Absence of p53 protein overexpression in precancerous lesions of the vulva

Kohlberger, Petra; Kirnbauer, Reinhard; Bancher, Dagmar; Gitsch, G.; Reinthaller, Alexander; Leodolter, Sepp; Tschachler, Erwin; Kainz, Christian; Breitenecker, G.

doi:10.1002/(sici)1097-0142(19980115)82:2<328::aid-cncr12>3.0.co;2-0

Cited by 21 publications

(20 citation statements)

References 24 publications

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“…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. 2), but these differences were nonsignificant.…”

Section: Discussionmentioning

confidence: 49%

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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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“…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. 2), but these differences were nonsignificant.…”

Section: Discussionmentioning

confidence: 49%

“…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.…”

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confidence: 99%

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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“…E6 targets p53 product for degradation via the ubiquitin pathway (Scheffner et al, 1990), while E7 complexes and inactivates Rb (Dyson et al, 1989). A proportion of vulval squamous cell carcinoma (VSCC) and the vast majority of vulval intraepithelial neoplasia (VIN) are associated with oncogenic HPV infection (Hording et al, 1994;Kohlberger et al, 1998;Rosenthal et al, 2001). The different patients' ages (Hording et al, 1994;Monk et al, 1995), histological subtypes (Hording et al, 1994;Monk et al, 1995) and the presence of VIN (Hording et al, 1994;Ngan et al, 1999) in HPV-positive but not HPV-negative VSCC, all support the hypothesis that VSCC can arise via both an HPV-dependent and HPV-independent pathway.…”

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confidence: 99%

“…Some studies suggest absent p53 immunoreactivity in lone VIN (Kurvinen et al, 1993;Tervahauta Received 3 October 2002;accepted 9 October 2002accepted 9 October et al, 1993Pilotti et al, 1995;Kohlberger et al, 1998), while others have found 17 -52% p53 immunoreactivity in VIN associated with VSCC (Milde-Langosch et al, 1995;Kagie et al, 1997a ,b;McConnell et al, 1997;Emanuels et al, 1999). It is therefore possible that p53 immunoreactivity could represent a marker for risk of invasion.…”

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confidence: 99%

Immunohistochemical analysis of p53 in vulval intraepithelial neoplasia and vulval squamous cell carcinoma

et al. 2003

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Human papillomavirus (HPV) is thought to cause some vulval squamous cell carcinomas (VSCC) by degrading p53 product. Evidence on whether HPV-negative VSCC results from p53 mutation is conflicting. We performed immunohistochemistry for p53 product on 52 cases of lone vulval intraepithelial neoplasia (VIN), 21 cases of VIN with concurrent VSCC and 67 cases of VSCC. We had previously performed HPV detection and loss of heterozygosity (LOH) analyses on these samples. Abnormal p53 immunoreactivity (p53-positive) rates in HPV-positive VSCC and HPV-negative VSCC were 22% (12/54) and 31% (4/13), respectively (Po0.74). p53 immunoreactivity was associated with LOH at the p53 locus (Po0.004), but neither technique differentiated between HPV-positive and HPV-negative VSCC. p53 immunoreactivity was associated with overall LOH rates (p53-positive VSCC vs p53-negative VSCC mean fractional regional allelic loss 0.41 vs 0.24, respectively, Po0.027). LOH at 3p25 was more frequent in p53-positive VSCC cf p53-negative VSCC (70 vs 21%, respectively, Po0.007). There was a trend in p53 disruption associated with invasive disease; HPVpositive VSCC demonstrated more disruption than VIN associated with VSCC, which had more disruption than lone VIN III (22 vs 10 vs 0%, respectively, Po0.005). In all, three out of 73 cases of VIN were p53-positive. All three were associated with concurrent or previous VSCC. Meta-analysis of previous studies revealed significantly more p53 disruption in HPV-negative VSCC cf HPV-positive VSCC (58 vs 33%, respectively; Po0.0001). p53 immunoreactivity/mutation in VIN only appeared in association with VSCC. These data suggest that HPV-independent vulval carcinogenesis does not exclusively require disruption of p53, p53 disruption may work synergistically with LOH at specific loci and p53-positive VIN should be checked carefully for the presence of occult invasion.

