Somatic mutation profiling of vulvar cancer: Exploring therapeutic targets.
Identifieur interne : 000489 ( Main/Exploration ); précédent : 000488; suivant : 000490Somatic mutation profiling of vulvar cancer: Exploring therapeutic targets.
Auteurs : Sebastian Zi Ba [Pologne] ; Artur Kowalik [Pologne] ; Kamil Zalewski [Pologne] ; Natalia Rusetska [Pologne] ; Krzysztof Goryca [Pologne] ; Agata Pia Cik [Pologne] ; Marcin Misiek [Pologne] ; