Genes, pathways and vulvar carcinoma - New insights from next-generation sequencing studies

Zięba, Sebastian; Chechlińska, Magdalena; Kowalik, Artur; Kowalewska, Magdalena

doi:10.1016/j.ygyno.2020.05.034

Cited by 15 publications

(15 citation statements)

References 60 publications

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“…In this study, we also investigated the molecular profile of a subset of dVIN and de-VIL, with a view to facilitate the identification of other potential diagnostic markers. In dVIN, TP53 and CDKN2A mutations were detected most frequently, in line with previous reports [47,[54][55][56][57][58][59]. Interestingly, TP53 mutations were also detected in de-VIL, and dVIN that showed wild-type-expression on p53-IHC.…”

Section: Discussionsupporting

confidence: 89%

Evaluation of Immunohistochemical Markers, CK17 and SOX2, as Adjuncts to p53 for the Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia (dVIN)

et al. 2021

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Histological diagnosis of differentiated vulvar intraepithelial neoplasia (dVIN), the precursor of human papillomavirus (HPV)-independent vulvar squamous cell carcinoma (VSCC), can be challenging, as features of dVIN may mimic those of non-dysplastic dermatoses. To aid the diagnosis, p53-immunohistochemistry (IHC) is commonly used, and mutant expression patterns are used to support a histological diagnosis of dVIN. However, a proportion of dVIN can show wild-type p53-expression, which is characteristic of non-dysplastic dermatoses. Furthermore, recent research has identified a novel precursor of HPV-independent VSCC—the p53-wild-type differentiated exophytic vulvar intraepithelial lesion (de-VIL). Currently, there are no established diagnostic IHC-markers for p53-wild-type dVIN or de-VIL. We evaluated IHC-markers, cytokeratin 17 (CK17), and SRY-box 2 (SOX2), as diagnostic adjuncts for dVIN. For this, IHC-expression of CK17, SOX2, and p53 was studied in dVIN (n = 56), de-VIL (n = 8), and non-dysplastic vulvar tissues (n = 46). For CK17 and SOX2, the percentage of cells showing expression, and the intensity and distribution of expression were recorded. We also performed next generation targeted sequencing (NGTS) on a subset of dVIN (n = 8) and de-VIL (n = 8). With p53-IHC, 74% of dVIN showed mutant patterns and 26% showed wild-type expression. Median percentage of cells expressing CK17 or SOX2 was significantly higher in dVIN (p53-mutant or p53-wild-type) and de-VIL than in non-dysplastic tissues (p < 0.01). Diffuse, moderate-to-strong, full epithelial expression of CK17 or SOX2 was highly specific for dVIN and de-VIL. With NGTS, TP53 mutations were detected in both dVIN and de-VIL. We infer that immunohistochemical markers CK17 and SOX2, when used along with p53, may help support the histological diagnosis of dVIN.

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Section: Discussionsupporting

confidence: 89%

Evaluation of Immunohistochemical Markers, CK17 and SOX2, as Adjuncts to p53 for the Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia (dVIN)

et al. 2021

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“…The ultimate goal would be to identify LS patients at risk for the development of VSCC and tailor the treatment accordingly. Our findings also suggest that patients with vulvar pre-cancers could potentially benefit from therapy targeted against cell cycle regulatory molecules, as previously proposed for VSCC [ 54 ], including the PI3K-Akt pathway members [ 31 ]. Numerous strategies for such targeted treatment modalities have been proposed, and some are being examined in ongoing clinical trials for other cancer types [ 55 ].…”

Section: Discussionsupporting

confidence: 81%

“…In AGO CaRE-1, a retrospective survey of VSCC patients, HPV DNA was detected in 78% of the p16-postitive tumors [ 30 ]. However, CDKN2A mutations were detected at low frequencies and similar in HPV(−) and HPV(+) VSCC (approximately 16% of cases) [ 31 ]. p16 protein induction may by mediated by inactivation of p53 and pRB by HPV oncoproteins and via epigenetic de-repression of p16 by KDM6B (JMJD3) histone demethylase in HPV infected cells.…”

Section: Discussionmentioning

confidence: 99%

“…Genomic DNA was isolated from paraffin-embedded tissue specimens using Maxwell®16 FFPE DNA Purification Kit (Promega, Madison, WI, USA) according to the manufacturer's protocol. The hrHPV status was determined as previously stated [23] using the AmpliSens HPV HCR-genotype-titre-FRT test (InterLabService Ltd., Moscow, Russian Federation), which detects 14 hrHPV genotypes, namely: HPV16, 18,31,33,35,39,45,51,52,56,58,59, 66, and 68, following the manufacturer's instructions.…”

