Somatic mutation profiling of vulvar cancer: Exploring therapeutic targets

Zięba, Sebastian; Kowalik, Artur; Zalewski, Kamil; Rusetska, Natalia; Goryca, Krzysztof; Piaścik, Agata; Misiek, Marcin; Bakuła-Zalewska, Elwira; Kopczyński, Janusz; Kowalski, Kamil; Radziszewski, Jakub; Bidziński, Mariusz; Góźdż, Stanisław; Kowalewska, Magdalena

doi:10.1016/j.ygyno.2018.06.026

Cited by 47 publications

(52 citation statements)

References 29 publications

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“…In contrast, Zieba et al observed no significant difference in p53 mutation frequency between HPV-dependent and HPV-independent vulvar squamous carcinomas in a cohort of 43 Polish patients 42. These findings are not consistent with the studies of Nooij et al, Weberpals et al, and Han et al that showed a higher frequency of p53 mutations in HPV− tumors 39–41.…”

Section: Methodsmentioning

confidence: 79%

Clinical and molecular classification of vulvar squamous pre-cancers

Cohen

Anderson

Eva

et al. 2019

Int J Gynecol Cancer

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Vulvar intraepithelial neoplasia (VIN) is a precursor to vulvar squamous cell carcinoma and is defined histopathologically by the presence of atypia. VIN has been classified into two types: usual vulvar intraepithelial neoplasia (uVIN), which is also referred to as a vulvar high-grade squamous intra-epithelial lesion (HSIL), and differentiated VIN (dVIN). The former is associated with chronic infection by sub-types of the human papilloma virus (HPV), whereas dVIN is HPV-independent and frequently associated with lichen sclerosus. The distinction is important because dVIN has a greater risk of, and more rapid transit to, vulvar squamous cell carcinoma. Furthermore, dVIN-associated vulvar cancers have an increased risk of recurrence and higher mortality than those arising from HSIL. Molecular characterization of vulvar squamous cell carcinoma precursors using next-generation sequencing is a relatively novel, but rapidly advancing field. This review appraises recent studies that have investigated the risks of progression to vulvar malignancy associated with HSIL and dVIN, the prognosis of HPV-dependent and HPV-independent vulvar squamous cell carcinomas, and conducted next generation sequencing mutation analyses to elucidate the genomic profiles underlying VIN. These studies suggest that HSIL and dVIN are characterized by different underlying molecular alterations that may have important implications for treatment and follow-up of women diagnosed with vulvar squamous cell cancer.

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Section: Methodsmentioning

confidence: 79%

Clinical and molecular classification of vulvar squamous pre-cancers

Cohen

Anderson

Eva

et al. 2019

Int J Gynecol Cancer

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“…Few studies have investigated genetic abnormalities in non HPV-related VSCC, and showed a frequent occurrence of TP53 mutations (13)(14)(15). The upcoming techniques to search for genetic changes are promising to provide more information on the aetiology of (pre)malignant vulvar lesions.…”

Section: Abstract Background/aim: Differentiated Vulvar Intraepithelmentioning

confidence: 99%

Clonal Relationship Between Lichen Sclerosus, Differentiated Vulvar Intra-epithelial Neoplasia and Non HPV-related Vulvar Squamous Cell Carcinoma

