Detection of methylthioadenosine phosphorylase (MTAP) and p16 gene deletion in T cell acute lymphoblastic leukemia by real-time quantitative PCR assay

M'soka, TJ; Nishioka, Junji; Taga, Atsushi; Kato, Koji; Kawasaki, Hiromu; Yamada, Yasuaki; Yu, Alice L.; Komada, Yoshihiro; Nobori, Tsutomu

doi:10.1038/sj.leu.2401771

Cited by 36 publications

(18 citation statements)

References 26 publications

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“…We found a bi-allelic deletion of MTAP in 38% of the T-ALLs studied, corresponding to 53% of cases with a CDKN2A deletion. These results are consistent with those of Batova et al (1996) andM'Soka et al (2000), who reported frequencies of 33 and 38%, respectively. Moreover, our real-time PCR assay permitted detection of an MTAP heterozygous deletion in 17% of cases.…”

Section: Discussionsupporting

confidence: 93%

CDKN2A, CDKN2B, and MTAP gene dosage permits precise characterization of mono‐ and bi‐allelic 9p21 deletions in childhood acute lymphoblastic leukemia

Bertin

Acquaviva

Mirebeau

et al. 2003

Genes Chromosomes & Cancer

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Deletion of the 9p21 chromosomal region is frequently found in childhood acute lymphoblastic leukemia (ALL). The target of these deletions is CDKN2A, a gene encoding both p16(INK4a) and p14(ARF). However, contiguous genes such as CDKN2B, encoding p15(INK4b), or MTAP, encoding methylthioadenosine phosphorylase, can be included in the deletions. Gene dosage by use of real-time PCR has recently been proposed as a promising technical option for the diagnosis of deletions. However, its reliability and its capacity to detect mono-allelic deletions in tumor samples are controversial. To evaluate the frequency and extent of deletions in 284 children with ALL, we devised a real-time PCR assay for CDKN2A, CDKN2B exons 1beta and 3, and MTAP gene dosage and validated it by comparison with loss-of-heterozygosity analysis. We show that, if several controls and adjustments are performed, real-time PCR can provide a reliable test for mono- and bi-allelic deletions in ALL. We propose a strategy that overcomes the major caveats of such a dosage in tumor samples: aneuploidy and contamination by normal cells. By use of this assay, we found bi-allelic deletions in 58 and 17% of T- and B-lineage ALL, respectively. Mono-allelic deletion was observed in about 15% of cases, stressing the importance of their detection in ALL. CDKN2B and/or MTAP co-deletions were highly variable in both T- and B-lineage ALL, making ALL with 9p21 a rather heterogeneous group. Because proteins encoded by these genes might influence the response to treatment, the prognosis of 9p21-deleted ALL could vary according to the extent of the deletion.

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Section: Discussionsupporting

confidence: 93%

CDKN2A, CDKN2B, and MTAP gene dosage permits precise characterization of mono‐ and bi‐allelic 9p21 deletions in childhood acute lymphoblastic leukemia

Bertin

Acquaviva

Mirebeau

et al. 2003

Genes Chromosomes & Cancer

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“…The use of Q-PCR in the detection of genomic deletions has been applied in a number of cancer studies (Braga et al, 2002;M'soka et al, 2000;Senchenko et al, 2003). Recently, Senchenko et al (2003) showed that this technique is sensitive enough to distinguish between one and two alleles by examining differences in gene dosage between the X and Y chromosomes.…”

Section: E Expression Of Genes Located In Common R Regions Of Loss Ormentioning

confidence: 99%

“…We also report deletion of CBX7 at 22q13 in more 7 than 50% of ependymomas as validated by Q-PCR. Real-time PCR provides a means for continuous detection of product throughout the amplifi cation process, and this technique has been used to detect deletions and duplications in cancer (M'soka et al, 2000;Senchenko et al, 2003). Unlike loss of heterozygosity (LOH) analysis, it is not necessary to identify polymorphic markers.…”

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confidence: 99%

Microarray analysis of pediatric ependymoma identifies a cluster of 112 candidate genes including four transcripts at 22q12.1-q13.3