Section: Dna Isolation and Hpv Genotypingmentioning

confidence: 99%

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Somatic Mutation Profiling in Premalignant Lesions of Vulvar Squamous Cell Carcinoma

Zięba

Pouwer

Kowalik

et al. 2020

IJMS

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Vulvar squamous cell carcinoma (VSCC) originates from the progression of either a high-grade squamous intraepithelial lesion (HSIL) or differentiated-type vulvar intraepithelial neoplasia (dVIN), often in a background of lichen sclerosus (LS). The mechanisms leading to the progression of these premalignant lesions to VSCC are elusive. This study aims to identify pathogenic mutations implicated in VSCC development. Using next-generation sequencing, 38 HSIL, 19 dVIN, 20 LS, of which 10 were solitary lesions and 10 with adjacent VSCC, and 10 VSCC adjacent to LS, were screened for hotspot mutations in 50 genes covered by the Ion AmpliSeq Cancer Hotspot Panel v2 Kit (Thermo Fisher Scientific). Pathogenic mutations of TP53 were the most common genetic alterations identified in 53% and 24% of dVIN and HSIL cases, respectively, followed by CDKN2A (p16) mutated in 42% and 0% of dVIN and HSIL, respectively. Seven (70%) and three (30%) of 10 cases of VSCC associated with LS carried TP53 and CDKN2A mutations, respectively, whereas neither solitary LS nor LS associated with VSCC cases harbored mutations in these genes. It appears that TP53 mutations are early events during VSCC carcinogenesis, being present in both HSIL and dVIN lesions. Our preliminary data do not support a genetic background for the notion of LS as the VSCC premalignant lesion.

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“…Although p16-positivity considered a surrogate for hrHPV-positive cases is related with better survival [7], so far, there is no difference in therapeutic options for hrHPV-dependent and -independent disease [8]. Our recent review [9] of next-generation sequencing studies allowed recognition of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway as the main pathway deregulated in both hrHPV-induced and hrHPVunrelated VSCC. Thus, novel therapeutic options targeting the PI3K/Akt pathway should be considered as potentially effective in VSCC patients' management.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory Proteins HMGA2 and PRTN3 as Drivers of Vulvar Squamous Cell Carcinoma Progression

Fatalska

Rusetska

Bakuła-Zalewska

et al. 2020

Cancers

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Current knowledge on the biology of squamous cell vulvar carcinoma (VSCC) is limited. We aimed to identify protein markers of VSCC tumors that would permit to stratify patients by progression risk. Early-stage tumors from patients who progressed (progVSCC) and from those who were disease-free (d-fVSCC) during follow-up, along with normal vulvar tissues were examined by mass spectrometry-based proteomics. Differentially expressed proteins (DEPs) were then verified in solid tissues and blood samples of patients with VSCC tumors and vulvar premalignant lesions. In progVSCC vs. d-fVSCC tumors, the immune response was the most over-represented Gene Ontology category for the identified DEPs. Pathway profiling suggested bacterial infections to be linked to aggressive VSCC phenotypes. High Mobility Group AT-Hook 2 (HMGA2) and Proteinase 3 (PRTN3) were revealed as proteins predicting VSCC progression. HMGA2 and PRTN3 abundances are associated with an aggressive phenotype, and hold promise as markers for VSCC patient stratification. It appears that vulvovaginal microflora disturbances trigger an inflammatory response contributing to cancer progression, suggesting that bacterial rather than viral infection status should be considered in the development of targeted therapies in VSCC.

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Genes, pathways and vulvar carcinoma - New insights from next-generation sequencing studies

Cited by 15 publications

References 60 publications

Evaluation of Immunohistochemical Markers, CK17 and SOX2, as Adjuncts to p53 for the Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia (dVIN)

Evaluation of Immunohistochemical Markers, CK17 and SOX2, as Adjuncts to p53 for the Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia (dVIN)

Somatic Mutation Profiling in Premalignant Lesions of Vulvar Squamous Cell Carcinoma

Inflammatory Proteins HMGA2 and PRTN3 as Drivers of Vulvar Squamous Cell Carcinoma Progression

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