Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p16-cyclin D-Cdk4(6)-pRB-E2F and p73 pathways are involved in the control of cell-cycle progression, and genetic lesions in both pathways frequently occur in breast carcinomas and other human cancers. The p16INK4a gene is involved in regulation of the G1/S transition, and when overexpressed, the p73 gene activates transcription of p53-responsive genes and promotes apoptosis. These pathways are related, for instance, p73 is also downstream of E2F-1, since E2F-1 induces p73-mediated apoptosis in the absence of p53. We studied 93 breast cancer patients to identify alterations in the expression of p16INK4a and p73 by semiquantitative RT-PCR analysis and possible interactions between them and correlations with clinicopathological parameters. p73 was overexpressed in 24 cases. Overexpression of p16INK4a was detected in 17 cases and underexpression in 32 cases. A significant correlation was observed between the overexpression of both genes (P = 0.05). Concurrent overexpression of p73 and p16INK4a was significantly correlated with metastases in three or more lymph nodes (P = 0.0007), positive immunohistochemistry for p53 (P = 0.014), vascular invasion (P = 0.048) and negative progesterone receptors (P = 0.004). These results indicate that concomitant overexpression of p16INK4a and p73 may be involved in breast cancer and associated with poor tumor characteristics.
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PMID:Overexpression of p16INK4a correlates with high expression of p73 in breast carcinomas. 1545 Apr 20

Cell cycle regulating proteins are important in tumour development. To investigate whether alterations in Cyclin D1, p14, CDK4 and Rb are associated with tumour cell proliferation, tumour progression and patient survival in malignant melanoma, we examined 202 vertical growth phase tumours and 68 corresponding metastases for expression of Cyclin D1, p14, CDK4 and Rb, and compared the results with Ki-67 expression, p16 and p53 expression, clinico-pathological variables, and survival data. Nuclear staining of Cyclin D1 was strong in 35% of cases, and correlated with high levels of Rb (p=0.05), but not with survival or other markers tested. Strong staining of p14 was found in 63% of nodular melanomas and was associated with strong p53 expression (p=0.014), and with high levels of CDK4 (p<0.0001). Low p14 expression was associated with increased tumour thickness (p=0.008) and increasing level of invasion (p=0.020). Strong nuclear staining for CDK4 was found in 81% of cases and was associated with tumour thickness below the median value of 3.7 mm and improved survival (log-rank test, p=0.024). Further, 56% of the tumours showed strong nuclear staining for Rb, and these cases were significantly associated with absent/low levels of p16 staining (p=0.030), high levels of p14 (p=0.010), as well as high Ki-67 expression (p=0.005). Our results seem to confirm that the p16-Rb pathway plays an important role in tumour progression and prognosis in vertical growth phase melanomas, whereas alterations in the p14-p53 pathway might be less important.
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PMID:Altered expression of cell cycle regulators Cyclin D1, p14, p16, CDK4 and Rb in nodular melanomas. 1554 91

All-trans-retinoic acid (atRA) exerts its effects via apoptosis and cell cycle re-distribution. However, the mechanisms behind the effects have not been fully understood. In this study, we used a model system of matched primary and metastatic melanoma cells to investigate whether expression of Id1 and p16 proteins were involved in atRA-induced apoptosis and cell cycle re-distribution. Melanoma cells were exposed to 0.1 or 10 microM atRA for 1-96 h. Apoptosis and cell cycle were measured by flow cytometry. Expression of Id1 and p16 proteins was examined by Western blotting and immunocytochemistry. After exposure to atRA we found a marked increase in apoptosis and cell cycle re-distribution in both primary and metastatic melanoma cells. Expression level of Id1 protein was decreased and the p16 was increased in a dose- and time-dependent (P<0.05) manner after treatment with atRA. Alterations of these proteins were more pronounced in the primary melanoma cells than the matched metastases (P<0.05). These data suggested that the alterations of Id1 and/or p16 proteins were involved in atRA-induced apoptosis and cell cycle re-distribution in melanoma. These expression profiles of Id1 and p16 proteins may provide molecular evidence for better chemotherapy primarily for early stages of melanoma.
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PMID:Expression profiles of Id1 and p16 proteins in all-trans-retinoic acid-induced apoptosis and cell cycle re-distribution in melanoma. 1559 94

