Selective deletion of p14(ARF) exon 1β of the INK4a locus in oral squamous cell carcinomas of Indians

Muthusamy, Viswanathan; Tsuchida, Nobuo; Shanmugam, G.

doi:10.1016/s1368-8375(00)00112-3

Cited by 12 publications

(9 citation statements)

References 25 publications

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“…Selective inactivation of p14 ARF without p16 has been reported in other sporadic tumors (20) and a p14 ARF -specific germline mutation has been described in familial melanoma-neural tumor syndrome (21). However, in UCC, specific inactivation of p14 ARF occurs only rarely (22); thus, in this type of tumor, it seems that either inactivation of both genes is necessary for tumorigenesis or that inactivation of p14 ARF alongside p16 is simply a coincidence of their proximity and unusual exon sharing arrangement.…”

mentioning

confidence: 85%

Comprehensive Analysis of CDKN2A Status in Microdissected Urothelial Cell Carcinoma Reveals Potential Haploinsufficiency, a High Frequency of Homozygous Co-deletion and Associations with Clinical Phenotype

Chapman

Harnden²,

Chambers³

et al. 2005

Clinical Cancer Research

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Purpose: There are significant differences in reported frequencies, modes of inactivation, and clinical significance of CDKN2A in urothelial cell carcinoma (UCC). We aimed to address these issues by investigating all possible modes of inactivation and clinicopathologic variables in a single tumor panel. Experimental Design: Fifty microdissected UCCs were examined. CDKN2A gene dosage (quantitative real-time PCR), allelic status (microsatellite analysis), hypermethylation (methylationspecific PCR), mutation status (denaturing high-performance liquid chromatography and sequencing), protein expression (immunohistochemistry), and clinicopathologic variables (stage, grade, and disease recurrence during follow-up) were assessed. Results: Exon 2 was underrepresented in 20 of 46 (43%) and exon1h in 21of 46 (46%) of cases. Underrepresentation of exon 2 was accompanied by loss of heterozygosity (LOH) of 9p in 6 of 18 (30%) and of exon 1h in 11of 19 assessable cases (58%). Overall, LOH of 9p was identified in 15/41 (37%). Homozygous deletion of exons 2 and 1h was detected in 16 of 46 (35%) and 10 of 46 tumors (22%), respectively. Co-deletion was most common, but exon 2^specific homozygous deletion was also detected. In tumors without homozygous deletion, p16 promoter hypermethylation was detected in 1of 18 (6%). Hypermethylation of the p14 ARF promoter or mutations in CDKN2A were not observed. Homozygous deletion of exon 2 or LOH on 9p were associated with invasion. Homozygous deletion of exon 2 or exon1h was associated with recurrent disease. Conclusions: These results confirm CDKN2A as a clinically relevant target for inactivation in UCC and show that the true frequency of alteration is only revealed by comprehensive analysis. Our results suggest that CDKN2A may be haploinsufficient in human cancer.

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mentioning

confidence: 85%

Comprehensive Analysis of CDKN2A Status in Microdissected Urothelial Cell Carcinoma Reveals Potential Haploinsufficiency, a High Frequency of Homozygous Co-deletion and Associations with Clinical Phenotype

Chapman

Harnden²,

Chambers³

et al. 2005

Clinical Cancer Research

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“…In comparison, exon 1h deletions have been reported in the range of 24% to 28% in oral SCC (35,36). In addition, several studies report that exon 1h deletions are frequently accompanied by deletions of exons 2 and 1a, indicating complete loss of the INK4a/ARF locus in end-stage oral cancer (35,36). Over 60% (5 of 8) of PVL patients with exon 1h deletion had concomitant loss of exon 1a, whereas none showed homozygous deletion of shared exon 2.…”

Section: P16mentioning

confidence: 98%

“…Strikingly, homozygous deletion of exon 1h of the p14 ARF gene was prevalent in 40.0% (8 of 20) of PVL lesions. In comparison, exon 1h deletions have been reported in the range of 24% to 28% in oral SCC (35,36). In addition, several studies report that exon 1h deletions are frequently accompanied by deletions of exons 2 and 1a, indicating complete loss of the INK4a/ARF locus in end-stage oral cancer (35,36).…”

Section: P16mentioning

confidence: 99%

Frequent Alterations of p16INK4a and p14ARF in Oral Proliferative Verrucous Leukoplakia

