CDKN2A(p16) and HRAS are frequently mutated in vulvar squamous cell carcinoma

Trietsch, Marjolijn D.; Spaans, Vivian M.; Haar, Natalja T. ter; Osse, Elisabeth M.; Peters, Alexander; Gaarenstroom, Katja N.; Fleuren, Gert Jan

doi:10.1016/j.ygyno.2014.07.094

Cited by 53 publications

(57 citation statements)

References 32 publications

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“…p53 IHC was positive in only 5% of the unquestionably HPV‐associated tumors and in 66.7% of the unquestionably HPV‐independent tumors. These results are in keeping with previous reports showing that p53 abnormalities are infrequent in HPV‐associated tumors and present in about two‐thirds of HPV‐independent tumors . Interestingly, the percentage of p53 positivity in HPV DNA−/p16+ tumors was comparable to the unquestionably HPV‐associated neoplasms whereas HPV DNA+/p16− tumors were more similar to the indisputably HPV‐independent carcinomas.…”

Section: Discussionsupporting

confidence: 91%

“…These results are in keeping with previous reports showing that p53 abnormalities are infrequent in HPV-associated tumors and present in about two-thirds of HPV-independent tumors. 14,49 Interestingly, the percentage of p53 positivity in HPV DNA2/ p161 tumors was comparable to the unquestionably HPVassociated neoplasms whereas HPV DNA1/p162 tumors were more similar to the indisputably HPV-independent carcinomas. These results add further evidence indicating that DNA2/ p161 tumors probably represent false-negative results of HPV DNA detection, whereas many of the HPV DNA1/p162 tumors are false-positive HPV DNA cases.…”

Section: Discussionmentioning

confidence: 92%

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"Histological characteristics of HPV‐associated and ‐independent squamous cell carcinomas of the vulva: A study of 1,594 cases”

Rakislova

Clavero

Alemany

et al. 2017

Intl Journal of Cancer

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There are at least two different etio-pathogenic pathways for the development of vulvar squamous cell carcinoma (VSCC): one associated with infection by human papillomavirus (HPV) and another independent of HPV. We aimed to describe the histological characteristics of HPV-associated and -independent tumors and to determine the best strategy to identify HPV in VSCC. A single paraffin block was available for review from a series of 1,594 VSCCs. In all cases HPV DNA detection was analyzed using the SPF10PCR/DEIA/LiPA25 system and p16 immunohistochemistry (IHC). A tumor was considered as unquestionably HPV-associated if both HPV DNA and p16 IHC were positive. A tumor was considered indisputably HPV-independent if both HPV DNA and p16 IHC were negative. Two groups of tumors were classified as non-conclusive: (1) HPV DNA+/p16- and (2) HPV DNA-/p16+. WHO typing and a thorough histological evaluation were conducted in all cases. Four hundred and forty-one tumors were HPV DNA+ with 367 cases (23.0%) being HPV DNA+/p16+. The latter tumors were more frequently basaloid or warty (49.8%), but 36.5% were of the keratinizing type; 1,153 tumors were HPV DNA-, with 1,060 cases (66.5%) being HPV DNA-/p16-. These HPV DNA-/p16- tumors were mostly keratinizing (81.2%) but were occasionally basaloid or warty (5.2%). The features of HPV DNA-/p16+ cases (n = 93) were similar to those of the HPV-associated VSCC, and HPV DNA+/p16- (n = 74) cases had a more diverse profile, although they were more similar to HPV-independent tumors. Several histological characteristics were more frequently associated with HPV-related VSCC (koilocytotic-like change, necrosis, moderate to marked pleomorphism, invasive front in nests; p < 0.001), however, none of these characteristics allowed differentiation between HPV-associated and -independent VSCC. In conclusion, histological criteria do not allow differentiation between HPV-associated and -independent VSCC. p16 Alone is a clinically easy strategy to determine HPV status in VSCC.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 92%

"Histological characteristics of HPV‐associated and ‐independent squamous cell carcinomas of the vulva: A study of 1,594 cases”

Rakislova

Clavero

Alemany

et al. 2017

Intl Journal of Cancer

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“…In total, 30% cervical cancers harbour PIK3CA mutations associated with poor outcomes following chemoradiotherapy (McIntyre et al , 2013; de la Rochefordiere et al , 2015), but similar findings are also reported in vulval (Trietsch et al , 2014) and penile cancers (McDaniel et al , 2015). Similarly the inverse relationship between HPV involvement and TP53 mutations is documented in HNSCC (Westra et al , 2008) and vulval cancer (Trietsch et al , 2014). …”

Section: Molecular Mechanisms For Differential Sensitivity To Crt In supporting

confidence: 64%

Biomarkers in anal cancer: from biological understanding to stratified treatment

et al. 2016

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Squamous cell carcinomas of the anus and anal canal represent a model of a cancer and perhaps the first where level 1 evidence supported primary chemoradiotherapy (CRT) in treating locoregional disease with curative intent. The majority of tumours are associated with infection with oncogenic subtypes of human papilloma virus and this plays a significant role in their sensitivity to treatment. However, not all tumours are cured with CRT and there remain opportunities to improve outcomes in terms of oncological control and also reducing late toxicities. Understanding the biology of ASCC promises to allow a more personalised approach to treatment, with the development and validation of a range of biomarkers and associated techniques that are the focus of this review.

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“…Previous work already identified somatic mutations in HRAS in HPV À VCs and showed an association with a worse prognosis (6). HRAS is an oncogene involved in the RTK/RAS/PI(3)K pathway, and somatic mutations lead to cell proliferation (13,14).…”

Section: Discussionmentioning

confidence: 99%

“…5). 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).…”

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

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126

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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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CDKN2A(p16) and HRAS are frequently mutated in vulvar squamous cell carcinoma

Cited by 53 publications

References 32 publications

"Histological characteristics of HPV‐associated and ‐independent squamous cell carcinomas of the vulva: A study of 1,594 cases”

"Histological characteristics of HPV‐associated and ‐independent squamous cell carcinomas of the vulva: A study of 1,594 cases”

Biomarkers in anal cancer: from biological understanding to stratified treatment

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

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