Inactivation of the CDKN2A and the p53 tumour suppressor genes in external genital carcinomas and their precursors

Soufir, Nadem; Queillé, Sophie; Liboutet, Muriel; Thibaudeau, Olivier; Bachelier, F.; Delestaing, G.; Balloy, B. Cavelier; Breuer, Judith; Janin, Anne; Dubertret, Louis; Vilmer, C; Basset-Séguin, Nicole

doi:10.1111/j.1365-2133.2006.07604.x

Cited by 54 publications

(58 citation statements)

References 31 publications

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“…7,9 Predictably, a majority (70%) of the mutations found in differentiated vulvar intraepithelial neoplasia and vulvar squamous cell carcinoma were located in exons previously shown to contain the highest incidence of mutations in vulvar squamous cell carcinoma, exons 5 through 9. 9,19,20 Four out of five differentiated vulvar intraepithelial neoplasia-associated carcinomas were Tp53 mutation-positive.…”

Section: Discussionmentioning

confidence: 99%

“…Immunohistochemistry over-expression of p53 has been reported in lichen simplex chronicus, lichen sclerosus, and differentiated vulvar intraepithelial neoplasia adjacent to HPV-negative vulvar cancer. 7,11,12,19,20 The immunohistochemistry signal observed in lichen simplex chronicus and lichen sclerosus is usually weak and confined to a single, un-expanded layer of basal Tp53 mutations in differentiated vulvar intraepithelial neoplasias cells. 12,21 In these entities, Tp53 mutations are usually not found; therefore, the p53 protein signal has been attributed to upregulation of p53 wild-type protein, possibly reflecting a stress response to inflammation or ischemia.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies had revealed the presence of Tp53 mutations in some of these tumors. [7][8][9] Clinicopathological overlap between HPV-associated and non-HPV-associated tumor may be observed in some cases, in which immunohistochemistry with p16 and HPV testing are more reliable than morphology for classification of both vulvar intraepithelial neoplasia and vulvar squamous cell carcinoma. 10,11 In the HPV-related pathway, classic VIN is generally accepted as a precursor of invasive carcinoma.…”

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Differentiated vulvar intraepithelial neoplasia contains Tp53 mutations and is genetically linked to vulvar squamous cell carcinoma

et al. 2010

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Differentiated vulvar intraepithelial neoplasia is a unique precursor to vulvar squamous cell carcinoma that is typically HPV-negative and frequently associated with nuclear p53 staining. These features imply a mode of pathogenesis involving somatic mutations. However, the genetic relationship of differentiated vulvar intraepithelial neoplasm and vulvar squamous cell carcinoma and the role of Tp53 mutations in this process have not been resolved. We analyzed 11 differentiated vulvar intraepithelial neoplasms and 6 associated vulvar squamous cell carcinomas. Sections were stained for p53 and p63 and DNA from multiple epithelial sites, representing normal control tissues (n ¼ 10), differentiated vulvar intraepithelial neoplasias (n ¼ 18), and vulvar squamous cell carcinomas (n ¼ 6), were obtained by laser capture microdissection, and sequenced for exons 2-11 of Tp53. Six of 10 cases contained at least one Tp53 mutation-positive differentiated vulvar intraepithelial neoplasia focus; 4 strongly p53 immuno-positive and 2 negative. Staining for p53 and p63 co-localized, targeting the immature epithelium, but surface epithelium was Tp53 mutation-positive. Four of five vulvar squamous cell carcinomas were Tp53 mutation-positive; two shared identical Tp53 mutation with adjacent differentiated vulvar intraepithelial neoplasia. Disparate foci of differentiated vulvar intraepithelial neoplasia often showed different mutations consistent with multiple neoplastic clones. Differentiated vulvar intraepithelial neoplasia is, with few exceptions, associated with Tp53 mutations and will be p53 immunopositive when missense mutations (versus some nonsense and all deletion mutations) are present. Multiple Tp53 mutations in different sites supports the presence of multiple independent genetic events, but shared Tp53 mutations in both differentiated vulvar intraepithelial neoplasia and vulvar squamous cell carcinoma support a genetic relationship between the two. The confinement of p53 staining to immature cell nuclei is consistent with maturation-dependent degradation of mutant p53 protein.

