoma of breast were evaluated taking into account various parameters like age, tumour size, grade, lymph node involvement, ER and PR. HER-2 and p53 was done in 352 cases.Results:The age range was 23-90 years with a mean of 50.7 years. Majority of tumours were T2 (79.6%) and Grade II (60.9%). Our data showed overall 47.6% ER, 48.8% PR, 29.6% HER-2 and 69.2% p53 positivity. There was no significant correlation between HER-2 and age, tumour size, lymph node status, ER, and PR. There was significant correlation between HER-2 and tumour grade (P = 0.031), p53 (P < 0.001). There was no inverse correlation between HER-2 and combined ER, PR status. Triple-negative breast cancers which constituted 22.7% of our cases did not reveal any correlation with various parameters.Conclusion:In our study, ER status was low, and incidence of p53 was high. These findings suggest that many of the tumours in Indian females may be of an aggressive type, and novel treatment approaches may be tried. We conclude that the assessment of all four markers is desirable.

Immunohistochemical evaluation of p53 and Ki67 expression in skin epithelial tumors.

Background and Aims:The cellular mechanisms responsible for initiating or limiting the tumors including skin types are of great importance. The p53 is a tumor-inhibiting gene which is believed to be defective in many malignant situations. Ki67 is a non-histonic protein which is mainly interfere with the proliferation and has many controlling effects during the cell cycle. Because of their importance in skin tumor cell growth, this study aimed at evaluating the p53 and Ki67 expression in skin epithelial tumors by immunohistochemical method.Materials and Methods:In a descriptive setting, 50 biopsy samples (30 basal cell carcinomas (BCCs), 10 squamous cell carcinomas (SCCs), 8 keratoacanthomas (KAs), and 2 trichoepitheliomas (TEs)) were immunohistochemically evaluated for p53 and Ki67 expression during a 14-month period. The incidence and expression rate of these two variables were separately reported in each group of samples.Results:The expression rate of p53 was 67.77% for the BCCs, 50.20% for the SCCs, and null for the KAs. For both TEs, it was 50%. The expression rate of Ki67 was 57.33% for the BCCs, 47.70% for the SCCs, 37.5% for the KAs, and 0.0% for TEs. The incidence of P53+ cells was 100% and 90% in the BCC and SCC samples, respectively. The both TEs were positive in this regard. The incidence of Ki67+ cells was 100% for the BCC, SCC, and KA samples. The both TEs were negative in this regard.Conclusion:This study showed that the incidence rate of p53- and Ki67-positive cells is very high in skin malignant epithelial tumors. The expression rate of these two variables is comparable with reports in the literature. Further studies with large sample size are recommended to be carried out for KA and TE samples.

Burkitt lymphoma in Brazil is characterized by geographically distinct clinico-pathological features and lack of p53 mutations

Burkitt lymphoma (BL) is a highly aggressive non-Hodgkin lymphoma with a consistent MYC translocation. Epstein Barr virus (EBV) has been associated with BL at different frequencies depending on the clinical variant and geographic regions. This is a large-scale study of BL in Brazil, including 234 patients from five geographic regions that are widely disparate socioeonomically, including both the pediatric (61.1%) and adult (37.6%) populations. EBV was present in 52.5 percent of all BL cases, varying from 28.6 percent in the South to 76.4 percent in the North. Most of the cases were EBV type A. The frequency was higher in the pediatric group and EBV association within this age range predominated in all regions except the South. p53 protein expression was observed in 16.2 percent and only rare cases showed p63 expression. BL in Brazil is regionally distinct, has a low incidence of p53 over expression and a higher than expected association with EBV in sporadic cases.

