Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Circulating free DNA (CFDNA) has been shown to be a good source of liver tissue-derived DNA in African and Asian patients with chronic liver disease or HCC. In Egypt, HCC is a frequent carcinoma and mostly occur in the context of chronic infection by HCV, a widespread infection in the Egyptian population. Here we have examined the presence of mutations in TP53 at codon 249 (Ser-249, considered as a hallmark of mutagenesis by aflatoxin) and in CTNNB1 (gene encoding beta-catenin) in CFDNA of patients with HCC or chronic liver disease, from Alexandria, Egypt. The DNA concentrations were significantly higher in HCC patients compared to HBV and HCV carriers without cancer, and to sero-negative individuals. Ser-249 TP53 mutations were determined using PCR-restriction digestion (RFLP) in CFDNA of 255 subjects, and confirmed by sequencing. Ser-249 was found in CFDNA of 12 subjects (4.8%), with the highest prevalence in subjects with chronic liver disease and infection by HBV (6/36; 16.7%) Mutations in CTNNB1 were examined using PCR combined to DHPLC and followed by sequencing. No mutations were found in CTNNB1 neither in CFDNA or in tumour tissue. In parallel, studies on DNA extracted from 20 HCC biopsies showed the presence of ser-249 mutation in two cases (10%). These results indicate that mutagenesis by aflatoxin may play a role in hepatocarcinogenesis in Egypt, and CFDNA may serve as a convenient source of material in monitoring the effects of aflatoxin exposure and viral infections in chronic liver disease and cancer.
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PMID:Ser-249 TP53 and CTNNB1 mutations in circulating free DNA of Egyptian patients with hepatocellular carcinoma versus chronic liver diseases. 1831 40

Somatic PIK3CA mutations are often present in colorectal cancer. Mutant PIK3CA activates AKT signaling, which up-regulates fatty acid synthase (FASN). Microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) are important molecular classifiers in colorectal cancer. However, the relationship between PIK3CA mutation, MSI and CIMP remains uncertain. Using Pyrosequencing technology, we detected PIK3CA mutations in 91 (15%) of 590 population-based colorectal cancers. To determine CIMP status, we quantified DNA methylation in eight CIMP-specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by real-time polymerase chain reaction (MethyLight). PIK3CA mutation was significantly associated with mucinous tumors [P = .0002; odds ratio (OR) = 2.44], KRAS mutation (P < .0001; OR = 2.68), CIMP-high (P = .03; OR = 2.08), phospho-ribosomal protein S6 expression (P = .002; OR = 2.19), and FASN expression (P = .02; OR = 1.85) and inversely with p53 expression (P = .01; OR = 0.54) and beta-catenin (CTNNB1) alteration (P = .004; OR = 0.43). In addition, PIK3CA G-to-A mutations were associated with MGMT loss (P = .001; OR = 3.24) but not with MGMT promoter methylation. In conclusion, PIK3CA mutation is significantly associated with other key molecular events in colorectal cancer, and MGMT loss likely contributes to the development of PIK3CA G>A mutation. In addition, Pyrosequencing is useful in detecting PIK3CA mutation in archival paraffin tumor tissue. PIK3CA mutational data further emphasize heterogeneity of colorectal cancer at the molecular level.
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PMID:PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations. 1851 90

Loss of genomic imprinting is an epigenetic alteration of some cancers involving the absence of parental origin-specific expression of imprinted genes. Loss of genomic imprinting of insulin-like growth factor II is often detected in colorectal cancer. However, the genetic alterations accompanied by colorectal cancer with insulin-like growth factor II loss of genomic imprinting have not been fully determined. Genomic DNA samples were collected from 52 colorectal cancer tissues and analyzed. The loss of insulin-like growth factor II genomic imprinting status was determined by assessing the demethylation of the insulin-like growth factor II differentially methylated region using bisulfite sequencing. The molecular signatures were also examined: genetic mutations of KRAS, BRAF, and PIK3CA; the expression of CTNNB1 and TP53; and microsatellite instability status. Several cases of colorectal cancer with normal insulin-like growth factor II imprinting were located in the distal colon; in contrast, colorectal cancer with loss of genomic imprinting tended to be found in the proximal colon (22.7 versus 56.6%). The PIK3CA gene mutation was highly detected in normal imprinting tumors compared to colorectal cancers with insulin-like growth factor II loss of genomic imprinting (27.3% versus 6.7%). In multivariate analysis of these clinicopathologic and molecular factors of tumors, statistically significant relationships were observed among the proximal location of the tumor (odds ratio, 12.9; 95% confidence interval, 1.52-110.13), PIK3CA genetic mutation (odds ratio, 0.082; 95% confidence interval, 0.01-0.73), and insulin-like growth factor II genomic imprinting status. Our findings indicate that colorectal cancers with demethylation of the insulin-like growth factor II gene are distinct from normal imprinting tumors, both in clinical and genetic features.
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PMID:Genetic alterations in colorectal cancers with demethylation of insulin-like growth factor II. 1861 47