Kresty

Mallery²,

Knobloch

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Proliferative verrucous leukoplakia (PVL) represents a rare but highly aggressive form of oral leukoplakia with >70% progressing to malignancy. Yet, PVL remains biologically and genetically poorly understood. This study evaluated the cell cycle regulatory genes, p16 INK4aand p14 ARF , for homozygous deletion, loss of heterozygosity, and mutation events in 20 PVL cases. Deletion of exon 1B, 1A, or 2 was detected in 40%, 35%, and 0% of patients, respectively. Deletions of exons 1A and 1B markedly exceed levels reported in non-PVL dysplasias and approximate or exceed levels reported in oral squamous cell carcinomas. Allelic imbalance was assessed for markers reported to be highly polymorphic in squamous cell carcinomas and in oral dysplasias. Loss of heterozygosity was detected in 35.3%, 26.3%, and 45.5% of PVLs for the markers IFNa, D9S1748, and D9S171, respectively. INK4a and ARF sequence alterations were detected in 20% and 10% of PVL lesions, accordingly. These data show, for the first time, that both p16INK4a and p14 ARF aberrations are common in oral verrucous leukoplakia; however, the mode and incidence of inactivation events differ considerably from those reported in non-PVL oral premalignancy. Specifically, concomitant loss of p16INK4a and p14 ARF occurred in 45% of PVL patients greatly exceeding loss reported in non-PVL dysplastic oral epithelium (15%). In addition, p14 ARF exon 1B deletions were highly elevated in PVLs compared with non-PVL dysplasias. These data illustrate that molecular alterations, even within a specific genetic region, are associated with distinct histologic types of oral premalignancy, which may affect disease progression, treatment strategies, and ultimately patient prognosis. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3179 -87)

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“…The ARF À/À cells are highly susceptible to Ras transformation and are resistant to both Ras-and culture-induced senescence (Groth et al, 2000). In addition, exon 1b is frequently targeted in human cancers (Kumar et al, 1998;Iida et al, 2000;RandersonMoor et al, 2001;Rizos et al, 2001;Viswanathan et al, 2001). The N-terminal portion (amino acids (aa) 1-64) of p14 ARF is necessary and sufficient for growth arrest Zhang et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

ARF promotes accumulation of retinoblastoma protein through inhibition of MDM2

et al. 2007

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The INK4a/ARF locus, encoding two tumor suppressor proteins, p16INK4a and p14 ARF (ARF), plays key roles in many cellular processes including cell proliferation, apoptosis, cellular senescence and differentiation. Inactivation of INK4a/ARF is one of the most frequent events during human cancer development. Although p16INK4a is a critical component in retinoblastoma protein (Rb)-mediated growth regulatory pathway, p14ARF plays a pivotal role in the activation of p53 upon oncogenic stress signals. A body of evidence indicates that ARF also possesses growth suppression functions independent of p53, the mechanism of which is not well understood. We have recently shown that MDM2 interacts with Rb and promotes proteasome-dependent Rb degradation. In this study, we show that ARF disrupts MDM2-Rb interaction resulting in Rb accumulation. Wild-type ARF, but not ARF mutant defective in MDM2 interaction, stabilizes Rb and inhibits colony foci formation independent of p53. In addition, ablation of Rb impairs ARF function in growth suppression. Thus, this study demonstrates that ARF plays a direct role in regulation of Rb and suggests that inactivation of ARF may lead to defects in both p53 and Rb pathways in human cancer development.

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Selective deletion of p14(ARF) exon 1β of the INK4a locus in oral squamous cell carcinomas of Indians

Cited by 12 publications

References 25 publications

Comprehensive Analysis of CDKN2A Status in Microdissected Urothelial Cell Carcinoma Reveals Potential Haploinsufficiency, a High Frequency of Homozygous Co-deletion and Associations with Clinical Phenotype

Comprehensive Analysis of CDKN2A Status in Microdissected Urothelial Cell Carcinoma Reveals Potential Haploinsufficiency, a High Frequency of Homozygous Co-deletion and Associations with Clinical Phenotype

Frequent Alterations of p16INK4a and p14ARF in Oral Proliferative Verrucous Leukoplakia

ARF promotes accumulation of retinoblastoma protein through inhibition of MDM2

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