Carcinoma ex pleomorphic adenoma of the salivary gland: an immunohistochemical study

The proliferative activity of the tumor cells and the expression of tumor-associated genes and sex steroid hormone receptors were investigated immunohistochemically in ten cases of carcinoma ex pleomorphic adenoma (Ca-ex-PA) of the salivary glands. These were analyzed in benign and malignant components separately, and then were compared with ten cases of the other malignant tumors [adenocarcinomas, not otherwise specified (ACN) and salivary duct carcinomas (SDC)] and ten cases of pleomorphic adenomas (PA). The results obtained in this study were as follows: (1) malignant component of Ca-ex-PA showed a higher incidence of PCNA and Ki67 than benign component of Ca-ex-PA. A significant difference between benign component of Ca-ex-PA and PA was not observed. (2) A significant difference in the incidence of p53, c-erbB-2, EGFR overexpression was observed only between malignant component of Ca-ex-PA and benign component of Ca-ex-PA. (3) The incidence of PCNA, Ki67, p53, c-erbB-2 overexpression in malignant component of Ca-ex-PA showed the highest data among the four groups. These results suggest that Ca-ex-PA acquired the particular biological behavior in contrast to the other salivary neoplasms in the long-standing process while PA undergoes malignant transformation.

Genetic status of p53 in stomach cancer: Somatic mutations and polymorphism of codon 72

The incidence of somatic mutagenesis of p53 oncosuppressor protein in malignant tumors of the stomach and genetic polymorphism of p53 were studied in patients with stomach cancer on DNA samples isolated from tumor tissues obtained during surgery. The incidence of Pro/Pro genotype increased in the patients, while the percentage of Arg/Pro heterozygotes was markedly lower compared to long-living persons without cancer. The incidence of p53 somatic mutations in exons 5, 7, 8 was 70.8%; multiple mutations were detected in half of the examined patients. The relationship between the intensity of p53 mutagenesis and histological structure of the tumor was detected. The contribution of p53 genetic status to the risk of stomach cancer can be more effectively evaluated on DNA samples isolated from not only tumor cells, but also from normal tissues. The effects of epigenetic factors determining the intensity of somatic mutagenesis of p53 in tumors should be taken into account.

Clinical significance of combination study of apoptotic factors and proliferating cell nuclear antigen in estimating the prognosis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common recurrence diseases, which affects the patient's prognosis. The aim of this report is to evaluate recurrence risk after primary treatment by the combination study with the clinical features and immunohistological findings. 153 removable HCCs were examined by immunohistochemical study of the proliferating cell nuclear antigen (PCNA), p53, or Bax. The relationships of these factors with histological grades, the presence of intra-hepatic metastasis (IM), tumor size, value of serum alpha-fetoprotein (AFP), and prognosis were studied. PCNA labeling index (LI) was calculated to count positive nuclei in 1,000 cells. PCNALI was significantly higher in cancer and correlated with tumor size. PCNALI and the tumor diameter in themselves could be a good predictor for patient prognosis and the combination study of them was an even stronger indicator. The value of AFP was significantly higher in positive p53 cases. The incidence of p53 was associated with histological types. The presence of IM was found in negative Bax cases of main tumors. The appearance of Bax was not correlated with histological types. The incidence of p53 or Bax was indicated to distinguish the patient prognosis of the lower grade histological cases, in which differences could not be found by the routine histological study. The combination study of the immunohistochemical findings and the clinical features could be one of the most important aids in interpreting the status of HCC.

Usefulness of p53 gene mutations in the supernatant of bile for diagnosis of biliary tract carcinoma: comparison with K- ras mutation

The sensitivity of bile cytology for the diagnosis of biliary tract carcinoma (BTCa) is still low. In addition, the incidence of detection of genetic mutations in the bile of BTCa is not satisfactory yet. To improve the molecular diagnosis of BTCa, we analyzed p53 and K- ras mutations in DNA extracted from not only the sediment but the supernatant of bile samples. Polymerase chain reaction-single-strand conformation polymorphism and direct sequencing were used for analyses of p53 mutations in exons 5 through 8. K- ras mutations at codon 12 were examined by mutant allele-specific amplification. In bile supernatant from patients with BTCa, p53 and K- ras mutations were detected in 50.0% (15/30) and 56.7% (17/30) of cases, respectively. The incidence of p53and K- ras mutations in the sediment was 33.3% and 43.3%, respectively. When a combination assay with both genes was used, molecular abnormalities were detected in 80.0% of cases, including 3 in which p53 alone was positive. In addition, either p53 or K- rasmutations were detected in 12 of 15 (80.0%) cases of BTCa in which the cytologic diagnoses were negative. p53 mutations were detected in neither supernatant nor sediment in 20 patients with cholelithiasis, although the incidence of K- ras mutations in the sediment was 20%. The incidence of p53 and K- ras mutations is higher in the supernatant than in the sediment, and simultaneous analyses of p53 and K- ras in the two bile fractions could enhance the genetic diagnosis of BTCa. Notably, the specificity of p53 mutations for cancer was very high in bile samples, and the sensitivity was also relatively high.