Not all patients with metastatic breast carcinoma (MBC) in a sentinel lymph node (SLN) have metastasis in additional axillary nodes (ANs). A biological marker that can predict this occurrence may be beneficial in triaging only appropriate patients for AN dissection (AND). Our aim was to study p16 expression in SLNs and to determine whether it is a predictor of metastases to additional ANs and a marker of poor prognosis. We correlated p16 expression in SLNs and ANs of 54 patients with MBC with clinicopathologic features and the nodal proliferative index (PI). We sequenced p16 from DNA in 7 cases. We found that 35 of 54 cases (65%) had p16-positive tumor cells. Nine of 17 (53%) cases in which both SLN and AND were done had MBC in additional ANs. The SLNs of 8 of 9 cases (89%) were p16 positive (73% positive predictive value). Eight of 17 (47%) cases had no metastases in ANs even though their SLNs had metastases. The SLNs of 5 of 8 (62.5%) of these cases were p16 negative (83% negative predictive value). Ductal MBCs were p16 positive in 27 of 37 cases (73%). Carcinomas with a lobular component were p16 negative in 9 of 11 cases (82%). Nine of 12 (75%) p16-negative ductal carcinomas were estrogen receptor (ER) positive. Some 75% of T2 and T3 tumors were p16 positive, compared with 50% of T1 tumors. The highest PI (defined as > or =50%) was seen in p16-positive SLNs (5 of 6 cases). The p16 DNA sequence was normal, and no mutations were found. Our findings indicate that p16 expression in SLNs with MBC predicts (1) increased likelihood of metastasis in additional ANS, and its expression along with other markers and clinicopathologic parameters may serve as an indicator for proceeding to a formal AND; (2) poor prognosis and is associated with larger primary tumors with a high nodal PI and ER-negative status; and (3) histological subtypes. Gene mutations were not responsible for the expression of p16 in our cases.
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PMID:p16 expression in sentinel nodes with metastatic breast carcinoma: evaluation of its role in developing triaging strategies for axillary node dissection and a marker of poor prognosis. 1561 12

Cancers often exhibit aberrant methylation of gene promoter regions associated with loss of tumor suppressor and/or DNA repair gene function. Such methylation constitutes an excellent marker for the molecular detection of micro-metastases and the diagnosis of tumor recurrences. We have developed a multiplex methylation-specific PCR (MSP) procedure for rapid and simultaneous assessment of the methylation of 5 loci: the tumor suppressor genes p16INK4a, death-associated protein kinase (DAPK) and p14ARF, and the DNA repair genes hMLH1 and O6-methylguanine-DNA-methyltransferase (MGMT). This multiplex test uses one single PCR reaction and only one electrophoretic run. In 98 samples of colorectal cancer studied, methylation of MGMT, DAPK, p16, hMLH1 and p14 was present in 31, 20, 17, 16 and 14% of tumors, respectively. In 58% of the tumors at least one methylated gene was found. This multiplex MSP constitutes a simple and inexpensive method for screening of molecular signatures in colorectal cancer and can be used profitably before employing more expensive and complex techniques such as microarray testing.
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PMID:Development and application of a multiplex PCR procedure for the detection of DNA methylation in colorectal cancer. 1564 19

Despite clearly defined histologic criteria, the prediction of tumor behavior for patients with gastrointestinal stromal tumors (GIST) still poses a challenge to pathologists. Therefore, searching for alternative markers that allow for better prognostic evaluation is an important task. To determine the practicability of immunohistochemical staining for p16 in clinical cases, we examined p16 protein expression in a group of 284 GISTs, a subset of which had long-term follow-up (median, 45 months; range, 1-204 months). P16 protein expression was ascertained on tissue microarrays as well as on standard sections. Survival analyses were carried out in 157 patients. P16 loss was found in 50% of GISTs, there being no correlation with age, sex, histologic subtype, signs of necrosis, or metastases. Patients having p16-negative tumors had a worse prognosis than those with p16-positive tumors (P = 0.012) with a 2.3-fold relative increased risk of dying of disease. P16 loss identified a subgroup of gastric tumors with a worse prognosis (P = 0.03). The multivariate configural frequency analysis identified two "antitypes," whose observed frequency was found to be significantly lower than the expected frequency [i.e., marker combinations: p16 positive, no metastases, and death of disease and p16 loss, metastases, and still alive]. The "type" whose observed frequency was significantly higher than the expected frequency consisted of the following marker pattern: p16 loss, necrosis, and death of disease (P < 0.001). In the multivariate Cox regression analysis, p16 loss, necrosis, and metastases each had independent prognostic value. P16 loss is a common molecular abnormality in GISTs and might be used in routine diagnosis to identify patients with high-risk tumors.
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PMID:Loss of p16 protein defines high-risk patients with gastrointestinal stromal tumors: a tissue microarray study. 1570 51

