Identification of molecular targets in vulvar cancers

Palisoul, M.; Mullen, Mary M.; Feldman, Rebecca; Thaker, Premal H.

doi:10.1016/j.ygyno.2017.05.011

Cited by 30 publications

(24 citation statements)

References 44 publications

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“…PD-L1-positivity of immune cells was more frequently observed within vSCC than PD-L1-positivity of cancer cells (60.7% vs. 32.1%). We found only two publications dealing with PD-L1 in vulvar cancer [ 13 , 14 ]. None of these papers provided data neither on patterns of PD-L1 staining within primary tumor nor on frequency of PD-L1 expression in vSCC.…”

Section: Discussionmentioning

confidence: 99%

PD-L1 expression on immune cells is a favorable prognostic factor for vulvar squamous cell carcinoma patients

et al. 2017

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BackgroundAnti-immune programmed death-ligand 1 (PD-L1) pathway is used by the tumor to overcome immune system and serves as immunotherapy target in various malignancies.AimTo investigate the expression of PD-L1 in vulvar squamous cell carcinoma (vSCC) and to assess it's clinicopathological and prognostic significance.MethodsImmunohistochemical PD-L1 expression was evaluated in 84 vSCCs with previously defined status of p16 and DNA-HPV, infiltration of immune cells: CD8+, CD4+, FOXP3+, CD56+, CD68+, and GZB+ cells. PD-L1 positivity was defined as ≥5% of PD-L1-positive cells. Survival analyses included the Kaplan–Meier method, log-rank test and Cox proportional hazards model.ResultsPD-L1 expression was detected on cancer and peritumoral immune cells. PD-L1-positivity of cancer nests (27/84, 32.1%) was correlated with higher infiltration of CD4+ (p=0.037), CD8+ (p=0.02), FOXP3+ (p=0.007), CD68+ (p=0.021) cells, while PD-L1 positivity of peritumoral immune cells (51/84, 60.7%) was correlated with higher infiltration of intraepithelial FOXP3+ cells only (p=0.037).PD-L1-positivity of cancer cells but not immune cells, was more frequently observed in p16-negative tumors (p=0.004). High-risk HPV-status did not correlate with the PD-L1 status of cancer and immune cells (p=1.000) and (p=1.000) respectively). Median follow up was 89.20 months (range 1.7-189.5). PD-L1 positivity of peritumoral immune cells was found to be an independent favorable prognostic factor for OS. Conclusion: This study highlights the importance of comprehensive PD-L1 assessment in both cancer and immune cells. PD-L1 expression on peritumoral immune cells seems to be an additional prognostic factor in vSCC patients and may influence the results by anti-PD-L1 treatment.

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Section: Discussionmentioning

confidence: 99%

PD-L1 expression on immune cells is a favorable prognostic factor for vulvar squamous cell carcinoma patients

et al. 2017

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“…The analysis of a series of 23 cases of adenocarcinoma VC, revealed a nearly 65% rate of PTEN loss measured by immunohistochemistry [71]. This rate was higher but not significantly different from the one obtained on squamous cancer samples.…”

Section: Vulvar Cancermentioning

confidence: 99%

PTEN and Gynecological Cancers

Nero

Ciccarone

Pietragalla

et al. 2019

Cancers

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PTEN is a tumour suppressor gene, and its loss of function is frequently observed in both heritable and sporadic cancers. It is involved in a great variety of biological processes, including maintenance of genomic stability, cell survival, migration, proliferation and metabolism. A better understanding of PTEN activity and regulation has therefore emerged as a subject of primary interest in cancer research. Gynaecological cancers are variously interested by PTEN deregulation and many perspective in terms of additional prognostic information and new therapeutic approaches can be explored. Here, we present the most significant findings on PTEN in gynaecological cancers (ovarian, endometrial, cervical, vulvar and uterine cancer) focusing on PTEN alterations incidence, biological role and clinical implications.

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“…16 - 20 PIK3CA mutations have been reported, but frequencies have varied widely, from 7% to 60%. 17 , 20 Other reported mutations in vSCC have involved CDKN2A , FBXW7 , HRAS , FAT1 , FGFR3 , and PTEN , 18 - 21 and copy number analyses have reported CCND1 and EGFR amplifications significantly enriched in HPV– tumors. 22 - 24 Although these previous analyses have suggested genetic differences between HPV-positive (HPV+) and HPV– vSCC, restricted sample volume and testing modalities have limited comprehensive identification of statistically significant differences.…”

Section: Introductionmentioning

confidence: 99%

Vulvar Squamous Cell Carcinoma: Comprehensive Genomic Profiling of HPV+ Versus HPV– Forms Reveals Distinct Sets of Potentially Actionable Molecular Targets

Williams¹,

Werth

Sharaf³

et al. 2020

JCO Precision Oncology

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PURPOSE Vulvar squamous cell carcinoma (vSCC) encompasses two predominant variants: one associated with detectable high-risk strains of human papillomavirus (hrHPV) and a second form often occurring in the context of chronic dermatitis in postmenopausal women. Genomic assessment of a large-scale cohort of patients with aggressive vSCC may identify distinct mutational signatures. MATERIALS AND METHODS Tumor samples from a total of 280 patients with vSCC underwent hybridization capture with analysis of up to 406 cancer-related genes. Human papillomavirus (HPV) sequences were detected by de novo assembly of nonhuman sequencing reads and aligned to the RefSeq database. Immunohistochemistry for programmed death-ligand 1 (PD-L1) was assessed. RESULTS One hundred two of 280 vSCCs (36%) contained hrHPV sequences, predominantly HPV 16 (88%). The HPV-positive (HPV+) group was significantly younger (median age, 59 v 64 years; P = .001). Compared with HPV-negative (HPV–) vSCCs, HPV+ tumors showed more frequent pathogenic alterations in PIK3CA (31% v 16%; P = .004), PTEN (14% v 2%; P < .0001), EP300 (14% v 1%; P < .0001), STK11 (14% v 1%; P < .0001), AR (5% v 0%; P = .006), and FBXW7 (10% v 3%; P = .03). In contrast, HPV– vSCCs showed more alterations in TP53 (83% v 6%; P < .0001), TERTp (71% v 9%; P < .0001), CDKN2A (55% v 2%; P < .0001), CCND1 amplification (22% v 2%; P < .0001), FAT1 (25% v 4%; P < .0001), NOTCH1 (19% v 6%; P = .002), and EGFR amplification (11% v 0%; P < .0001), as well as a higher rate of 9p24.1 ( PDL1/PDL2) amplification (5% v 1%) and PD-L1 immunohistochemistry high-positive tumor staining (33% v 9%; P = .04). CONCLUSION Comprehensive molecular profiles of vSCC vary considerably with hrHPV status and may inform patient selection into clinical trials. Sixty-one percent of HPV+ vSCCs had a pathogenic alteration in the PI3K/mTOR pathway, whereas HPV– vSCCs showed alterations in TP53, TERTp, CDKN2A, CCND1, and EGFR, and biomarkers associated with responsiveness to immunotherapy.

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Identification of molecular targets in vulvar cancers

Cited by 30 publications

References 44 publications

PD-L1 expression on immune cells is a favorable prognostic factor for vulvar squamous cell carcinoma patients

PD-L1 expression on immune cells is a favorable prognostic factor for vulvar squamous cell carcinoma patients

PTEN and Gynecological Cancers

Vulvar Squamous Cell Carcinoma: Comprehensive Genomic Profiling of HPV+ Versus HPV– Forms Reveals Distinct Sets of Potentially Actionable Molecular Targets

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