ALTERATIONS OF K-ras AND p53 MUTATIONS IN COLORECTAL CANCER PATIENTS IN CENTRAL EUROPE

Many molecular investigations of colorectal cancer (CRC) have suggested that the accumulation of specific mutations in proto-oncogenes and tumor suppressor genes regulating cell growth via signal transduction trigger the stagewise progression to malignancy. In this study, the frequency, location, and type of mutations of the K-ras proto-onco-gene exon 1 and p53 tumor suppressor gene exons 5-8 were analyzed in colorectal carcinomas of 65 patients from Central Europe, using polymerase chain reaction (PCR)-cold single-strand conformation polymorphism (SSCP) screening and direct sequencing. The incidence of K-ras activating mutations in these Central European samples was lower (25%) compared to that obtained in American and western European populations (40-50% at least), while the incidence of p53 inactivating mutations was similar (58%). These results suggest that some other genetically linked mechanisms may play a role in CRC development and progression, and hence K-ras and p53 mutations cannot be considered to be universal genetic markers for CRC.

Low frequency of p53 and ras mutations in bile of patients with hepato-biliary disease: a prospective study in more than 100 patients.

The diagnosis of biliary disease, namely malignant disorders, is frequently hampered by the inconclusive cytology. We investigated prospectively the frequency of molecular changes in p53 and ras compared with cytology in patients with primary or secondary hepato-biliary disease. We investigated 118 consecutive patients, aged 24-89 with the following clinical diagnoses: choledocho/cholecystolithiasis (28), cholangiocellular carcinoma (21), gall bladder tumor (8), liver metastasis (3), autoimmune disease (8), chronic pancreatitis (16), pancreatic carcinoma (11), papillary disease (4), hepatic cirrhosis (6), cholangitis (2), anomalies (2), and normal (9). Bile was aspirated during routine endoscopic retrograde cholangio pancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC). DNA was prepared freshly from a native aliquot. p53 mutations were detected by polymerase chain reaction (PCR) for exons 5 through 8 followed by TGGE. PCR for ras mutations was performed as RFLP-PCR with sequencing. In four cases, mutations in p53 could be found in exons 6 and 7. Twenty-two samples showed ras mutations; ras mutations were found in choledocholithiasis (4/28), bile duct (5/21), gall bladder (3/8) and pancreatic (1/11) carcinoma, liver metastasis (3/3), ulcerative colitis (2/3), PSC (1/2), and chronic pancreatitis (1/16). Cytology was clearly positive in seven cases, suspicious in three other, inconclusive in six, and negative in the rest. The molecular analysis resulted in a sensitivity of 33% and specificity of 87%, respectively, for the diagnosis of a malignant condition. PCR for p53 and ras mutations may aid the diagnosis of primary and secondary (metastatic) hepatobiliary disease if a malignant condition of the bile ducts and the liver is suspected and cytology is inconclusive or negative. However, the incidence of p53 and ras mutations in bile seems less frequent than in other malignant conditions of the gastrointestinal tract and the pancreas and lower than in tissue, leaving a poor sensitivity and specificity. Nevertheless, the presence of a p53 and/or ras mutation per se supports a clinical suspicion of malignancy, even when the conventional cytology is negative or inconclusive.

Incidence of P53 and K-ras alterations in ovarian mucinous and serous tumors.

