Homozygous deletions within human chromosome band 9p21 in melanoma.

Fountain, Jane W.; Karayiorgou, Maria; Ernstoff, Marc S.; Kirkwood, John M.; Vlock, Daniel R.; Titus-Ernstoff, Linda; Bouchard, Brigitte; Setaluri, Vijayasaradhi; Houghton, Alan N.; Lahti, Jill M.

doi:10.1073/pnas.89.21.10557

Cited by 272 publications

(126 citation statements)

References 34 publications

Supporting

Mentioning

117

Contrasting

Unclassified

Order By: Relevance

“…Homozygous deletions of chromosome 9p2i-p22 have been detected in various tumour types including leukaemia, mesothelioma, melanoma, bladder carcinomas, lung cancer and renal cell carcinoma (Diaz et al, 1990;Fountain et al, 1992;Cairns et al, 1993;Cheng et al, 1993;Mead et al, 1994). Recently, two putative tumour-suppressor genes p16 (MTS1) and p15 (MTS2), both encoding cyclin-dependent kinase 4 (CDK4) inhibitors, have been mapped to the short arm of chromosome 9 (p21) (Kamb et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Recurrent DNA copy number changes in 1q, 4q, 6q, 9p, 13q, 14q and 22q detected by comparative genomic hybridization in malignant mesothelioma

Björkqvist

Tammilehto²,

Anttila³

et al. 1997

Br J Cancer

View full text Add to dashboard Cite

Summary Comparative genomic hybridization (CGH) analyses were performed on 27 human pleural mesothelioma tumour specimens, consisting of 18 frozen tumours and nine paraffin-embedded tumours, to screen for gains and losses of DNA sequences. Copy number changes were detected in 15 of the 27 specimens with a range from one to eight per specimen. On average, more losses than gains of genetic material were observed. The loss of DNA sequences occurred most commonly in the short arm of chromosome 9 (p21-pter), in 60% of the abnormal specimens. Other losses among the abnormal specimens were frequently detected in the long arms of chromosomes 4 (q31 .1-qter, 20%), 6 (q22-q24, 33%), 13 (33%), 14 (q24-qter, 33%) and 22 (q13, 20%). A gain in DNA sequences was found in the long arm of chromosome 1 (cen-qter) in 33% of the abnormal specimens. Our analysis is the first genome-wide screening for gains and losses of DNA sequences using comparative genomic hybridization in malignant pleural mesothelioma tumours. The recurrent DNA sequence changes detected in this study suggest that the corresponding chromosomal areas most probably contain genes important for the initiation and progression of mesothelioma.

show abstract

Section: Discussionmentioning

confidence: 99%

Recurrent DNA copy number changes in 1q, 4q, 6q, 9p, 13q, 14q and 22q detected by comparative genomic hybridization in malignant mesothelioma

Björkqvist

Tammilehto²,

Anttila³

et al. 1997

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…Investigations on cutaneous melanoma have demonstrated that multiple genetic abnormalities exist within these tumours (reviewed in Rees and Healy, 1996). Cytogenetic studies have detected gains and losses of genetic material on multiple chromosomes, and subsequent studies on loss of heterozygosity (LOH) have con®rmed the ®nding of frequent allelic loss (Cowan et al, 1988;Dracopoli et al, 1989;Trent et al, 1990;Millikin et al, 1991;Fountain et al, 1992;Isshiki et al, 1993Isshiki et al, , 1994Herbst et al, 1994;Holland et al, 1994;Walker et al, 1994;Healy et al, 1995Healy et al, , 1996aThompson et al, 1995). Recent work has shown that 6q, 9p and 10q are the chromosome arms most frequently lost in this tumour, with evidence that allelic losses on 6q and 10q may be responsible for the malignant phenotype in this neoplasm (Healy et al, 1996a).…”

Section: Introductionmentioning

confidence: 90%

Prognostic significance of allelic losses in primary melanoma

et al. 1998

View full text Add to dashboard Cite

Loss of genetic material, including loss of loci on chromosome arms 6q, 9p, and 10q, occurs frequently in cutaneous melanoma but infrequently in benign melanocytic nevi or other melanocytic lesions, suggesting that these genetic alterations are important in the development and progression of melanoma. To examine whether allelic loss is of prognostic importance in melanoma, disease-free survival was related to loss of heterozygosity on 6q, 9p and 10q in 83 individuals with sporadic primary cutaneous melanoma. Loss of chromosome arms 6q and 10q were each signi®cantly associated with a poorer clinical outcome (P=0.013 and P=0.001 respectively). In a subgroup of 41 subjects whose primary tumours were allelotyped, the fractional allelic loss (FAL) at 39 autosomal arms also signi®cantly correlated with disease-free survival (P=0.013), with an increase in FAL associated with a poorer outcome; this association remained signi®cant when controlled for tumour thickness (P=0.035). In addition, a greater proportion of cells were immunopositive for Ki67 antigen, p53 and p21 WAF1 protein in the primary melanomas than in the benign melanocytic nevi, however, only p53 overexpression was signi®cantly associated with improved survival (P=0.041).

show abstract

“…Homozygous deletions at CDKN2A/9p21 are common in bladder tumors 6,[15][16][17] and have been described in a variety of other sporadic tumors, including melanomas 18 and gliomas. 19 Pancreatic adenocarcinomas show inactivation of CDKN2A by either homozygous deletion or point mutation, 20 whereas esophageal tumors commonly show inactivation by point mutation.…”

mentioning

confidence: 99%

Measurement of Relative Copy Number of CDKN2A/ARF and CDKN2B in Bladder Cancer by Real-Time Quantitative PCR and Multiplex Ligation-Dependent Probe Amplification

Aveyard¹,

Knowles²

2004

The Journal of Molecular Diagnostics

View full text Add to dashboard Cite

Many tumors have large homozygous deletions of the CDKN2A locus (encoding p14 ARF and p16) and of CDKN2B (p15). Our aim was to determine which gene is the major target in bladder cancer. We used quantitative real-time PCR (RTQ-PCR) to determine copy number of p15, of p14 ARF exon 1␤, and p16 exon 2 in 22 tumor cell lines and 83 bladder tumors, some of which had been assessed previously by duplex PCR. Titration experiments showed that homozygous deletion could be detected in the presence of up to 30% normal DNA. Results for cell lines were compatible with previous cytogenetic analyses. Ten cell lines and 32 tumors (38.5%) had homozygous deletion of at least one target. Thirteen tumors (15.7%) had deletion of all three targets. Two tumors had deletion of p14 ARF exon 1␤ alone and four of p16 exon 2 alone. RTQ-PCR detected more homozygous deletions than duplex PCR. Finally we used a multiplex ligation-dependent probe amplification kit to provide independent confirmation of results. We conclude that with appropriate controls RTQ-PCR is a sensitive and robust method to detect copy number changes in tumors even in the presence of contaminating normal cell DNA. More than 60% of transitional cell carcinomas (TCC) of the bladder of all stages and grades show loss of heterozygosity (LOH) of chromosome 9. 1-6 Although many tumors have LOH on both arms of the chromosome, a significant number (ϳ10% of tumors overall) have a region of interstitial LOH of 9p. 7 Many such deletions are small and this has allowed the identification of a critical region at 9p21 that contains CDKN2B and CDKN2A/ARF. These two loci encode three tumor suppressor genes, p15, p16, and p14 ARF , all of which are cyclin-dependent kinase inhibitors with key functions in cell cycle regulation. 8,9The CDKN2A locus encodes p16 and p14 ARF , both of which are capable of inducing cell cycle arrest. 10,11 p16 and p14 ARF have different first exons (1␣ and 1␤, respectively) approximately 13 kb apart, 12 giving rise to products in alternate reading frames with no homology at the protein level 13,14 (Figure 1). Exons 1␣, 2, and 3 encode p16, which induces G1 cell cycle arrest via the Rb pathway. Exons 1␤, 2, and 3 encode p14 ARF , which inhibits p53 degradation via binding to mdm2.The mechanism of CDKN2A/ARF inactivation in human cancers is somewhat tumor specific. Homozygous deletions at CDKN2A/9p21 are common in bladder tumors 6,15-17 and have been described in a variety of other sporadic tumors, including melanomas 18 and gliomas. 19 Pancreatic adenocarcinomas show inactivation of CDKN2A by either homozygous deletion or point mutation, 20 whereas esophageal tumors commonly show inactivation by point mutation. 21 A third mechanism of inactivation, transcriptional silencing by promoter hypermethylation, is commonly found in colorectal carcinoma. 22 Point mutations have only rarely been identified in bladder tumors 15,23,24 and promoter methylation, only infrequently. 25 Since the discovery of p14 ARF , 14 much interest has centered on the relative involvement of ...

show abstract

Homozygous deletions within human chromosome band 9p21 in melanoma.

Cited by 272 publications

References 34 publications

Recurrent DNA copy number changes in 1q, 4q, 6q, 9p, 13q, 14q and 22q detected by comparative genomic hybridization in malignant mesothelioma

Recurrent DNA copy number changes in 1q, 4q, 6q, 9p, 13q, 14q and 22q detected by comparative genomic hybridization in malignant mesothelioma

Prognostic significance of allelic losses in primary melanoma

Measurement of Relative Copy Number of CDKN2A/ARF and CDKN2B in Bladder Cancer by Real-Time Quantitative PCR and Multiplex Ligation-Dependent Probe Amplification

Contact Info

Product

Resources

About