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)

Sporadic and familial malignant melanoma susceptibility has been linked to defects in the chromosomal region 9p21. Recently, a putative 9p21 tumor suppressor gene, the cyclin dependent kinase inhibitor 2 (CDKN2) or p16 gene, has been shown to be deleted, mutated, or rearranged in a high percentage of sporadic melanoma cell lines, as well as mutated in the germline of a proportion of familial melanoma patients. CDKN2 encodes a M(r) 16,000 protein (p16) that plays a key role in cell cycle control by binding to the cyclin-dependent kinase 4 enzyme and inhibiting its ability to phosphorylate critical substrates necessary for transition past the G1 phase of the cell cycle. Thus, mutations or deletions of the CDKN2 gene could result in abnormal proliferation via defective cell cycle control. The correlation of 9p21 cytogenetic and molecular alterations with the clinical stages of melanoma progression suggests that dysfunction of a gene within this chromosomal region is critical to the evolution of melanoma. However, it remains unclear whether this gene is the CDKN2 gene. If so, then loss of p16 is potentially an initiating or early event in melanoma progression. To address the issues of what is the potential involvement of the CDKN2 gene in sporadic melanoma and precisely when during the clinically evident stages of melanoma progression defects in CDKN2 occur, we have evaluated by immunohistochemistry the expression of p16 protein in 103 melanocytic lesions representing all stages in the progression of melanoma. Our results suggest that loss of p16 protein expression is (a) not necessary for tumor initiation in malignant melanoma because all melanomas in situ and the majority of primary invasive melanomas retain expression of this protein; and (b) potentially more related to invasiveness or the ability to metastasize, because 52% of primary invasive tumors and 72% of metastatic lesions show partial or complete loss of expression of p16.
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PMID:Loss of expression of the p16/cyclin-dependent kinase inhibitor 2 tumor suppressor gene in melanocytic lesions correlates with invasive stage of tumor progression. 779 91

To examine for the genetic basis of metastatic progression in cutaneous melanoma, we have compared loss of heterozygosity (LOH) of several selected chromosome regions that are implicated in the initiation and progression of melanoma, and alterations of the p16INK4a gene in 14 pairs of primary tumor and synchronous or asynchronous metastasis excised from the same patients. The most frequent genetic alteration during metastatic progression detected was the loss of p16INK4a protein expression (four of 14 cases), whereas no somatic p16INK4a gene mutations were found in any primary or metastatic tumors. LOH analyses showed that most of the chromosome losses including 6q, 8p, 9p, 9q, and 18q were shared between primary tumors and their metastases. Nevertheless, LOH of 6q and 11q and LOH of 7q not detected in primary tumors were, respectively, observed in two lymph node metastases. These results suggest that loss of p16INK4a protein expression (but not p16INK4a gene mutation) and the losses of chromosome arms 6q, 7q, and 11q play an important role in the acquisition of metastatic potential in sporadic melanoma. Furthermore, comparison of genetic profiles between the primary tumor and its metastasis revealed in several cases that heterogenous tumor cell populations might already exist at the early stage of tumorigenesis and evolve independently in the primary tumor and its metastasis, strongly suggesting that metastatic progression of sporadic melanoma is not accounted for by a linear progression model.
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PMID:Comparison of genetic profiles between primary melanomas and their metastases reveals genetic alterations and clonal evolution during progression. 985 96

Using different molecular techniques, DNA has been detected in the plasma of cancer patients with various types of tumors. We undertook the present study to investigate the presence of plasma DNA, before mastectomy, in patients with breast cancer at diagnosis and to analyze the clinicopathological spectrum of this subgroup of patients with respect to patients without DNA with tumor characteristics. We studied 62 patients with breast cancer, who were selected sequentially after mastectomy and diagnosis of breast carcinomas. Genomic DNA extracted from tumor and normal tissues, normal blood cells, and plasma was used for molecular studies. Alterations in polymorphic markers selected because they had been found to show a high rate of alterations in breast cancer in previous studies (D17S855, D17S654, D16S421, TH2, D10S197, and D9S161), as well as mutations in the p53 gene and aberrant methylation at the first exon of p16INK4a, were used to identify and characterize tumor and plasma DNA. Thirteen clinicopathological parameters were analyzed in each patient. We identified 56 cases (90%) with at least one molecular event in tumor DNA, and 41 cases (66%) with a similar alteration in plasma DNA. Comparison of the clinicopathological parameters between patients with and without plasma DNA revealed significant differences in the axillary involvement, rate of invasive ductal carcinoma, high proliferative index, and the parameter comprised of lymph node metastases, histological grade II, and peritumoral vessel involvement. A high proportion of breast cancer patients exhibited plasma DNA at diagnosis similar to tumor DNA, and its presence correlated significantly with pathological parameters associated with a poor prognosis.
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PMID:Presence of tumor DNA in plasma of breast cancer patients: clinicopathological correlations. 1039 73