Adenoid basal tumors are uncommon cervical lesions that some pathologists consider invasive carcinomas but others consider "epitheliomas" due to their low-grade histological appearance and rarely documented malignant behavior. We report the clinicopathologic features of 10 tumors comprised of both typical low-grade adenoid basal tumors (epitheliomas) intimately associated with invasive carcinomas having infiltrative growth, increased cytological atypia and mitotic activity, and various types of differentiation, including adenoid basal/squamous, pure squamous, adenoid cystic, and small cell neuroendocrine. Tumors were evaluated for the presence of human papillomavirus (HPV) DNA and immunohistochemical p16 expression. The patients in the study group ranged in age from 45 to 81 years (mean, 65 years). Most of the patients presented with abnormal cervicovaginal smears. The initial diagnosis was made on specimens obtained by cervical biopsy, laser electrocautery excision procedure (LEEP), or cone biopsy in 8 patients. Two 2 patients were incidentally diagnosed in hysterectomy specimens. All 10 patients had squamous intraepithelial lesions (9 high-grade, 1 low-grade). In all cases diagnosed in LEEP or cone biopsy specimens, the invasive carcinoma component was present in the excisional specimen and extended to the margins. Seven patients diagnosed on excisional or biopsy specimens who underwent hysterectomy had residual tumor in the cervix, ranging from microscopic foci to deeply invasive. No lymph node metastases were identified in 4 patients who were staged. Seven patients with follow-up were alive without evidence of disease after follow-up intervals of 8 to 84 months (mean, 45 months; median, 29 months). One patient with a component of small cell carcinoma died of other causes without evidence of disease at 18 months. HPV 16 DNA was detected in both the adenoid basal epithelioma and invasive carcinoma components in 9 tumors by in situ hybridization, and HPV 33 was detected by polymerase chain reaction in 1 tumor. All tumors expressed p16 diffusely. Adenoid basal tumors are high-risk HPV-related tumors that can be comprised of both a low-grade adenoid basal tumor, which can be designated as epithelioma, and invasive carcinomas of various types. The invasive component is usually evident in the excisional biopsy specimen, allowing for recognition of a tumor that needs further management.
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PMID:Cervical adenoid basal tumors comprised of adenoid basal epithelioma associated with various types of invasive carcinoma: clinicopathologic features, human papillomavirus DNA detection, and P16 expression. 1571 86

The vast majority of endocervical adenocarcinomas are high-risk human papillomavirus (HPV)-related neoplasms, characterized by p16 expression and frequent loss of hormone receptor expression, which infrequently metastasize to the ovaries. We report 10 cases of endocervical adenocarcinomas with ovarian metastases in which the ovarian tumors simulated primary ovarian surface epithelial neoplasms. The presence of HPV DNA was assessed to determine whether the ovarian neoplasms were metastases or independent neoplasms. Immunohistochemistry for hormone receptors and p16 was also performed. The ovarian metastases presented concurrently with the primary endocervical tumors in 5 cases, subsequent to the endocervical tumors in 3 cases, and prior to diagnosis of the endocervical tumors in 2 cases. The ovarian tumors ranged in size from 2 to 30 cm, with tumors in 7 cases measuring 10 cm or greater. The ovarian tumors were unilateral in 8 cases and bilateral in 2. In all cases, the ovarian tumors were initially diagnosed as or thought to represent independent primary ovarian surface epithelial tumors (atypical proliferative [borderline] tumors or well-differentiated carcinomas of endometrioid or mucinous type). The endocervical tumors ranged in size from microscopic foci to 3 cm, with depth of invasion ranging from 0.2 to 1.5 cm; in 2 cases, the invasive foci qualified as microinvasive according to Federation Internationale de Gynecologie et d'Obstetrique staging criteria for cervical carcinoma. Adenocarcinoma in situ was identified in all tumors. In all cases, the paired endocervical and ovarian tumors contained identical HPV types. All evaluable tumors were diffusely positive for p16; and in 8 cases, there was absent or only limited expression of hormone receptors. Two of the minimally invasive endocervical tumors were initially interpreted as adenocarcinoma in situ and not recognized as unequivocally invasive even when evaluated in conjunction with the histologically identical ovarian tumors. HPV DNA detection in the ovarian tumors of 2 patients without known cervical disease led to discovery of occult cervical adenocarcinomas in those patients. Endocervical adenocarcinomas, including some qualifying as microinvasive, can metastasize to the ovaries and simulate primary ovarian surface epithelial neoplasms. The presence of HPV DNA in these ovarian tumors confirms that they are metastatic endocervical adenocarcinomas.
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PMID:Synchronous and metachronous endocervical and ovarian neoplasms: evidence supporting interpretation of the ovarian neoplasms as metastatic endocervical adenocarcinomas simulating primary ovarian surface epithelial neoplasms. 1632 48