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confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Differentiated vulvar intraepithelial neoplasia contains Tp53 mutations and is genetically linked to vulvar squamous cell carcinoma

et al. 2010

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“…Most studies have suggested tumor markers for characterization and VSCC prognostication (3)(4)(5)(6)(7). Furthermore, TP53 mutation and CDKN2A promoter methylation have been associated with VSCC (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

An Integrative Approach Uncovers Biomarkers that Associate with Clinically Relevant Disease Outcomes in Vulvar Carcinoma

Lavorato-Rocha

Akagi

Maia

et al. 2016

Molecular Cancer Research

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Vulvar squamous cell carcinoma (VSCC) is a rare disease that has a high mortality rate ($40%). However, little is known about its molecular signature. Therefore, an integrated genomics approach, based on comparative genome hybridization (aCGH) and genome-wide expression (GWE) array, was performed to identify driver genes in VSCC. To achieve that, DNA and RNA were extracted from frozen VSCC clinical specimens and examined by aCGH and GWE array, respectively. On the basis of the integration of data using the CONEXIC algorithm, PLXDC2 and GNB3 were validated by RT-qPCR. The expression of these genes was then analyzed by IHC in a large set of formalin-fixed paraffin-embedded specimens. These analyses identified 47 putative drivers, 46 of which were characterized by copy number gains that were concomitant with overexpression and one with a copy number loss and downregulation. Two of these genes, PLXDC2 and GNB3, were selected for further validation: PLXDC2 was downregulated and GNB3 was overexpressed compared with non-neoplastic tissue. By IHC, both proteins were ubiquitously expressed throughout vulvar tissue. High expression of GNB3 and low PLXDC2 immunostaining in the same sample was significantly associated with less lymph node metastasis and greater disease-free survival. On the basis of a robust methodology never used before for VSCC evaluation, two novel prognostic markers in vulvar cancer are identified: one with favorable prognosis (GNB3) and the other with unfavorable prognosis (PLXDC2).Implications: This genomics study reveals markers that associate with prognosis and may provide guidance for better treatment in vulvar cancer.

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“…Few studies have investigated genetic alterations in VCs and its precursor lesions beyond HPV status (6)(7)(8)(9)(10)(11). These studies have analyzed a limited selection of genes using Sanger sequencing or small panel hotspot approaches (8,10,11). Thus far, a more comprehensive assessment of molecular alterations in VC and its precursors is lacking (12).…”

Section: Introductionmentioning

confidence: 99%

Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance

Nooij

Haar

Ruano

et al. 2017

Clinical Cancer Research

123

167

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Purpose: Vulvar cancer (VC) can be subclassified by human papillomavirus (HPV) status. HPV-negative VCs frequently harbor TP53 mutations; however, in-depth analysis of other potential molecular genetic alterations is lacking. We comprehensively assessed somatic mutations in a large series of vulvar (pre)cancers.Experimental Design: We performed targeted next-generation sequencing (17 genes), p53 immunohistochemistry and HPV testing on 36 VC and 82 precursors (sequencing cohort). Subsequently, the prognostic significance of the three subtypes identified in the sequencing cohort was assessed in a series of 236 VC patients (follow-up cohort).Results: Frequent recurrent mutations were identified in HPVnegative vulvar (pre)cancers in TP53 (42% and 68%), NOTCH1 (28% and 41%), and HRAS (20% and 31%). Mutation frequency in HPV-positive vulvar (pre)cancers was significantly lower (P ¼ 0.001). Furthermore, a substantial subset of the HPV-negative precursors (35/60, 58.3%) and VC (10/29, 34.5%) were TP53 wild-type (wt), suggesting a third, not-previously described, molecular subtype. Clinical outcomes in the three different subtypes (HPV þ , HPV À /p53wt, HPV À /p53abn) were evaluated in a follow-up cohort consisting of 236 VC patients. Local recurrence rate was 5.3% for HPV þ , 16.3% for HPV À /p53wt and 22.6% for HPV À /p53abn tumors (P ¼ 0.044). HPV positivity remained an independent prognostic factor for favorable outcome in the multivariable analysis (P ¼ 0.020).Conclusions: HPV À and HPV þ vulvar (pre)cancers display striking differences in somatic mutation patterns. HPV À /p53wt VC appear to be a distinct clinicopathologic subgroup with frequent NOTCH1 mutations. HPV þ VC have a significantly lower local recurrence rate, independent of clinicopathological variables, opening opportunities for reducing overtreatment in VC.

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Inactivation of the CDKN2A and the p53 tumour suppressor genes in external genital carcinomas and their precursors

Abstract: Our study shows a high prevalence of co-inactivating mutations of p53 and/or CDKN2A genes in EGC, that seem to occur preferentially in LS-derived tumours and late in oncogenesis.

Cited by 54 publications

References 31 publications

Differentiated vulvar intraepithelial neoplasia contains Tp53 mutations and is genetically linked to vulvar squamous cell carcinoma

Differentiated vulvar intraepithelial neoplasia contains Tp53 mutations and is genetically linked to vulvar squamous cell carcinoma

An Integrative Approach Uncovers Biomarkers that Associate with Clinically Relevant Disease Outcomes in Vulvar Carcinoma

Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance

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