Histopathologic grading of dysplasia in Barrett esophagus (BE) shows substantial interobserver and intraobserver variation. We used immunohistochemical analysis with a set of tumor cell markers, ie, epidermal growth factor receptor (EGFR), ERBB2 (HER2/neu), MYC, CDKN2A (p16), SMAD4, MET, CCND1 (cyclin D1), CTNNB1 (beta-catenin), and TP53 (p53), in histologic sections of endoscopic biopsies of 86 patients with BE in various stages of neoplastic progression. The markers, except SMAD4, were scored as 0 (<1% of cells stained), 1 (1%-25%), 2 (26%-50%), or 3 (>50%). All markers, except EGFR, showed a significant trend for immunohistochemical protein overexpression during malignant progression in BE (P <.01). When the successive stages along the metaplasia-low-grade dysplasia (LGD)-high-grade dysplasia (HGD)-adenocarcinoma axis were compared, protein overexpression of beta-catenin separated LGD from metaplasia, whereas protein overexpression of cyclin D1 and p53 discriminated HGD from LGD (all P <.001). beta-Catenin can be helpful for a diagnosis of LGD in BE, although it stains positively in a subset only, whereas p53 remains an appropriate marker to define HGD. In case of doubt, cyclin D1 can be added to separate LGD from HGD in BE.
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PMID:Immunohistochemical evaluation of a panel of tumor cell markers during malignant progression in Barrett esophagus. 1885 67

Lymph nodes metastasis is a major risk factor related to poor survival in larynx and pharynx carcinomas. The aim of this study is to search for markers of lymph node involvement analyzing the genetic differences between primary larynx and pharynx squamous cell carcinomas and their corresponding lymph node metastases. Twenty-five primary tumors and their corresponding lymph node metastases were examined. DNA copy number changes of 37 genes were analyzed by multiplex ligation-dependent probe amplification (MLPA). Loss of CDKN2A (9p21) occurred in 14 out of 25 pairs (56%) of primary tumor and lymph node metastases. Loss of LMNA (1q21) was exclusively detected in 8 lymph node samples (32%). Loss of CTNNB1 (3p22) and gain of CDKN2D (19p13) were also significantly more frequent in lymph node metastases. Other aberrations related to lymph node metastases were loss of MFHAS1 (8p23), RECQL4 (8q24) and gain of N33 (8p22) and TP53 (17p13). Primary tumor and corresponding lymph node metastases showed common genetic changes. However, the lymph node metastases presented with a number of additional alterations. Acquisition of these alterations may play a role in lymphatic metastasis development.
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PMID:Genetic differences between primary larynx and pharynx carcinomas and their matched lymph node metastases by multiplex ligation-dependent probe amplification. 1895 89

