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)

Episodic exposure of fair-skinned individuals to intense sunlight is thought to be responsible for the steadily increasing melanoma incidence worldwide over recent decades. Rarely, melanoma susceptibility is increased more than tenfold by heritable mutations in the cell cycle regulatory genes CDKN2A and CDK4. Effective treatment requires early diagnosis followed by surgical excision with adequately wide margins. Sentinel lymph node biopsy provides accurate staging, but no published results are yet available from clinical trials designed to assess the therapeutic efficacy of early complete regional node dissection in those with metastatic disease in a sentinel node. Magnetic resonance spectroscopy is one technique under investigation for non-invasive, in-situ assessment of sentinel nodes. Localised metastatic disease is best treated surgically. No postoperative adjuvant therapy is of proven value for improving overall survival, although numerous clinical trials of vaccines and cytokines are in progress. Medical therapies have contributed little to the control of established metastatic disease, but molecular pathways recently identified as being central to melanoma growth and apoptosis are under intense investigation for their potential as therapeutic targets.
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PMID:Cutaneous melanoma. 1595 Jul 9

The gene that encodes methylthioadenosine phosphorylase (MTAP), an enzyme involved in adenine and methionine salvage pathways, is located on chromosome 9p21 telomeric to the p16INK4A/CDKN2A tumor suppressor gene. Inactivation of the p16INK4A/CDKN2A gene occurs by three different mechanisms: hypermethylation of the gene promoter, intragenic mutation coupled with loss of the second allele, and homozygous deletion. Immunohistochemical labeling for the p16INK4A/CDKN2A gene product parallels gene status but does not elucidate the mechanism of gene inactivation. Since the MTAP gene is often co-deleted with p16INK4A/CDKN2A, concurrent immunolabeling for both proteins can identify cases with homozygous p16INK4A/CDKN2A gene deletion. MTAP loss itself has therapeutic implications since it may confer selective sensitivity to inhibitors of de novo purine biosynthesis, such as L-alanosine. Twelve tissue microarrays were constructed from 92 cases of Barrett-associated adenocarcinomas and precursor lesions and 112 cases of gastric adenocarcinoma and precursor lesions comprising 1161 individual cores. Multiple cores were arrayed from any given case, and when available, included the entire histologic spectrum of intestinal metaplasia-dysplasia-carcinoma. Tissue microarrays were labeled with monoclonal antibodies against MTAP protein (clone 6.9, Salmedix, Inc) and p16 (clone 16P07, Neomarkers). Complete loss of labeling was considered negative, while any labeling (p16: nuclear; MTAP: cytoplasmic and nuclear) was considered positive. Loss of MTAP labeling occurred exclusively in conjunction with loss of p16 labeling, confirming that the previous findings from this group that concurrent loss of MTAP and p16 labeling is a surrogate marker of 9p21 homozygous deletions. Complete loss of MTAP and p16 was seen in 4 of 25 (16%) patients with Barrett's esophagus, 4 of 18 (22%) with low-grade dysplasia, 5 of 39 (13%) with high-grade dysplasia, 17 of 78 (22%) with invasive adenocarcinoma, and 8 of 36 (22%) of metastases. There were 7 cases of esophageal adenocarcinoma with loss of both MTAP and p16 for which precursor lesions were available. In 6 on these 7 cases (85%), the precursor lesion(s) had loss of both MTAP and p16. Lack of MTAP and p16 expression was seen in 11 of 106 (10%) cases of gastric adenocarcinoma. All metaplastic (30 biopsies from 20 cases) and dysplastic (15 biopsies from 13 cases) gastric tissues had both intact MTAP and p16INK4A/CDKN2A gene products. No precursor lesions were available from the gastric cancers that had loss of both MTAP and p16. Two benign gastric hyperplastic polyps also had intact p16 and MTAP. Concurrent MTAP and p16 loss detected by immunohistochemistry can serve as a convenient surrogate for p16INK4A/CDKN2A gene homozygous deletion in archival tissues. Inactivation of p16INK4A/CDKN2A by homozygous deletion appears to be an early event in Barrett carcinogenesis, occurring in noninvasive precursor lesions, including nondysplastic Barrett mucosa, in subsets of cases. In the absence of MTAP, cells depend exclusively on the de novo synthesis pathway for production of adenosine. This loss of MTAP during 9p21 homozygous deletion might be exploited therapeutically using de novo purine synthesis antimetabolites to treat a subset of invasive gastroesophageal adenocarcinomas and esophageal precursor lesions.
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PMID:Concordant loss of MTAP and p16/CDKN2A expression in gastroesophageal carcinogenesis: evidence of homozygous deletion in esophageal noninvasive precursor lesions and therapeutic implications. 1622 17