Clarification of the pathogenic relationships existing among ovarian cystadenomas, tumors of low malignant potential (LMP) and various adenocarcinoma types, a series of 29 mucinous and 19 serous ovarian tumors including adenomas, LMP tumors and adenocarcinomas were examined. P53 protein was detected by the streptavidin-biotin method and point mutation of K-ras codon 12 was detected by polymerase chain reaction-restriction fragment length polymorphism analysis. P53 overexpression was observed more frequently in serous adenocarcinomas (5/8, 63%) than in mucinous adenocarcinomas (2/9, 22%) and was correlated with the malignant potential of serous tumors. Furthermore, the proportion of P53-positive cells was significantly higher in serous adenocarcinomas than in mucinous adenocarcinomas. P53 overexpression may therefore be closely related to the early events of carcinogenesis in serous tumors. Although mutation of the K-ras oncogene appears to be an important event in the early tumorigenesis of mucinous tumors, mutation of the K-ras oncogene in serous tumors may be dependent on morphology. Different complex pathways of oncogene and/or tumor suppressor gene abnormalities may be involved in the development of mucinous and serous adenocarcinomas.

Reduced expression of p53 and cyclin A in intraductal mucin-hypersecreting neoplasm of the pancreas compared with usual pancreatic ductal adenocarcinoma

OBJECTIVE: Intraductal mucin-hypersecreting neoplasm (IMHN) of the pancreas, a slow-growing malignancy with a favorable prognosis, is distinctly categorized from the high-grade malignancy of the more common ductal adenocarcinoma. The aim of the present study was to clarify the molecular differences underlying the biological differences between IMHN and ductal adenocarcinoma of the pancreas. METHODS: The expression of p53 and cyclin A in IMHN was compared with that in ductal adenocarcinoma of the pancreas immunohistochemically. RESULTS: In IMHN, the incidence of p53 and cyclin A ascertained by positive nuclear staining was significantly lower than that in ductal adenocarcinoma. Furthermore, in ductal adenocarcinoma, p53 and cyclin A are topographically coexpressed. CONCLUSIONS: These results suggest that the overexpression of p53 and cyclin A plays a role in the tumorigenesis of pancreatic ductal adenocarcinoma, and sparse expression of both antigens in IMHN may partly contribute to its low-grade malignant characteristics.

Reduced expression of p53 and cyclin A in intraductal mucin-hypersecreting neoplasm of the pancreas compared with usual pancreatic ductal adenocarcinoma.

Intraductal mucin-hypersecreting neoplasm (IMHN) of the pancreas, a slow-growing malignancy with a favorable prognosis, is distinctly categorized from the high-grade malignancy of the more common ductal adenocarcinoma. The aim of the present study was to clarify the molecular differences underlying the biological differences between IMHN and ductal adenocarcinoma of the pancreas. The expression of p53 and cyclin A in IMHN was compared with that in ductal adenocarcinoma of the pancreas immunohistochemically. In IMHN, the incidence of p53 and cyclin A ascertained by positive nuclear staining was significantly lower than that in ductal adenocarcinoma. Furthermore, in ductal adenocarcinoma, p53 and cyclin A are topographically coexpressed. These results suggest that the overexpression of p53 and cyclin A plays a role in the tumorigenesis of pancreatic ductal adenocarcinoma, and sparse expression of both antigens in IMHN may partly contribute to its low-grade malignant characteristics.

P53 and bcl-2 protein expression in non-small-cell lung carcinoma.

The diagnostic significance of p53 and bcl-2 proteins in epithelial non-small-cell lung cancers was examined, and the relationship between these proteins expression and other disease parameters, including stage of the disease and tumor differentiation, were studied. We analyzed p53 and bcl-2 proteins expression in 60 imprint smears of freshly resected lung tumors (37 squamous and 23 adenocarcinomas) using the immunocytochemical technique. There were seven patients with stage I disease, 24 with stage II, 23 with stage IIIa, and six with stage IIIb disease, according to the International Staging System classification. Sixteen of the tumors were bcl-2 positive and 25 were p53 positive. Twenty tumors were negative for both bcl-2 and p53 (33.3%). Statistical analysis showed no association between the incidence of p53 or bcl-2 positivity. Adenocarcinoma or squamous carcinoma analysis showed significant associations between p53 positivity and poor differentiation and advanced disease stage as well as bcl-2 and early disease stage and well-differentiated tumors. There was also an association between the stage of the disease and the degree of differentiation of the tumors. In conclusion, bcl-2 positivity must be considered a good prognostic sign. On the other hand, p53 positivity seems to indicate, even in tumors at a relatively early stage, that a serious aggressive tumor which will not be easily eradicated is present.