Transitional cell tumors of the ovary include 2 distinct clinicopathologic categories: Brenner tumors and transitional cell carcinomas (TCCs). Their molecular genetic alterations have not been fully investigated. We have performed a clinicopathologic, immunohistochemical, and molecular genetic analysis of 19 transitional cell tumors including 13 Brenner tumors (5 benign, 7 borderline, and 1 malignant) and 6 TCCs. Immunoreactivity for epidermal growth factor receptor (EGFR), Ras, Cyclin D1, p16, Rb, and p53, as well as fluorescence in situ hybridization analysis for EGFR were assessed in all cases. Screening for mutations in K-Ras, B-Raf, CTNNB1, PIK3CA, and p53 genes was also performed. The mean patient age was 58 years (range, 32 to 85 y). Abdominal enlargement and pain were the usual complaints. Treatment was known in 14 patients: 10 had hysterectomy with bilateral salpingo-oophorectomy, which was accompanied by omentectomy in 7; and 4 had only unilateral or bilateral salpingo-oophorectomy, 1 with omentectomy. Four patients had brachytherapy. Six borderline Brenner tumors were stage IA and 1 stage IIA. The malignant Brenner tumor was stage IA. One TCC was stage IA, one IC, 2 IIIC and the stage was unknown in 2 cases. Follow-up information was available only in 5 of the nonbenign cases. Two patients who had borderline Brenner tumors were alive and well at 3 and 10.9 years. The patient who had a malignant Brenner tumor died of pulmonary thromboembolism shortly postoperatively, and 2 patients with TCCs died of tumor 1.8 and 13 years, postoperatively. Brenner tumors and TCCs differed mainly in the expression of EGFR, p16, and p53. Benign Brenner tumors showed a low immunoexpression for all markers. Borderline Brenner tumors failed to immunoreact for p16, Rb, and p53; and showed weak immunostaining for Cyclin D1, moderate for Ras, and strong for EGFR. The malignant Brenner tumor was also negative for p16, Rb, and p53, and strongly positive for Cyclin D1, Ras, and EGFR. In contrast, TCCs had p53 mutations with p53 and p16 protein overexpression and showed a negative immunoreaction for EGFR, Cyclin D1, and Ras. Our results suggest that Brenner tumors and TCCs follow different tumorigenic pathways, whereas borderline and malignant Brenner tumors are low-grade neoplasms with activation of the PI3K/AKT pathway through EGFR, TCCs are high-grade tumors that have p53 mutations and p16 and p53 protein overexpression.
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PMID:Transitional cell tumors of the ovary: a comparative clinicopathologic, immunohistochemical, and molecular genetic analysis of Brenner tumors and transitional cell carcinomas. 1903 64

Most adrenocortical tumors are benign; adrenocortical carcinomas are rare but their prognosis is poor and few therapeutic options are available. In most adrenocortical tumors, the morphological approach provides enough elements to establish the differential diagnosis between a benign and a malignant tumor but in few cases, it is insufficient. Moreover, morphology is limited for predicting prognosis of adrenocortical carcinomas. These observations led to development of other approaches, in particular immunohistochemical and genetic approaches. The comprehension of the genetic syndromes associated with adrenocortical tumors led to progress in the identification of genetic abnormalities involved in sporadic adrenocortical tumorigenesis. Thus, in sporadic adrenocortical tumorigenesis, IGF-II overexpression and cyclin E overproduction have been associated with 11p15 alterations which are observed in Bethwith-Wiedemann syndrome and TP53 inactivating mutations and 17p13 locus abnormalities which are observed in Li-Fraumeni syndrome. Activation of the Wnt/ss-catenin signaling pathway which is observed in familial adenomatous polyposis has been found in adrenocortical adenomas and carcinomas associated to mutations of CTNNB1, the gene coding ss-catenin, suggesting a central role for this pathway in adrenocortical tumorigenesis. These genetics findings already have had repercussions for patients via the development of molecular markers for diagnosis and prognosis; in the future they should be helpful in the development of new therapeutics.
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PMID:[Sporadic adrenocortical tumors: genetics and perspectives for the pathologist]. 1906 95

