Disease relevance of CDKN2B

• Taken together, these results suggest that intragenic mutations in CDKN2A and CDKN2B occur in esophageal cancer, but that they are infrequent events [1].
• In conjunction with our previously published data, we have identified a total of eight nucleic acid substitutions among 60 esophageal carcinomas; here, we describe one new CDKN2B nonsense mutation and one new silent CDKN2B mutation that occurred somatically [1].
• Messenger RNA (mRNA) analysis showed that CDKN2C is expressed in all hepatoblastoma samples studied, while both CDKN2A and CDKN2B genes are not transcribed in the cancer specimens as well as in the matched normal liver tissues [2].
• The 500 C>G polymorphism, however, was in linkage disequilibrium with approximately 50 kb apart the C>A intronic polymorphism in the CDKN2B gene (determined in 44 melanomas and 90 controls; Fisher exact test, p<0.0001) [3].
• Genomic DNA and messenger RNA expression alterations of the CDKN2B and CDKN2 genes in esophageal squamous carcinoma cell lines [4].

High impact information on CDKN2B

• The cytokine TGF-beta inhibits growth by causing cell-cycle arrest as a result of increasing the concentration of the Cdk4/6 inhibitor p15(INK4B/MTS2) (refs 3, 4) [5].
• METHODS: The status of the INK4A and INK4B genes was determined in 46 soft tissue sarcomas by use of the following methods: Southern blotting, polymerase chain reaction (PCR), single-strand conformation polymorphism analysis, comparative multiplex PCR, and a methylation assay focusing on the p16 promoter [6].
• BACKGROUND: The INK4A and INK4B genes map to chromosome 9p21, with the INK4A gene encoding two protein products, p16 and pl9ARF [6].
• Alterations of INK4A and INK4B genes in adult soft tissue sarcomas: effect on survival [6].
• No CDKN2A exon 1beta or CDKN2B mutations were identified [7].

Chemical compound and disease context of CDKN2B

• At first or subsequent relapses, owing to highly effective salvage by arsenic trioxide, CDKN2B methylation did not impact on event-free survival or overall survival [8].
• Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2'-deoxycytidine (decitabine) treatment [9].
• At a concentration of 6.8 microM, F23Q also substantially inhibited the mineralization of benz[a]anthracene, benzo[a]pyrene (BaP), and chrysene by strain R1 as well as BaP mineralization by Pseudomonas saccharophila P15 [10].

Biological context of CDKN2B

• In view of the known high frequency of loss of heterozygosity at the chromosome 9p21 locus in esophageal cancers, the current data suggest that intragenic mutation is not the predominant mode of inactivation of CDKN2A and CDKN2B or that other genes are targets of deletion at this locus in these cancers [1].
• Structural analysis of the CDKN2A, CDKN2B, and CDKN2C genes in hepatoblastoma cases showed the absence of deletions and/or point mutations [2].
• Partial or complete methylation of the majority of CpG sites analyzed from each gene was detected in 32% of the tumors at the CDKN2A gene and at a similar percentage (41%) of the tumors at the p14ARF gene and the CDKN2B gene [11].
• Thus, it was indicated that the CDKN2A gene rather than the CDKN2B gene plays a critical role as a tumor suppressor gene in NSCLC [12].
• CDKN2 and CDKN2B belong to a family of cyclin-dependent kinase 4 inhibitors (INK41) and control cell proliferation during the G1 phase of the cell cycle [4].

Anatomical context of CDKN2B

• Two of the cell lines manifested homozygous deletions excluding CDKN2; one of these two deletions also excluded CDKN2B [4].
• The genes encoding the cyclin-dependent kinase inhibitors p16INK4A (CDKN2A) and p15INK4B (CDKN2B) are frequently homozygously deleted in a variety of tumor cell lines and primary tumors, including glioblastomas in which 40-50% of primary tumors display homozygous deletions of these two loci [13].
• De novo methylation of tumour suppressor genes CDKN2A and CDKN2B is a rare finding in B-cell chronic lymphocytic leukaemia [14].
• METHODS AND RESULTS: Using a combination of DNA sequencing, gene copy number by real time quantitative PCR, linkage analysis, and transcript analysis in haploid somatic cell hybrids, we found no evidence for germline alteration in either coding or non-coding domains of CDKN2A and CDKN2B [15].
• MTS1 but not MTS2 RNA was detected by Northern blotting in the human thymus [16].

Associations of CDKN2B with chemical compounds

• Serial studies of methylation of CDKN2B and CDKN2A in relapsed acute promyelocytic leukaemia treated with arsenic trioxide [8].
• Only G15 iron deficient rats had greater dopaminergic activity than controls as indicated by increased tyrosine hydroxylase levels, phosphorylated tyrosine hydroxylase levels, and cellular dopamine in prefrontal cortex and striatum at P15 [17].
• Circulating testosterone levels peak in male ferrets on postnatal day P15, and mothers provide maximal anogenital stimulation (AGS) to males at this same age [18].
• There were fewer glial cells per cross-section on day 15 and the cross-sectional areas of optic nerves were smaller on days G20, P15 and P90 in the ethanol exposed animals [19].
• Dispersion of ABM/P-15 in sodium hyaluronate carrier (PPutty) improves the handling properties of the graft material [20].

Other interactions of CDKN2B

• Intragenic mutations of CDKN2B and CDKN2A in primary human esophageal cancers [1].
• Indeed, p16INK4A and p15INK4B (products of expression of CDKN2A and CDKN2B respectively) were not observable while pl8INK4C (which is codified by CDKN2C) was clearly detectable in the samples analyzed [2].
• Interphase fluorescence in situ hybridization was performed on these samples using a 250-kb cosmid contig (COSp16), which encompasses MTAP, CDKN2A, and CDKN2B [21].
• These findings suggest that variable expression levels of cell-cycle inhibitor genes CDKN2A, CDKN2B, and CDKN1B due to regulatory polymorphisms could indeed influence the risk of childhood pre-B ALL and contribute to carcinogenesis [22].
• Yeast artificial chromosome (YAC) mapping localized PLAA proximal to the CDKN2A/CDKN2B genes and to a region flanked by D9S171 and INFA commonly deleted in many neoplasms [23].

Analytical, diagnostic and therapeutic context of CDKN2B

• Polymerase chain reaction (PCR) amplification revealed that five of the nine cell lines (55%) manifested homozygous deletions of CDKN2B, CDKN2, and/or flanking loci on chromosomal band 9p21 [4].
• Reverse transcriptase-PCR (RT-PCR) was used to examine CDKN2 and CDKN2B mRNA in the nine cell lines [4].
• Bi-allelic CDKN2B and MTAP co-inactivation were found in 36 (16%) and 24 (11%) of patients, respectively, and did not influence the 6-year event-free survival rate either, even when the analysis was restricted to CDKN2A inactivated ALL [24].
• Radiation hybrid mapping placed the gene 7.69 cR from WI-5735 (LOD >3.0), a marker in close proximity to CDKN2A and CDKN2B [23].
• In a series of 46 glioblastomas, 16 anaplastic astrocytomas and eight astrocytomas, all tumours retaining one or both alleles of CDKN2A (48 tumours) and CDKN2B (49 tumours) were subjected to sequence analysis (entire coding region and splice acceptor and donor sites) [25].

References