Pouwer

Einden

Linden

et al. 2020

Cancer Genomics Proteomics

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Background/Aim: Differentiated vulvar intraepithelial neoplasia (dVIN) and lichen sclerosus (LS) can give rise to vulvar squamous cell carcinoma (VSCC), but genetic evidence is currently still limited. We aimed to determine genetic abnormalities in VSCC and backtrack these abnormalities in the dVIN and LS lesions. Materials and Methods: DNA from VSCC and patient-matched dVIN and LS samples of twelve patients was collected. Highresolution genome-wide copy number analysis was performed and subsequently, we sequenced TP53. Results: Copy number alterations were identified in all VSCC samples. One dVIN lesion presented with three copy number alterations that were preserved in the paired VSCC sample. Targeted sequencing of TP53 identified mutations in five VSCCs. All five mutations were traced back in the dVIN (n=5) or the LS (n=1) with frequencies ranging from 3-19%. Conclusion: Our data provide genetic evidence for a clonal relationship between VSCC and dVIN or LS.Vulvar cancer is the fourth most common cancer affecting the female genital tract and has an increasing incidence of 2.5/100,000 women per year (1). Approximately 80% of all vulvar cancers are of squamous origin and can develop following two different pathways (2, 3). The minority of vulvar squamous cell carcinomas (VSCC) is caused by a persistent infection with high-risk human papillomavirus (HPV), inducing the precursor high-grade squamous intraepithelial lesion (HSIL); the oncogenesis of HPV-related VSCC resembles the development of cervical cancer. The second and most common type of VSCC is non HPV-related and accounts for over 80% of all VSCC (4, 5). These carcinomas arise in a background of the chronic inflammatory vulvar skin disease Lichen Sclerosus (LS) and/or differentiated vulvar intraepithelial neoplasia (dVIN). The exact role of LS and dVIN in the development of VSCC is not yet known, but patients with LS have a lifetime risk of 4-5% to develop VSCC (6).There is clinical evidence that dVIN is the precursor lesion of the non HPV-related pathway (7). We showed that of all VIN lesions diagnosed in the Netherlands between 1992 and 2005, only a minority were dVIN in comparison to HSIL; apparently dVIN is rarely found as a solitary lesion (8).Remarkebly, dVIN is present on the majority of the non HPVrelated VSCCs (4, 5). This discrepancy, low incidence of solitary dVIN lesions, but high incidence of dVIN adjacent to VSCC, can be explained by the fact that diagnosis of dVIN is clinically and histopathologically difficult (9) with an assumed short intraepithelial phase, which suggests that dVIN is possibly suffering from underdiagnosis (10). On the other hand, it has been hypothesised that dVIN is a border phenomenon of VSCC (11). Though the oncogenesis has not been fully clarified, there are strong indications that dVIN is 151 This article is freely accessible online. *These Authors share senior co-authorship.

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“…A recent study in cervical cancer showed that PIK3CA mutation status did not have any significant association with clinicopathological characteristics but highlighted an association with poor overall survival [117]. Somatic mutations in PIK3CA have been reported in low frequencies in Vulvar squamous cell carcinoma [118].…”

Section: Association Of Pik3ca Genetic Mutations With Cervical Ovarimentioning

confidence: 99%

PIK3CA Gene Mutations in Solid Malignancies: Association with Clinicopathological Parameters and Prognosis

Alqahtani

Ayesh

Halawani

2019

Cancers

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Phosphoinositide kinases (PIKs) are a group of lipid kinases that are important upstream activators of various significant signaling pathways. Hyperactivation of the PI3K/AKT/mTOR pathways—either via mutations or genomic amplification—confers key oncogenic activity, essential for the development and progression of several solid tumors. Alterations in the PIK3CA gene are associated with poor prognosis of solid malignancies. Although the literature reports contradictory prognostic values of PIK3CA in aggressive cancers, most of the available data highlight the important role of PIK3CA mutation in mediating tumorigenesis via increased signaling of the PI3K/AKT/mTOR survival pathway. Several inhibitors of PI3K/AKT/mTOR pathways are investigated as potential therapeutic options in solid malignancies. This article reviews the role of PIK3CA mutations and inhibitors of PI3K/AKT/mTOR pathways in major cancer types and examines its association with clinicopathological parameters and prognosis.

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Somatic mutation profiling of vulvar cancer: Exploring therapeutic targets

Cited by 47 publications

References 29 publications

Clinical and molecular classification of vulvar squamous pre-cancers

Clinical and molecular classification of vulvar squamous pre-cancers

Clonal Relationship Between Lichen Sclerosus, Differentiated Vulvar Intra-epithelial Neoplasia and Non HPV-related Vulvar Squamous Cell Carcinoma

PIK3CA Gene Mutations in Solid Malignancies: Association with Clinicopathological Parameters and Prognosis

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