Female rats of the BDII/Han inbred strain are prone to spontaneously develop endometrial carcinomas (EC) that in cell biology and pathogenesis are very similar to those of human. Human EC are classified into two major groups: Type I displays endometroid histology, is hormone-dependent, and characterized by frequent microsatellite instability and PTEN, K-RAS, and CTNNB1 (beta-Catenin) mutations; Type II shows non-endometrioid histology, is hormone-unrelated, displays recurrent TP53 mutation, CDKN2A (P16) inactivation, over-expression of ERBB2 (Her2/neu), and reduced CDH1 (Cadherin 1 or E-Cadherin) expression. However, many human EC have overlapping clinical, morphologic, immunohistochemical, and molecular features of types I and II. The EC developed in BDII rats can be related to type I tumors, since they are hormone-related and histologically from endometrioid type. Here, we combined gene sequencing (Pten, Ifr1, and Ctnnb1) and real-time gene expression analysis (Pten, Cdh1, P16, Erbb2, Ctnnb1, Tp53, and Irf1) to further characterize molecular alterations in this tumor model with respect to different subtypes of EC in humans. No mutation in Pten and Ctnnb1 was detected, whereas three tumors displayed sequence aberrations of the Irf1 gene. Significant down regulation of Pten, Cdh1, p16, Erbb2, and Ctnnb1 gene products was found in the tumors. In conclusion, our data suggest that molecular features of spontaneous EC in BDII rats can be related to higher-grade human type I tumors and thus, this model represents an excellent experimental tool for research on this malignancy in human.
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PMID:Molecular classification of spontaneous endometrial adenocarcinomas in BDII rats. 1907 38

Genetic instability in relation to clinical behavior was studied in 52 cases of giant cell tumor of bone (GCTB). Ploidy was determined in the mononuclear cell population by using native cell smears and image cytometry. A relocalization technique allowed fluorescent in situ hybridization (FISH) analysis of CD68-negative neoplastic cells for numerical changes of chromosomes X, 3, 4, 6, 11, and telomeric association on 11p. Genome-wide alterations were tested using array comparative genomic hybridization (array-CGH) on magnetically separated CD68-negative tumor cells. CTNNB1, TP53, and BCL2 protein expression was also analyzed in formol-paraffin sections to see if their pathways are involved in the development of chromosomal instability. CD68-positive histiocytes showed no significant numerical chromosome and telomeric alterations. Based on ploidy values and clinical outcome, we could distinguish five groups as follows: diploid nonrecurrent (n = 20), tetraploid nonrecurrent (n = 6), diploid recurrent (n = 5), tetraploid and/or aneuploid recurrent (n = 14), and malignant cases (n = 7). Random individual-cell aneusomy was significantly (P < 0.001) more frequent in the recurrent groups (36.01 +/- 11.94%) than in the benign nonrecurrent cases (10.65 +/- 3.66%). The diploid recurrent group showed significantly (P < 0.001) increased balanced aneusomy compared with the diploid nonrecurrent group and the tetraploid nonrecurrent group represented eusomic polysomy. Array-CGH and FISH showed clonal aberrations almost exclusively in the malignant group. None of the protein markers tested showed significant correlation with elevated aneuploidy/polysomy (P = 0.56). Our results show that ploidy determination combined with FISH analysis may help predicting recurrence potential of GCTB and suggest that chromosomal abnormalities superimposed on telomeric associations could be responsible for an aggressive clinical course.
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PMID:Genomic instability in giant cell tumor of bone. A study of 52 cases using DNA ploidy, relocalization FISH, and array-CGH analysis. 1924 28

Ovarian clear cell carcinoma (CCC) is one of the most malignant types of ovarian carcinomas, particularly at advanced stages. Unlike the more common type of ovarian cancer, high-grade serous carcinoma, ovarian CCC is often resistant to platinum-based chemotherapy, and therefore an effective treatment for this tumor type at advanced stages is urgently needed. In this study, we analyzed 97 ovarian CCCs for sequence mutations in KRAS, BRAF, PIK3CA, TP53, PTEN, and CTNNB1 as these mutations frequently occur in other major types of ovarian carcinomas. The samples included 18 CCCs for which affinity-purified tumor cells from fresh specimens were available, 69 microdissected tumors from paraffin tissues, and 10 tumor cell lines. Sequence mutations of PIK3CA, TP53, KRAS, PTEN, CTNNB1, and BRAF occurred in 33%, 15%, 7%, 5%, 3%, and 1% of CCC cases, respectively. Sequence analysis of PIK3CA in 28 affinity-purified CCCs and CCC cell lines showed a mutation frequency of 46%. Samples with PIK3CA mutations showed intense phosphorylated AKT immunoreactivity. These findings demonstrate that ovarian CCCs have a high frequency of activating PIK3CA mutations. We therefore suggest that the use of PIK3CA-targeting drugs may offer a more effective therapeutic approach compared with current chemotherapeutic agents for patients with advanced-stage and recurrent CCC.
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PMID:Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma. 1934 52


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