Systematic analyses of cancer genomes promise to unveil patterns of genetic alterations linked to the genesis and spread of human cancers. High-density single-nucleotide polymorphism (SNP) arrays enable detailed and genome-wide identification of both loss-of-heterozygosity events and copy-number alterations in cancer. Here, by integrating SNP array-based genetic maps with gene expression signatures derived from NCI60 cell lines, we identified the melanocyte master regulator MITF (microphthalmia-associated transcription factor) as the target of a novel melanoma amplification. We found that MITF amplification was more prevalent in metastatic disease and correlated with decreased overall patient survival. BRAF mutation and p16 inactivation accompanied MITF amplification in melanoma cell lines. Ectopic MITF expression in conjunction with the BRAF(V600E) mutant transformed primary human melanocytes, and thus MITF can function as a melanoma oncogene. Reduction of MITF activity sensitizes melanoma cells to chemotherapeutic agents. Targeting MITF in combination with BRAF or cyclin-dependent kinase inhibitors may offer a rational therapeutic avenue into melanoma, a highly chemotherapy-resistant neoplasm. Together, these data suggest that MITF represents a distinct class of 'lineage survival' or 'lineage addiction' oncogenes required for both tissue-specific cancer development and tumour progression.
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PMID:Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. 1600 Oct 50

Gastrointestinal stromal tumors (GISTs) have a wide spectrum of biologic behavior ranging from benign to malignant. Risk grading based on tumor size and mitotic counts has been proposed in an effort to predict the adverse outcome of GIST in the literature so far. Recent molecular studies have reported the prognostic values of several parameters, including alteration of cell-cycle regulators. The aim of this study was to elucidate the prognostic values of risk grade and alterations of cell-cycle-related proteins, including Ki-67, cyclin A, cyclin B1, cyclin D1, cyclin E, p16, p21, p27, p53, cdc2, and cdk2, in addition to the conventional factors. Eighty cases of primary c-kit-positive GISTs were classified into 2 cases of very-low-risk grade, 20 cases of low-risk grade, 25 cases of intermediate-risk grade, and 33 cases of high-risk grade. The risk grade was correlated with the presence of metastases and/or recurrence. A high level of Ki-67 and cyclin A expression was correlated with risk grade (P = .0027 and .0441, respectively). Overexpression of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, was associated with the Ki-67 labeling index (LI) (P = .0007, .0475, and .0040, respectively). According to univariate analysis, tumor grade (high risk), tumor size (> or =5 cm), mitotic counts (> or =5/50 high-power fields), Ki-67 LI (> or =4.92%), cyclin A LI (> or =1.61%), and cdc2 LI (> or =1.25%) were all found to be significantly associated with a shorter period of disease-free survival (P = .0001, .0270, .0004, .0001, .0001, and .0011, respectively). According to multivariate analysis, both high Ki-67 LI and high-risk grade were found to be significantly associated with a shorter period of disease-free survival (P = .0083 and .0246, respectively). In conclusion, our results strongly support the hypothesis that Ki-67 LI and risk grade are useful for predicting the aggressive biologic behavior of GISTs. Furthermore, alteration of G2-M regulators, such as cyclin A, cyclin B1, and cdc2, is also a useful marker for predicting aggressive behavior and play an important role, at least in part, in the cell proliferation of GIST.
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PMID:Prognostic significance of expressions of cell-cycle regulatory proteins in gastrointestinal stromal tumor and the relevance of the risk grade. 1608 54


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