p53 protein overexpression is common and independent of human papillomavirus infection in squamous cell carcinoma of the vulva

Kagie, Marjolein J.; Kenter, Gemma G.; Tollenaar, Rob A.E.M.; Hermans, J.; Trimbos, J. Baptist; Fleuren, Gert Jan

doi:10.1002/(sici)1097-0142(19971001)80:7<1228::aid-cncr5>3.0.co;2-g

Cited by 37 publications

(52 citation statements)

References 34 publications

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“…p53 may be involved in progression from VIN to VSCC as p53 product accumulated in 53% of VSCCs (n ϭ 66) 13 and 44% (n ϭ 34) 14 of VIN associated with VSCC, but 0% of VIN not associated with VSCC (n ϭ 28). 4 In our series, the p53 locus was lost more in VSCC(ϩ) than in VIN(ϩ), which in turn had more loss of p53 than VIN(Ϫ) (Fig.…”

Section: Discussionsupporting

confidence: 87%

“…The loci studied were chosen for specific reasons: 17p13 because it harbors p53, which accumulates in 53-68% of VSCC 13,14 and 9p21 (p16 gene) and 3p25 because they frequently exhibit LOH in squamous head and neck cancer. [15][16][17] p16 is also disrupted in VIN and VSCC.…”

Section: Discussionmentioning

confidence: 99%

“…This hypothesis concurs with another study that found accumulation of p53 product in 53% of HPVnegative VSCC (n ϭ 54). 13 The observation that 58% of HPVnegative VSCC underwent LOH at 3p25 suggests that this locus may be the site of a tumor suppressor involved in an HPV-independent pathway of vulval carcinogenesis. The fact that this locus was lost significantly more in HPV-negative VSCC than in HPV-positive VSCC (Fig.…”

Section: Discussionmentioning

confidence: 99%

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High frequency of loss of heterozygosity in vulval intraepithelial neoplasia (VIN) is associated with invasive vulval squamous cell carcinoma (VSCC)

et al. 2001

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Vulval intraepithelial neoplasia (VIN) is thought to be the premalignant phase of human papillomavirus (HPV)-associated vulval squamous cell carcinoma (VSCC).Various molecular events have been suggested as markers for progression from VIN to VSCC, but loss of heterozygosity (LOH) in vulval neoplasia has rarely been studied in this context. We performed LOH analysis by polymerase chain reaction (PCR) amplification of polymorphic microsatellite markers at 6 chromosomal loci (17p13-p53, 9p21-p16, 3p25, 4q21, 5p14 and 11p15). The presence of HPV was assessed using consensus PCR primers and DNA sequencing. Key words: VIN; vulval; cancer; LOH; HPVVulval intraepithelial neoplasia (VIN) is thought to be the premalignant phase of invasive vulval squamous cell carcinoma (VSCC). This hypothesis is based on the observation that VIN frequently occurs adjacent to VSCC, 1 that VIN and a subgroup of VSCC are associated with similar risk factors [smoking, 2 immunosuppression 3 and human papillomavirus (HPV) infection 2,4 ] and that VIN is a monoclonal neoplastic condition. 5 The risk of progression of VIN to VSCC is unclear. 6,7 Limited evidence is available about molecular events in vulval carcinogenesis. Loss of heterozygosity (LOH) is a common molecular event in malignancy, but has been studied only in relatively small numbers of VIN and VSCC. 8 -11 We set out to document the LOH rates in VIN and VSCC in a larger series, to examine the relationship between the 2 conditions. Events common to both conditions could be early events in vulval carcinogenesis. Events occurring in VIN associated with VSCC but not in lone VIN could be markers for risk of progression to VSCC.Because human papillomavirus (HPV) is thought to be involved in the development of VIN-associated VSCC, but is not found so often in VSCC occurring in the absence of VIN, 2 we also performed HPV analysis, to compare LOH in HPV-positive and HPV-negative VSCC. MATERIAL AND METHODS SamplesPatients with VIN and VSCC diagnosed between 1989 and 1997 were identified using the computerized database of the pathology departments of St. Bartholomew's and the Royal London Hospitals. Samples containing both normal and neoplastic tissue were as follows: 43 cases of VIN III alone, 42 cases of VSCC alone and 21 cases of VIN associated with concurrent VSCC (18 of which had the concurrent VSCC still remaining on the specimen blocks after serial sectioning). Of the 60 VSCC cases, 24 were stage I, 11 were stage II, 9 were stage III, 3 were stage IV and in 13 information for accurate staging was not available. Of the 21 cases of VIN associated with VSCC, 18 were VIN III, 2 were VIN II and 1 was VIN