Genetic alterations occur during the adenoma-carcinoma sequence of colon cancer formation and drive the initiation and progression of colon cancer formation. The aberrant methylation of genes is an alternate, epigenetic mechanism for silencing tumor suppressor genes in colon cancer. The aim of this study was to determine on a global and gene-specific level the role of CpG island methylation in the initiation and progression of colon cancer. Consequently, we assessed the frequency of gene methylation in tumors representative of the commonly recognized histological steps of the adenoma-carcinoma progression sequence through the analysis of eight genes previously identified to be methylated in colon cancer, MGMT, HLTF, MLH1, p14(ARF), CDKN2A, TIMP3, THBS1, and CDH1. We observed that the proportion of tumors carrying methylated alleles increased from adenomas to adenocarcinomas but that the proportion of tumors with methylated alleles was not different between adenocarcinomas and metastases (69% versus 90%, P = 0.01 and 90% versus 81%, P > 0.05). The most substantial difference occurred between early and advanced adenomas (47% versus 84%, P = 0.018). Furthermore, we observed that the frequency of gene methylation at the different steps of the progression sequence varied between genes. Thus, the aberrant methylation of genes appears to increase most significantly during the progression of early adenomas to advanced adenomas, and the frequency of specific gene methylation at the different steps of the adenoma-carcinoma progression sequence varies in a gene-specific fashion.
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PMID:CpG island methylation of genes accumulates during the adenoma progression step of the multistep pathogenesis of colorectal cancer. 1670 52

Hypermethylation in the promoter region has been associated with a loss of gene function that may give a selective advantage to neoplastic cells. In this study, the methylation pattern of genes CDKN2A (alias p14, p14(ARF), p16, p16(INK4a)), DAPK1, CDH1, and ADAM23 was analyzed in 43 samples of head and neck tumors using methylation-specific polymerase chain reaction. In the oropharynx, there was a statistically significant association between hypermethylation of the DAPK1 gene and the occurrence of lymph node metastases, and in the larynx there was statistically significant evidence of an association between hypermethylation of the ADAM23 gene and advanced stages of the tumors. Thus, a correlation was observed between hypermethylation of the promoter region of genes DAPK1 and ADAM23 and the progression of head and neck cancer.
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PMID:Methylation profile of genes CDKN2A (p14 and p16), DAPK1, CDH1, and ADAM23 in head and neck cancer. 1728 67

The histologic differential diagnosis between a second primary cutaneous melanoma and cutaneous melanoma metastasis in a patient with a previous history of melanoma can be very difficult. This case report describes the first application of CDKN2A mutation analysis for discriminating a cutaneous melanoma metastasis from a new primary melanoma. In 2005, we received a skin excision of the right arm of a 38-year-old female patient for second opinion. Histologically, we considered the lesion to be a melanoma. The patient had a history of superficial spreading melanoma in the right subclavicular region, with a Breslow thickness of 1.1 mm, in 1998. The morphology showed resemblance to the present melanoma on the right arm, but the differential diagnosis between metastasis or second primary melanoma could not be made with certainty based on histology alone. We decided to perform TP53 and CDKN2A mutation analysis on both tumors. Molecular analysis revealed that both the melanoma of 1998 and of 2005 contained an identical CDKN2A mutation (a deletion in exon 1alpha, c.95_112del (p.Leu32_Leu37del)), which was absent in normal control tissue of the patient, thereby excluding a germline mutation. TP53 mutations were absent in both tumors and in normal skin. Based on these molecular findings the present melanoma on the right arm was diagnosed as a metastasis. Seven months later the patient died of widespread metastatic disease confirming the metastatic nature of the lesion. This case illustrates that molecular analysis can contribute to the sometimes-difficult differentiation between a second primary melanoma and a melanoma metastasis.
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PMID:CDKN2A (INK4A-ARF) mutation analysis to distinguish cutaneous melanoma metastasis from a second primary melanoma. 1741 13

Melanoma is the most dangerous of all common skin cancers, due to its propensity to metastasize. Therefore, identification of at-risk populations may allow early detection of disease at a curable stage. In Europe and North America, between 8-14% of melanoma patients have a family history of the disease, and a subset of these individuals possess germline mutations in the CDKN2A gene, which encodes the p16(INK4A) and p14(ARF) tumor suppressors. We identified 30 patients (29 families) from Southern Brazil, who had a family history of melanoma and/or pancreatic cancer; or a personal history of multiple primary melanoma. We screened this cohort for mutations in the CDKN2A and CDK4 genes, and detected two functional mutations: a G-34T transversion in 5'untranslated region; and a M53I alteration encoded in exon 2. Both mutants have been previously associated with melanoma and demonstrate founder effects. We conclude that germline mutations of CDKN2A occur in the Brazilian population, and that these mutations likely originated in Europe.
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PMID:Clinical and molecular characterization of patients at risk for hereditary melanoma in southern Brazil. 1771 69