Combined analysis of p53 and vascular endothelial growth factor expression in colorectal carcinoma for determination of tumor vascularity and liver metastasis

Recent studies have demonstrated that the p53 tumor suppressor gene plays an important role in controlling tumor angiogenesis. We examined the expression of p53 and vascular endothelial growth factor (VEGF), a well-characterized angiogenic inducer, together with microvessel density to investigate the role of p53 in the regulation of angiogenesis and its clinical significance in human colorectal carcinoma. Surgically resected specimens of 163 colorectal carcinomas were studied by immunohistochemical staining for p53 protein, VEGF and factor VIII-related antigen. Positive p53 protein accumulation and VEGF expression was found in 41.7% and 49.1% of tumors, respectively. p53 and VEGF staining status was identical in 65.6% of tumors. The incidence of p53- or VEGF-positive tumors was significantly higher in patients with venous invasion and liver metastases than in those without. The microvessel count (MVC) in p53- or VEGF-positive tumors was significantly higher than that in negative tumors, and MVC in both p53- and VEGF-positive tumors was significantly higher than that in the other subgroups. Neither synchronous nor metachronous hepatic metastases were found in patients with p53- and VEGF-negative tumors, while 52.2% of patients with both-positive tumors had liver metastases and had a poorer prognosis than those with both-negative tumors. Our findings suggest the presence of a p53-VEGF pathway regulating tumor angiogenesis in human colorectal carcinoma. Combined analysis of p53 and VEGF expression might be useful for predicting the occurrence of liver metastasis in patients with this disease. Int. J. Cancer 74:502–507, 1997. © 1997 Wiley-Liss, Inc.

Combined analysis of p53 and vascular endothelial growth factor expression in colorectal carcinoma for determination of tumor vascularity and liver metastasis.

Recent studies have demonstrated that the p53 tumor suppressor gene plays an important role in controlling tumor angiogenesis. We examined the expression of p53 and vascular endothelial growth factor (VEGF), a well-characterized angiogenic inducer, together with microvessel density to investigate the role of p53 in the regulation of angiogenesis and its clinical significance in human colorectal carcinoma. Surgically resected specimens of 163 colorectal carcinomas were studied by immunohistochemical staining for p53 protein, VEGF and factor VIII-related antigen. Positive p53 protein accumulation and VEGF expression was found in 41.7% and 49.1% of tumors, respectively. p53 and VEGF staining status was identical in 65.6% of tumors. The incidence of p53- or VEGF-positive tumors was significantly higher in patients with venous invasion and liver metastases than in those without. The microvessel count (MVC) in p53- or VEGF-positive tumors was significantly higher than that in negative tumors, and MVC in both p53- and VEGF-positive tumors was significantly higher than that in the other subgroups. Neither synchronous nor metachronous hepatic metastases were found in patients with p53- and VEGF-negative tumors, while 52.2% of patients with both-positive tumors had liver metastases and had a poorer prognosis than those with both-negative tumors. Our findings suggest the presence of a p53-VEGF pathway regulating tumor angiogenesis in human colorectal carcinoma. Combined analysis of p53 and VEGF expression might be useful for predicting the occurrence of liver metastasis in patients with this disease.

Incidence of p53 and Ha-ras gene mutations in chemically induced rat mammary carcinomas.