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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High frequency of loss of heterozygosity in vulval intraepithelial neoplasia (VIN) is associated with invasive vulval squamous cell carcinoma (VSCC)

et al. 2001

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“…Recently, p53 mutation frequency in vulvar carcinomas is reported to be much higher compared with cervical carcinoma by 24%, (Lee et al, 1994), 53% (Milde-Langosch et al, 1995) and Elderly Japanese women with cervical carcinoma show higher proportions of both intermediate-risk human papillomavirus types and p53 mutations 53% (Kagie et al, 1997). Vulvar cancer generally occurs in women over ten years older than women with cervical cancer, with a peak incidence between 65 and 75 years old (Langosch et al, 1995).…”

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confidence: 99%

Elderly Japanese women with cervical carcinoma show higher proportions of both intermediate-risk human papillomavirus types and p53 mutations

et al. 1999

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SummaryThe p53 mutation has been found only in 0-6% of cervical carcinomas. In light of recent studies demonstrating that mutation of p53 gene was found in over 20% of the patients with vulvar carcinoma, a disease of elderly women and a known human papillomavirus (HPV)-related malignancy, we analysed mutation of the p53 gene in 46 women with cervical carcinomas at the age of 60 or more (mean; 71 years, range; 60-96 years). The presence of HPV and its type were analysed by polymerase chain reaction (PCR)-based assay using the consensus primers for L1 region. Mutation of the p53 gene was analysed by PCR-based single-strand conformation polymorphism and DNA sequencing technique. Point mutation of the p53 gene was detected in 5 out of 46 (11%) cervical carcinomas: 1 of 17 (6%) samples associated with high-risk HPVs (HPV 16 and HPV 18) and 4 of 27 samples (15%) with intermediate-risk HPVs (P = 0.36) whereas no mutation was found in 2 HPV negative cases. The mutated residues resided in the selective sequence known as a DNA-binding domain. The immunohistochemistry revealed the overexpression in cancer tissues positive for p53 mutation. All of the observed mutations of the p53 gene were transition type, suggesting that the mutation may be caused by endogenous mutagenesis. Although falling short of statistical significance reduces the strength of the conclusion, data presented here imply that p53 gene mutation, particularly along with intermediaterisk HPV types, may constitute one pathogenetic factor in cervical carcinoma affecting elderly women.

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“…Neither have we found a relation between p53 and clinicopathological parameters age, depth of invasion and differentiation grade. In their study of vulvar carcinomas, Kagie et al (1997) did not find a relationship between p53 overexpression and diseasefree survival. Kohlberger et al (1995) have reported a relationship between p53 overexpression and survival in vulvar carcinomas, based on a group of 25 vulvar carcinomas.…”

Section: Discussionmentioning

confidence: 99%

In squamous cell carcinoma of the vulva, overexpression of p53 is a late event and neither p53 nor mdm2 expression is a useful marker to predict lymph node metastases

et al. 1999

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SummaryTo offer more tailored treatment to individual patients with squamous cell carcinoma of the vulva, more accurate prediction of lymph node metastases is required. As p53 and mdm2 are genes known to be involved in the development of other tumours, we studied expression of p53 and mdm2 in carcinogenesis of squamous cell carcinoma of the vulva and their clinical relevance. Archival material of 141 T1 and T2 vulvar tumours were used. Of the 141 primary tumours, the corresponding 39 lymph node metastases (LNM) were studied, and in 90 cases the pre-existent epithelia adjacent to the tumour (EAT) and in 14 cases vulvar intraepithelial neoplasia adjacent to the tumour (VIN) was also investigated. Detection of p53 and mdm2 protein was immunohistochemically performed. Scoring categories were: negative (1); weakly positive (2); moderately to markedly positive (3); and markedly positive (4). Overexpression of p53 was seen in 56% of the LNM, 39% of the primary tumours, 21% of the VIN lesions and 0% in the group of EAT. No relation was found between overexpression of p53 in the primary tumour and LNM. Expression of mdm2 was seen in 14% of the primary tumours, of which four cases were marked positive. In the group of LNM no mdm2-positive staining was observed. In the group of EAT, 25% was mdm2-positive, of which six cases were marked positive. In the group of VIN, 36% showed moderate (score 3) mdm2 expression. No relation was found between expression of mdm2 and LNM. In squamous cell carcinoma, overexpression of p53 is a late event in carcinogenesis. Marked expression of mdm2 is rarely seen in vulvar carcinomas, indicating that aberrant p53 cannot induce mdm2 expression. LNM cannot be predicted by detection of these proteins.

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p53 protein overexpression is common and independent of human papillomavirus infection in squamous cell carcinoma of the vulva

Cited by 37 publications

References 34 publications

High frequency of loss of heterozygosity in vulval intraepithelial neoplasia (VIN) is associated with invasive vulval squamous cell carcinoma (VSCC)

High frequency of loss of heterozygosity in vulval intraepithelial neoplasia (VIN) is associated with invasive vulval squamous cell carcinoma (VSCC)

Elderly Japanese women with cervical carcinoma show higher proportions of both intermediate-risk human papillomavirus types and p53 mutations

In squamous cell carcinoma of the vulva, overexpression of p53 is a late event and neither p53 nor mdm2 expression is a useful marker to predict lymph node metastases

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