Sebastian Zięba1, Artur Kowalik2, Kamil Zalewski3, Natalia Rusetska4, Krzysztof Goryca5, Agata Piaścik6, Marcin Misiek7, Elwira Bakuła-Zalewska6, Janusz Kopczyński8, Kamil Kowalski9, Jakub Radziszewski10, Mariusz Bidziński11, Stanisław Góźdź12, Magdalena Kowalewska13. 1. Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland. 2. Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland. Electronic address: arturko@onkol.kielce.pl. 3. Department of Gynecologic Oncology, Holycross Cancer Center, Kielce, Poland; Chair and Department of Obstetrics, Gynecology and Oncology, 2nd Faculty of Medicine, Warsaw Medical University, Poland; Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland. 4. Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland. 5. Department of Genetics, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland. 6. Department of Pathology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland. 7. Department of Gynecologic Oncology, Holycross Cancer Center, Kielce, Poland. 8. Department of Surgical Pathology, Holycross Cancer Center, Kielce, Poland. 9. Department of Cytology, Faculty of Biology, University of Warsaw, Poland. 10. Faculty of Nature, Siedlce University of Natural Sciences and Humanities, Poland; Department of General and Vascular Surgery, Multidisciplinary Hospital Warsaw-Miedzylesie, Warsaw, Poland. 11. Gynecologic Oncology Department, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland. 12. Oncology Clinic, Holycross Cancer Center, Kielce, Poland; Faculty of Heath Sciences, Jan Kochanowski University, Kielce, Poland. 13. Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland; Department of Immunology, Biochemistry and Nutrition, Medical University of Warsaw, Poland.
Abstract
BACKGROUND: Vulvar squamous cell carcinoma (VSCC) constitutes over 90% of vulvar cancer. Its pathogenesis can follow two different pathways; high risk human papillomavirus (hrHPV)-dependent and HPV-independent. Due to the rarity of VSCC, molecular mechanisms underlying VSCC development remain largely unknown. The study aimed to identify pathogenic mutations implicated in the two pathways of VSCC development. METHODS: Using next generation sequencing, 81 VSCC tumors, 52 hrHPV(+) and 29 hrHPV(-), were screened for hotspot mutations in 50 genes covered by the Ion AmpliSeq Cancer Hotspot Panel v2 Kit (Thermo Fisher Scientific). RESULTS: Mutations of TP53 (46% and 41%, of hrHPV(+) and hrHPV(-) cases respectively) and CDKN2A (p16) (25% and 21%, of hrHPV(+) and hrHPV(-) cases respectively) were the most common genetic alterations identified in VSCC tumors. Further mutations were identified in PIK3CA, FBXW7, HRAS, FGFR3, STK11, AKT1, SMAD4, FLT3, JAK3, GNAQ, and PTEN, albeit at low frequencies. Some of the identified mutations may activate the PI3K/AKT/mTOR pathway. The activation of mTOR was confirmed in the vast majority of VSCC samples by immunohistochemical staining. CONCLUSIONS: Detecting pathogenic mutations in 13/50 genes examined at comparable frequencies in hrHPV(+) and hrHPV(-) tumors suggest that genetic mechanisms of the two routes of VSCC pathogenesis may be similar, despite being initiated from different premalignant lesions. Importantly, our data provide a rationale for new anti-VSCC therapies targeting the PI3K/AKT/mTOR pathway.
BACKGROUND: Vulvar squamous cell carcinoma (VSCC) constitutes over 90% of vulvar cancer. Its pathogenesis can follow two different pathways; high risk human papillomavirus (hrHPV)-dependent and HPV-independent. Due to the rarity of VSCC, molecular mechanisms underlying VSCC development remain largely unknown. The study aimed to identify pathogenic mutations implicated in the two pathways of VSCC development. METHODS: Using next generation sequencing, 81 VSCC tumors, 52 hrHPV(+) and 29 hrHPV(-), were screened for hotspot mutations in 50 genes covered by the Ion AmpliSeq Cancer Hotspot Panel v2 Kit (Thermo Fisher Scientific). RESULTS: Mutations of TP53 (46% and 41%, of hrHPV(+) and hrHPV(-) cases respectively) and CDKN2A (p16) (25% and 21%, of hrHPV(+) and hrHPV(-) cases respectively) were the most common genetic alterations identified in VSCC tumors. Further mutations were identified in PIK3CA, FBXW7, HRAS, FGFR3, STK11, AKT1, SMAD4, FLT3, JAK3, GNAQ, and PTEN, albeit at low frequencies. Some of the identified mutations may activate the PI3K/AKT/mTOR pathway. The activation of mTOR was confirmed in the vast majority of VSCC samples by immunohistochemical staining. CONCLUSIONS: Detecting pathogenic mutations in 13/50 genes examined at comparable frequencies in hrHPV(+) and hrHPV(-) tumors suggest that genetic mechanisms of the two routes of VSCC pathogenesis may be similar, despite being initiated from different premalignant lesions. Importantly, our data provide a rationale for new anti-VSCC therapies targeting the PI3K/AKT/mTOR pathway.
Authors: Elysha Kolitz; Elena Lucas; Gregory A Hosler; Jiwoong Kim; Suntrea Hammer; Cheryl Lewis; Lin Xu; Andrew T Day; Melissa Mauskar; Jayanthi S Lea; Richard C Wang Journal: J Invest Dermatol Date: 2021-10-28 Impact factor: 7.590
Authors: Simona Maria Fragomeni; Frediano Inzani; Anna Fagotti; Luigi Della Corte; Stefano Gentileschi; Luca Tagliaferri; Gian Franco Zannoni; Giovanni Scambia; Giorgia Garganese Journal: J Cancer Res Clin Oncol Date: 2020-04-25 Impact factor: 4.553
Authors: Pavol Zubor; Yun Wang; Alena Liskova; Marek Samec; Lenka Koklesova; Zuzana Dankova; Anne Dørum; Karol Kajo; Dana Dvorska; Vincent Lucansky; Bibiana Malicherova; Ivana Kasubova; Jan Bujnak; Milos Mlyncek; Carlos Alberto Dussan; Peter Kubatka; Dietrich Büsselberg; Olga Golubnitschaja Journal: Int J Mol Sci Date: 2020-10-27 Impact factor: 5.923