To determine whether p53 alterations, which are frequent in human breast cancers, are also common in rat mammary tumors, we examined 40 tumors from 24 rats treated with 7,12-dimethylbenz[a]anthracene (DMBA) and 34 tumors from 14 rats treated with N-nitroso-N-methylurea (NMU) (an N-nitroso compound). DMBA and NMU are known genotoxic mutagens. The entire coding regions of the p53 and Ha-ras genes were examined for mutations by polymerase chain reaction single-strand conformational polymorphism analysis and by direct sequencing. One of the 40 DMBA-induced mammary tumors had a p53 mutation, a single-base substitution (AGC-->GGC) at codon 307, resulting in an amino-acid change from Ser to Gly. No mutations were found in NMU-induced tumors. The incidence of Ha-ras gene mutation was 79% (27 of 34) at codon 12 in the NMU group and 23% (nine of 40) at codon 61 in the DMBA group. Thus, p53 mutation, in contrast to Ha-ras mutation, did not seem to be a prerequisite for carcinogenesis in chemically induced rat mammary tumors.

Pathogenetic significance of p53 and c-Ki-ras gene mutations and human papillomavirus DNA integration in adenocarcinoma of the uterine cervix and uterine isthmus.

The pathogenetic significance of p53 and c-Ki-ras gene mutations and genomic integration of human papillomavirus (HPV) DNA was examined in surgically resected specimens of adenocarcinomas of the uterine cervix and isthmus using polymerase chain reaction (PCR), single-strand-conformation polymorphism and Southern blotting analysis. Among 25 cervical adenocarcinomas, p53 gene mutations between exons 5 and 8 were detected in 32%, and the incidence of these mutations was higher in cases at advanced clinical stages and with high grades of nuclear and structural atypia both in endocervical and in endometrioid types. HPV DNA type 16 or 18 in cervical adenocarcinomas was detected in 35% of cases by PCR and in 29% by Southern blotting, and, in contrast to the p53 mutations, the majority of cases with the HPV DNA were at a relatively early clinical stage with low-grade histological atypia. c-Ki-ras gene mutation was detected in only 4% of cervical adenocarcinomas. Among 8 isthmus adenocarcinomas, the incidence of p53 and c-Ki-ras gene mutations, and the presence and integration of HPV DNA type 16 or 18 were 38%, 50%, 57% and 25% respectively. The pattern of p53 mutations differed between isthmus and cervical adenocarcinomas: all of the mutations in the former were one-base substitutions of the transition type, whereas in the latter nearly half of the mutations were of the transversion type. Among cervical adenocarcinomas, p53 mutations between exons 5 and 8 were indicated as being mostly involved in the pathogenesis and development of biologically aggressive tumors, whereas HPV type 16 or 18 infection appeared to be involved in less aggressive cases. In isthmus adenocarcinoma, c-Ki-ras gene mutation, apart from p53 mutation and HPV-type-16 or -18 infection, appeared to be involved frequently in cancer development.

P53 Gene Mutations in Medulloblastoma

Medulloblastoma (MB), the most common malignant tumor of the CNS in children, bears a loss of the short arm of chromosome 17 in almost half of the cases. The tumor suppressor gene p53 is located on this chromosome and its role in the pathogenesis of this primitive tumor is controversial. Twenty-two MBs were analyzed by single-strand conformation polymorphism (SSCP) of polymerase chain reaction-amplified conserved exons. Fragments displaying a gel mobility shift were subsequently analyzed by direct sequencing. Immunohistochemistry for p53 was performed in all cases; three had cytogenetic analysis. Two cases (9%) were found to harbor a mutation: one homozygous and one heterozygous. The latter showed focal p53 immunostaining. None of the cases with chromosome 17p abnormality by cytogenetic analysis were found to have a mutation in the remaining allele. Loss of heterozygosity (LOH) of 17p, however, was found in four cases (one by SSCP and three by cytogenetic analysis). Together with the homozygous deletion in one case, the overall incidence of p53 allelic involvement in MB is 23%. Although LOH for the p53 gene may confer a selective advantage to tumor cells harboring mutations with dominant negative oncogenic effect, the infrequent occurrence of p53 mutations in face of frequent LOH for this gene supports the previously formulated hypothesis of a novel tumor-related locus distal to p53 on chromosome 17p.