The cyclin dependent kinase inhibitor p27 binds to and inhibits preferentially S-phase kinases thereby halting cell cycle progression. Loss of p27 expression has been shown to be associated with aggressive behavior in a variety of human epithelial tumors including prostate cancer. In this review, the role of p27 in cell cycle progression as well as its regulation by the ubiquitin-proteasome pathway are discussed. The experimental evidence pointing to the role of p27 as a tumor suppressor gene is outlined. The data generated to date on the prognostic significance of loss of p27 protein expression in human prostate cancers are summarized. Finally, the implications of the changes in p27 expression which occur as a result of androgen ablation in normal and neoplastic prostate are discussed.
Cancer Metastasis Rev
PMID:Role of p27 in prostate carcinogenesis. 1045 77

Transformation of normal melanocytes to metastatic melanoma cells is characterized by loss of dependency on external growth factors required for the viability and proliferation of normal melanocytes. The molecular events that lead to melanoma cell autonomous growth are not well defined, but are likely to include sustained activity of cyclin-dependent kinases (CDK2, CDK4 and CDK6) as a result of loss of CDK inhibitors (such as p16INK4a and possibly p27KIP1), and persistent upregulation of several cyclins (cyclin D1, cyclin A and cyclin E), the positive regulators of CDKs. CDKs phosphorylate, and consequently, inactivate the retinoblastoma family of tumor suppressor proteins (pRb, p107 and p130), termed pocket proteins. The inactivation of pocket proteins liberates E2F transcription factors from suppressive complexes ('free' E2F) that, in turn, induces the continuous expression of target genes whose products promote cell cycle progression. In normal melanocytes, external growth factors suppress the activity of all three pocket proteins, allowing E2F activity to accumulate and sustain transcription of target genes required for cell proliferation. In contrast, in melanoma cells from advanced lesions, all three pocket proteins are highly phosphorylated and inactive, even in the absence of environmental mitogens, and free E2F activity is constitutively high. Manipulations of normal mouse melanocytes in vitro, and in vivo in transgenic mouse expressing ectopic genes, further support the notion that growth rate, and release from dependency on external mitogens, positively correlate with inactivation of pocket proteins. The latter has been accomplished by sustained cell surface receptor stimulation, such as constitutive high expression of a growth factor, or by sequestration with dominantly acting viral proteins. Taken together, chronic hyperphosphorlyation/inactivation of pRb, p107 and p130 is probably one of the key events in converting growth-factor dependent normal melanocytes, to autonomously growing melanoma cells. Since all pocket proteins are regulated by CDKs activity, it is likely that agents that inhibit this class of enzymes will be effective in treating melanoma patients.
Cancer Metastasis Rev 1999
PMID:Melanoma cell autonomous growth: the Rb/E2F pathway. 1072 88

Malignant melanoma (MM) is thought to arise by sequential accumulation of genetic alterations in normal melanocytes. Previous cytogenetic and molecular studies indicated the 9p21 as the chromosomal region involved in MM pathogenesis. In addition to the CDKN genes (p16/CDKN2A, p15/CDKN2B and p19(ARF), frequently inactivated in familial MM), widely reported data suggested the presence within this region of other melanoma susceptibility gene(s). To clearly assess the role of the 9p21 region in sporadic melanoma, we evaluated the presence of microsatellite instability (MSI) and loss of heterozygosity (LOH) in primary tumours as well as in synchronous or asynchronous metastases obtained from the same MM patients, using 9 polymorphic markers from a 17-cM region at 9p21. LOH and MSI were found in 27 (41%) and 11 (17%), respectively, out of 66 primary tumours analysed. In corresponding 58 metastases, MSI was found at higher rate (22; 38%), whereas a quite identical pattern of allelic deletions with 27 (47%) LOH+ cases were observed. Although the CDKN locus was mostly affected by LOH, an additional region of common allelic deletion corresponding to marker D9S171 was also identified. No significant statistical correlation between any 9p21 genetic alteration (LOH, MSI or both) and clinicopathological parameters was observed.
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PMID:Definition of the role of chromosome 9p21 in sporadic melanoma through genetic analysis of primary tumours and their metastases. The Melanoma Cooperative Group. 1110 70