This study sought to determine whether the presence of hypermethylated genes in the surgical margins can predict local recurrences in head and neck squamous cell carcinomas (HNSCCs). We prospectively collected tumour and surgical margin specimens from patients with HNSCCs who had undergone surgical resections. Quantitative methylation-specific PCR (QMSP) of CDKN2A, CCNA1 and DCC were performed in these specimens and correlated with clinical data. Of the 42 patients eligible for the study, 27 were hypermethylation informative for the above three genes. This latter group was associated with longer disease-free survivals (P=0.007) and longer time to disease-specific deaths (P=0.004). Multivariate analyses confirmed hypermethylation non-informative tumours as an independent prognosticating factor for disease-specific deaths (risk ratio 3.8, P=0.026). Quantitative MSP of the margins of 24 hypermethylation informative tumours revealed that 11 patients had molecularly positive margins, of which, five developed disease-specific events (DSEs, three local recurrences and two metastases), compared to none in patients with molecularly negative margins, after a median follow-up of 48 months. Log-rank analyses showed that molecularly positive margins were associated with shorter time to local recurrences and disease-specific deaths (P=0.03 and 0.01, respectively). This study demonstrated that QMSP of hypermethylated promoters in surgical margins predicted all the local recurrences in our series of HNSCC patients. We have also identified hypermethylation non-informative tumours as an independent predictor for the development of DSEs.
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PMID:Quantitative methylation analyses of resection margins predict local recurrences and disease-specific deaths in patients with head and neck squamous cell carcinomas. 1859 22

Chondrosarcomas are highly resistant to conventional radiation and chemotherapy, and surgical removal is the only option for curative treatment. Consequently, there is nothing to offer patients with inoperable tumours and metastatic disease. The aim of this study is to investigate genes involved in cell cycle control: CDK4, CDKN2A/p16, cyclin D1, p21, p53, MDM2 and c-MYC, which may point towards new therapeutic strategies. The pRb pathway was targeted using CDKN2A/p16 overexpressing vectors and shRNA against CDK4 in chondrosarcoma cell lines OUMS27, SW1353, and CH2879. Cell survival and proliferation were assessed. CDK4, MDM2 and c-MYC expression levels were investigated by qPCR and immunohistochemistry (IHC) in 34 fresh frozen and 90 FFPE samples of enchondroma and chondrosarcoma patients. On a subset of 29 high-grade chondrosarcomas IHC for cyclin D1, p21 and p53 was performed. The overexpression of CDKN2A/p16 and knockdown of CDK4 by shRNA in OUMS27, SW1353 and CH2879 resulted in a significant decrease in cell viability and proliferation and a decreased ability to form colonies in vitro. Expression of CDK4 and MDM2 was associated with high-grade chondrosarcoma both at the mRNA and protein level. Combining these results with the expression of cyclin D1 and the previously shown loss of CDKN2A/p16 expression show that the majority (96%; 28/29) of high-grade chondrosarcomas contain alterations in the pRb pathway. This suggests a role for the use of CDK4 inhibitors as a treatment of metastatic or inoperable high-grade chondrosarcoma.
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PMID:Central chondrosarcoma progression is associated with pRb pathway alterations: CDK4 down-regulation and p16 overexpression inhibit cell growth in vitro. 1862 51

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

Nonresectable ependymomas are associated with poor prognosis despite intensive radiochemotherapy and radiation. The molecular pathogenesis of ependymoma initiation and progression is largely unknown. We here present a case of therapy-refractory, progressive ependymoma with cerebrospinal as well as extraneural metastases, which allowed us for the first time to follow the stepwise accumulation of chromosome aberrations during disease progression. Genome-wide DNA copy-number analysis showed sequential deletions on chromosomes 1, 9, and 14 as well as a homozygous deletion of the CDKN2A locus, underscoring its role in tumor progression. Gradual loss at 1p36 was associated with loss of protein expression of the putative tumor suppressor gene AJAP1/SHREW1. In summary, this is the first report on acquired genomic aberrations in ependymoma over time pointing to novel candidate tumor suppressor genes. This analysis provides molecular insights into the chronology of genetic events in this case from initial localized tumor to widespread metastasized disease.
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PMID:Stepwise accumulation of distinct genomic aberrations in a patient with progressively metastasizing ependymoma. 1902 95


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