Suárez-Merino¹,

Hubank²,

Révész³

et al. 2005

Neuro-Oncol

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Ependymomas are glial cell-derived tumors characterized by varying degrees of chromosomal abnormalities and variability in clinical behavior. Cytogenetic analysis of pediatric ependymoma has failed to identify consistent patterns of abnormalities, with the exception of monosomy of 22 or structural abnormalities of 22q. In this study, a total of 19 pediatric ependymoma samples were used in a series of expression profi ling, quantitative real-time PCR (Q-PCR), and loss of heterozygosity experiments to identify candidate genes involved in the development of this type of pediatric malignancy. 12,627 genes analyzed, a subset of 112 genes emerged as being abnormally expressed when compared to three normal brain controls. Genes with increased expression included the oncogene WNT5A; the p53 homologue p63; and several cell cycle, cell adhesion, and proliferation genes. Underexpressed genes comprised the NF2 interacting gene SCHIP-1 and the adenomatous polyposis coli (APC)-associated gene EB1 among others. We validated the abnormal expression of six of these genes by Q-PCR. The subset of differentially expressed genes also included four underexpressed transcripts mapping to 22q12.3-13.3. By Q-PCR we show that one of these genes, 7 CBX7 (22q13.1), was deleted in 55% of cases. Other genes mapping to cytogenetic hot spots included two overexpressed and three underexpressed genes mapping to 1q31-41 and 6q21-q24.3, respectively. These genes represent candidate genes involved in ependymoma tumorigenesis. To the authors' knowledge, this is the fi rst time microarray analysis and Q-PCR have been linked to identify heterozygous/homozygous deletions.- Neuro-Oncology 7, 20-31, 2005 (Posted to Neuro-Oncology [serial online], Doc. y 04-059, December 6, 2004

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“…1). Loss of MTAP expression has been observed in many different tumor-derived cell lines and primary tumors including gliomas, osteosarcoma, melanoma, non-small-cell lung cancers, and T-cell acute lymphocytic leukemia (5)(6)(7)(8)(9). Loss of MTAP activity in tumors is primarily thought to be because of homozygous deletion of the MTAP gene that is located on human chromosome 9p21, approximately 100 Kb distal to the p16(INK4a)/p14(ARF) tumor suppressor gene (10).…”

Section: Introductionmentioning

confidence: 99%

Loss of Methylthioadenosine Phosphorylase and Elevated Ornithine Decarboxylase Is Common in Pancreatic Cancer

Subhi¹,

Tang²,

Balsara³

et al. 2004

Clinical Cancer Research

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Purpose: Loss of the methylthioadenosine phosphorylase (MTAP) gene at 9p21 is observed frequently in a variety of human cancers. We have shown previously that MTAP can act as a tumor suppressor gene and that its tumor suppressor function is related to its effect on polyamine homeostasis. Ornithine decarboxylase is a key enzyme in the regulation of polyamine metabolism. The aim of this study is to analyze MTAP and ornithine decarboxylase (ODC) expression in primary pancreatic tumor specimens.Experimental Design: We measured MTAP and ODC activity in protein extracts derived from 30 surgically resected tumor samples and eight normal pancreas samples. In a subset of six samples, we also examined MTAP DNA using interphase fluorescence in situ hybridization. In addition, we examined the effect of the ODC inhibitor difluoromethylornithine on two pancreatic adenocarcinoma-derived cell lines.Result: MTAP activity was 2.8-fold reduced in adenocarcinomas and 6.3-fold reduced in neuroendocrine tumors compared with control pancreas. Conversely, ODC activity was 3.6-fold elevated in adenocarcinomas and 3.9-fold elevated in neuroendocrine tumors compared with control pancreas. Using interphase fluorescence in situ hybridization, we found in tumor samples that 43 to 75% of the nuclei had lost at least one copy of MTAP locus, indicating that loss of MTAP activity was at least partially because of deletion of the MTAP locus. We also show that inhibition of ODC by difluoromethylornithine caused decreased cell growth and increased apoptosis in two MTAP-deleted pancreatic adenocarcinoma-derived cell lines.Conclusions: MTAP activity is frequently lost, and ODC activity is frequently elevated in both pancreatic adenocarcinoma and neuroendocrine tumors. Inhibition of ODC activity caused decreased cell growth and increased apoptosis in pancreatic tumor-derived cell lines. These findings suggest that MTAP and polyamine metabolism could be potential therapeutic targets in the treatment of pancreatic cancer.

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Detection of methylthioadenosine phosphorylase (MTAP) and p16 gene deletion in T cell acute lymphoblastic leukemia by real-time quantitative PCR assay

Cited by 36 publications

References 26 publications

CDKN2A, CDKN2B, and MTAP gene dosage permits precise characterization of mono‐ and bi‐allelic 9p21 deletions in childhood acute lymphoblastic leukemia

CDKN2A, CDKN2B, and MTAP gene dosage permits precise characterization of mono‐ and bi‐allelic 9p21 deletions in childhood acute lymphoblastic leukemia

Microarray analysis of pediatric ependymoma identifies a cluster of 112 candidate genes including four transcripts at 22q12.1-q13.3

Loss of Methylthioadenosine Phosphorylase and Elevated Ornithine Decarboxylase Is Common in Pancreatic Cancer

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