Mutated and wild-type p53 expression and HPV integration in proliferative verrucous leukoplakia and oral squamous cell carcinoma

Gopalakrishnan, Rajaram; Weghorst, Christopher M.; Lehman, Teresa A.; Calvert, Richard J.; Bijur, Gautam N.; Sabourin, Carol L.; Mallery, Susan R.; Schuller, David E.; Stoner, Gary D.

doi:10.1016/s1079-2104(97)90148-7

Cited by 63 publications

(59 citation statements)

References 24 publications

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“…Each PVL case was stained for P53 using standard immunohistochemical procedures. A previous report evaluating aberrant P53 accumulation in PVL lesions from patients from the same oral pathology service as our study cohort reported positive staining in 80% (8 of 10) of the cases as defined by a relative positive area of >23.25% and a mean labeling index of 31.9% (9). As indicated in Table 2, we noted similar rates of P53-positive staining in PVL cases.…”

Section: P53supporting

confidence: 83%

“…protein staining and aberrations in INK4a/ARF in the PVL tissues assessed. p53 mutation analysis was not conducted in this study, as a previous assessment in 10 patients revealed no mutations (9). In the present study, we report, for the first time, that the cell cycle regulatory genes p16…”

Section: P53mentioning

confidence: 57%

“…14, 21). Considering previous reports of aberrant P53 accumulation in PVL lesions (9,22) and the linkage between p53 mutations and decreased survival in patients with SCC (23), we also included an immunohistochemical assessment of P53 in the PVL cases under study. Advancing our molecular knowledge of these aggressive premalignant lesions may facilitate improved diagnostic, preventive, and treatment strategies.…”

Section: Ink4amentioning

confidence: 99%

“…Silverman et al reported 68% of PVL patients to be positive for Candida albicans but did not find the fungal infection to be linked PVL occurrence or progression to carcinoma (2). To date, several studies in relatively small cohorts have investigated the role of HPV in verrucous lesions reporting between 0% and 89% of PVL lesions to be HPV positive (3,(5)(6)(7)(8)(9)(10)(11). Conflicting results with respect to HPV have also been reported for SCCs and verrucous carcinomas (12,13); however, one of the largest studies evaluating HPV in verrucous and conventional leukoplakias reported HPV DNA rates of 24.1% and 25.5%, respectively (3).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: P53supporting

confidence: 83%

Section: P53mentioning

confidence: 57%

Section: Ink4amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…Our data, that VC and VH show a strikingly lower frequency of loss at 17p (near or in the tp53 locus) in VC compared with SCC, is consistent with the hypothesis of an HPV etiology for the verrucous lesions. The low rate of 17p loss could be explained by the assumption that p53 protein is inactivated by HPV protein through a ubiquitous pathway instead of through p53 mutation and chromosome losses (Gopalakrishnan et al, 1997).…”

Section: Loh In Verrucous Lesionsmentioning

confidence: 99%

A High Frequency of Allelic Loss in Oral Verrucous Lesions May Explain Malignant Risk

Poh

Zhang

Lam³

et al. 2001

Laboratory Investigation

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SUMMARY:Verrucous carcinoma (VC), a variant of squamous cell carcinoma (SCC), is distinct from SCC in morphology and behavior. The underlying genetic changes involved in the development of VC and its precursor verrucous hyperplasia (VH) are unknown. This study determined whether chromosomal regions frequently lost during the development of SCC are also lost in the VH/VC variant. Twenty-five VH and 17 VC were analyzed for loss of heterozygosity (LOH) at 19 loci on 7 chromosome arms using microsatellite analysis. These data were compared with those from 47 reactive hyperplasias, 92 dysplasias (54 low-and 38 high-grade), and 41 SCCs. The results showed that VC/VH shared many of the losses present in dysplasia/SCC but differed in two aspects. First, VC/VH showed early acquisition of loss, compared with a gradual accumulation of losses from dysplasias to SCC. The LOH pattern of VH was similar to that of high-grade dysplasia and sharply different from reactive hyperplasia. The loss in VH often involved multiple arms (in 60% of VH vs 0% of reactive lesions). Only a marginal elevation of loss was observed at 9p (p ϭ 0.06) and 4q (p ϭ 0.05) from VH to VC because of the high degree of loss already present in VH. Second, a strikingly lower frequency of loss at 17p was noted in VH/VC compared with dysplasia/SCC and may indicate human papillomavirus (HPV) involvement. The finding of high-risk LOH profiles in VH may partly account for the high-progression risk seen for VH and also has potentially important clinical implications. The difficult pathological diagnosis of VH/VC from reactive hyperplasia frequently requires repeated biopsies and results in delay in diagnosis and significantly increased mortality/morbidity. Microsatellite analysis might facilitate this differential diagnosis. (Lab Invest 2001, 81:629 -634).O ral squamous cell carcinoma (SCC) is similar to SCC in many other organs (eg, uterine, cervix, skin, larynx, and pharynx) in that it is felt to develop in a multistep fashion through a series of histological stages with increasing risk of developing into invasive cancer, namely: epithelial hyperplasia; mild, moderate, and severe dysplasias; and carcinoma in situ (CIS). The presence of dysplasia and the breakage of the basement membrane (ie, invasion) are the hallmarks for judging malignancy in SCC (Fig. 1a). However, verrucous carcinoma (VC) (Fig. 1b), a variant of the conventional SCC in these organs, has unique clinicopathological features and biological behavior. VC and its precursor lesion, verrucous hyperplasia (VH) (Fig. 1c), are characterized by a prominent verrucous configuration, yet show minimal or no dysplasia and no breakage of the basement membrane. In the oral cavity, VC and SCC differ in the site of occurrence, with VC most commonly in the cheek and alveolus/ gingiva and SCC on the ventrolateral tongue and floor of mouth (Jacobson and Shear, 1972). VC does not metastasize, and it grows indolently (a 75% 5-year survival rate for VC versus less than 50% for SCC), although the growth is so relentles...

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Proliferative verrucous leukoplakia: Recognition and differentiation from conventional leukoplakia and mimics

et al. 2014

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The majority of conventional leukoplakia remains constant and only a subset progress to high-grade dysplasia or invasive carcinoma. A less recognized form known as proliferative verrucous leukoplakia (PVL) represents a unique progressive and elusive variant. Identifying patients with this form can only be achieved through the keen clinical observation of the temporal gross and histologic progression in individual patients with squamous cell carcinoma. The difficulty in the early diagnosis of PVL stems from the overlapping clinical and pathologic features with conventional multifocal leukoplakia with dysplasia. We present the current view on the clinicopathologic and biological characteristics of PVL and discuss their diagnosis, differential diagnosis, and management.

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Mutated and wild-type p53 expression and HPV integration in proliferative verrucous leukoplakia and oral squamous cell carcinoma

Cited by 63 publications

References 24 publications

Frequent Alterations of p16INK4a and p14ARF in Oral Proliferative Verrucous Leukoplakia

Frequent Alterations of p16INK4a and p14ARF in Oral Proliferative Verrucous Leukoplakia

A High Frequency of Allelic Loss in Oral Verrucous Lesions May Explain Malignant Risk

Proliferative verrucous leukoplakia: Recognition and differentiation from conventional leukoplakia and mimics

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