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)

Homozygous deletions of human chromosomal region 9p21 occur frequently in malignant melanoma and are associated with the loss of the tumor suppressor genes p16(INK4a) and p15(INK4b). In the same chromosomal region the methylthioadenosine phosphorylase (MTAP) gene is localized and therefore may also serve as a tumor suppressor gene. The aim of this study was to analyze MTAP mutations and expression patterns in malignant melanomas. To examine the MTAP gene and expression of MTAP protein we screened 9 human melanoma cell lines and primary human melanocytes by reverse transcriptase-polymerase chain reaction, sequencing, and immunoblotting. Analyzing the melanoma cell lines we found significant down-regulation of MTAP mRNA expression. In only one cell line, HTZ19d, this was due to homozygous deletion of exon 2 to 8 whereas in the other cell lines promoter hypermethylation was detected. MTAP expression was further analyzed in vivo by immunohistochemical staining of 38 tissue samples of benign melanocytic nevi, melanomas, and melanoma metastases. In summary, we demonstrate significant inverse correlation between MTAP protein expression and progression of melanocytic tumors as the amount of MTAP protein staining decreases from benign melanocytic nevi to metastatic melanomas. Our results suggest an important role of MTAP inactivation in the development of melanomas. This finding may be of great clinical significance because recently an association between MTAP activity and interferon sensitivity has been suggested.
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PMID:Characterization of methylthioadenosin phosphorylase (MTAP) expression in malignant melanoma. 1287 87

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