Homozygous deletion of CDKN2A and codeletion of the methylthioadenosine phosphorylase gene in the majority of pleural mesotheliomas Journal Article
| Authors: | Illei, P. B.; Rusch, V. W.; Zakowski, M. F.; Ladanyi, M. |
| Article Title: | Homozygous deletion of CDKN2A and codeletion of the methylthioadenosine phosphorylase gene in the majority of pleural mesotheliomas |
| Abstract: | Purpose: Homozygous deletions at chromosome region 9p21 targeting the CDKN2A gene have been reported as a common cytogenetic abnormality in mesothelioma. MTAP, a gene ∼100-kb telomeric to CDKN2A, encodes methylthioadenosine phosphorylase, an enzyme essential in the salvage of cellular adenine and methionine, and its codeletion with CDKN2A has been reported in other tumors. The aim of this study was to define the prevalence of homozygous deletion of CDKN2A alone or in combination with MTAP in a large series of pleural mesothelioma. Experimental Design: We used a fluorescent in situ hybridization assay for CDKN2A and MTAP on interphase nuclei in imprints of frozen tissue from 95 cases of pleural mesothelioma. Histologically, the cases were classified as epithelial (71), biphasic (19) and sarcomatous (5). In each experiment, a 9p21 locus specific probe and a chromosome 9 centromeric probe were used and fluorescent in situ hybridization signals for both probes were simultaneously recorded in at least 100 nuclei. Cases were considered homozygously deleted if both 9p21 signals were lost in at least 20% of nuclei. Results: Overall, 70 cases (74%) had homozygous deletion of CDKN2A. MTAP was codeleted in 64 of these cases (91%). No case with MTAP deletion without CDKN2A deletion was identified. Homozygous loss of CDKN2A was seen in 49 of 71 epithelial (70%), 16 of 19 biphasic (89%), and 5 of 5 sarcomatous (100%) mesotheliomas. Conclusions: Homozygous deletion of CDKN2A is seen in the majority of pleural mesotheliomas, and MTAP is codeleted in most of these cases. Previous cell line studies have shown that loss of MTAP renders cells dependent on de novo synthesis of purine derivatives. Thus, the particularly high prevalence of MTAP codeletion in mesothelioma makes it an ideal candidate for trials of targeted therapy using inhibitors of de novo AMP synthesis (e.g., L-alanosine). |
| Keywords: | adult; human tissue; aged; middle aged; unclassified drug; major clinical study; gene deletion; histopathology; drug targeting; gene; in situ hybridization, fluorescence; prevalence; chromosome 9p; gene product; cytogenetics; carcinogenesis; cell type; homozygosity; correlation analysis; fluorescence in situ hybridization; pleura mesothelioma; mesothelioma; purine derivative; pleural neoplasms; centromere; purine-nucleoside phosphorylase; genes, p16; cdkn2a gene; 5' methylthioadenosine phosphorylase; humans; human; male; female; priority journal; article; phosphorylase; purine synthesis; mtap gene |
| Journal Title: | Clinical Cancer Research |
| Volume: | 9 |
| Issue: | 6 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2003-06-01 |
| Start Page: | 2108 |
| End Page: | 2113 |
| Language: | English |
| PUBMED: | 12796375 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
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