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“…This assumption is based on observations that VIN frequently occurs contiguously with VSCC, 1 that VIN and a subgroup of VSCC are associated with similar risk factors (smoking, 2 immunosuppression 3 and HPV infection 2,4 ) and that VIN and VSCC are monoclonal neoplastic conditions. 5,6 Confirmation of this hypothesis is important for gaining insight into the process of vulval carcinogenesis.…”

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confidence: 99%

Molecular evidence of a common clonal origin and subsequent divergent clonal evolution in vulval intraepithelial neoplasia, vulval squamous cell carcinoma and lymph node metastases

Rosenthal

Ryan

Hopster

et al. 2002

Intl Journal of Cancer

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VIN is thought to be the precursor of some VSCCs because it is monoclonal, frequently occurs contiguously with VSCC and shares similar risk factors with a subgroup of VSCC. There has been no conclusive molecular evidence supporting this assumption. We performed X-chromosome inactivation analysis on 9 cases of lone VIN, 10 cases of VSCC and associated contiguous VIN and 11 cases of VSCC and associated noncontiguous VIN. Eight of the 9 cases of lone VIN appeared to be monoclonal. All 7 informative and monoclonal cases of VIN with contiguous VSCC and 6/9 informative cases of VIN with noncontiguous VSCC showed patterns of X-chromosome inactivation consistent with a common monoclonal origin for both VIN and VSCC. Two of the 9 cases of VIN with noncontiguous VSCC showed X-chromosome inactivation patterns consistent with a separate clonal origin. We performed LOH analysis at 6 chromosomal loci on these samples and 7 cases with lymph node metastases. Identical losses occurred 7 times in VIN and contiguous VSCC (random probability 1.2 ؋ 10 -9 ), twice in VIN and noncontiguous VSCC (random probability 1.5 ؋ 10 -3 ) and 3 times in VSCC and associated metastases (random probability 1.8 ؋ 10 -5 ). Some losses occurring in VSCC did not appear in the contiguous VIN or associated metastases and vice versa. These data provide molecular evidence that VIN is the precursor of VIN-associated VSCC, that multifocal disease may arise via either different clones or a single clone and that continued divergent clonal evolution may occur in vulval neoplasia. © 2002 Wiley-Liss, Inc. Key words: vulval intraepithelial neoplasia; vulval cancer; loss of heterozygosity; X-chromosome inactivation; vulval squamous cell carcinomaVIN has long been thought to be a premalignant condition that may progress to invasive VSCC. This assumption is based on observations that VIN frequently occurs contiguously with VSCC, 1 that VIN and a subgroup of VSCC are associated with similar risk factors (smoking, 2 immunosuppression 3 and HPV infection 2,4 ) and that VIN and VSCC are monoclonal neoplastic conditions. 5,6 Confirmation of this hypothesis is important for gaining insight into the process of vulval carcinogenesis. Furthermore, identifying molecular markers for risk of progression of VIN to VSCC is possible only if molecular evidence is compatible with a common monoclonal origin of the 2 conditions. We first wanted to confirm that VIN is a monoclonal condition. We then wanted to document the patterns of LOH events and X-chromosome inactivation in VSCC samples and contiguous and noncontiguous VIN, to examine whether VIN and VSCC could have arisen from the same clone. Because we had already studied the frequency of LOH at 6 chromosomal loci in lone VIN and VSCC, 7 it was possible to calculate the odds of identical losses occurring by chance in both VSCC and associated VIN. Finally, as primary cancers and their metastases are thought to have the same clonal origin, we compared the number of identical losses occurring in primaries and their metastases with the...

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Absence of p53 protein overexpression in precancerous lesions of the vulva

Abstract: These data suggest that p53 protein overexpression is not an early event in the pathogenesis of basaloid/warty type vulvar dysplasia and that HPV infection may contribute to the development of VIN.

Cited by 21 publications

References 24 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)

Immunohistochemical analysis of p53 in vulval intraepithelial neoplasia and vulval squamous cell carcinoma

Molecular evidence of a common clonal origin and subsequent divergent clonal evolution in vulval intraepithelial neoplasia, vulval squamous cell carcinoma and lymph node metastases

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