CDKN2A (INK4a/ARF) is frequently disrupted in various types of human cancer, and germline mutations of this locus can confer susceptibility to melanoma and other tumours. However, because CDKN2A encodes two distinct cell cycle inhibitory proteins, p16INK4a and p14ARF (p19Arf in mice), the mechanism of tumour suppression by CDKN2A has remained controversial. Genetic disruption of Cdkn2a(p19Arf) (hereafter Arf) alone predisposes mice to tumorigenesis, demonstrating that Arf is a tumour-suppressor gene in mice. We mutated mice specifically in Cdkn2a(p16Ink4a) (hereafter Ink4a). Here we demonstrate that these mice, designated Ink4a*/*, do not show a significant predisposition to spontaneous tumour formation within 17 months. Embryo fibroblasts derived from them proliferate normally, are mortal, and are not transformed by oncogenic HRAS. The very mild phenotype of the Ink4a*/* mice implies that the very strong phenotypes of the original Ink4a/ArfDelta2,3 mice were primarily or solely due to loss of Arf. However, Ink4a*/Delta2,3 mice that are deficient for Ink4a and heterozygous for Arf spontaneously develop a wide spectrum of tumours, including melanoma. Treatment of these mice with the carcinogen 7,12-dimethylbenzanthracene (DMBA) results in an increased incidence of melanoma, with frequent metastases. Our results show that, in the mouse, Ink4a is a tumour-suppressor gene that, when lost, can recapitulate the tumour predisposition seen in humans.
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PMID:Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. 1154 30

Clinical studies suggest prognostic relevance of p16INK4A in nonsmall cell lung cancer (NSCLC) while conflicting results for p53 have been published. However, the importance of the apoptosis regulating gene BAX, a downstream regulator of p53, on the prognosis of NSCLC is unknown. The present study investigated the prognostic relevance of BAX with respect to the status of p53 and P16INK4A in 61 patients with advanced NSCLC. Protein expression of BAX, p53 and p16INK4A was investigated retrospectively by immunohistochemistry. Tumour deoxyribonucleic acid (DNA) was screened for p53 mutations by single strand-conformation polymorphism polymerase chain reaction (PCR) and BAX frameshift mutations by fragment length analysis. Patients with positive BAX protein expression had a significantly longer median survival (14 months) than those patients without BAX expression (6 months, p=0.0004). In contrast, p53 status did not influence prognosis. Patients with p161NK4A negative tumours had a significantly shorter survival (4 months) than those with p16INK41 protein expression (15 months, p=0.0001). Furthermore, the loss of p16INK4A protein expression correlated strongly with the pressure of distant and advanced lymph-node metastases. The best survival was seen in a subgroup of 20 patients with positive p16INK4A expression and intact BAX (p=0.0002). The results of the present study suggest that the loss of BAX and p16INK4A expression are independent markers for poor prognosis in nonsmall cell lung cancer. The study suggests that multimarker analysis of genes involved in apoptosis may be useful for determining individual therapy and for identifying targets for gene-replacement therapy. This should be assessed in a prospective study with a larger cohort of patients.
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PMID:BAX and p16INK4A are independent positive prognostic markers for advanced tumour stage of nonsmall cell lung cancer. 1184 12

Lack of p14ARF expression or its functional inactivation has been observed in human and murine carcinomas. Although very few mutations of p14ARF have been detected in some cancer types, changes in expression seem to play an important role in the development of other human cancers such as mesotheliomas. To examine the p14ARF gene and expression of p14ARF protein in melanomas, we screened eight human melanoma cell lines and primary human melanocytes by RT-PCR, sequencing and immunoblotting. All melanoma cell lines analyzed expressed wild-type p14ARF mRNA as well as protein. P14ARF expression was investigated by immunohistochemical staining of 32 tissue samples of benign melanocytic nevi (n=14), melanomas (n=12) and melanoma metastases (n=6). In contrast to the results obtained from cell lines in vitro the immunohistochemical stainings revealed a correlation between the progression of melanoma and the lack of the p14ARF protein expression. Positive p14ARF protein staining was observed in 11 of 14 benign nevi, in 3 of 12 melanomas and in 0 of 6 melanoma metastases. In summary, we demonstrated a significant inverse correlation between p14ARF protein expression and progression of melanocytic tumors since the amount of p14ARF protein staining decreased from benign melanocytic nevi to metastatic melanoma in situ. These results suggest that p14ARF inactivation is important in the development of melanomas.
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PMID:Loss of p14ARF expression in melanoma. 1187 22

Oncogene and suppressor gene expression (cyclin D, p21WAF1, nm23-H1, Rb1, p16INK4A, and p53) was evaluated in 23 follicular thyroid carcinomas diagnosed in 20 women and 3 men operated or reoperated in Institute of Oncology in Gliwice in years 1992-1999. Positive reaction with p16INK4A, Rb1 and cyclin D1 antibodies was observed in all tumors, with nm23-H1 in 22 cases. The presence of p21WAF1 was stated in 8 cases (34.8%) and p53 in 7 cases (30.4%). A simultaneous presence of expression of p53 and lack of expression of p21WAF1 was stated three times and in two cases were accompanied by distant metastases. This pattern of expression was only rarely observed in minimally invasive follicular cancer. The prognostic significance of simultaneous immunohistochemical analysis of p53 and p21WAF1 in follicular thyroid carcinoma is suggested and has to be proved in further studies.
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PMID:[Prognostic significance of selected oncogene and suppressor gene expression in follicular thyroid carcinoma]. 1218 65


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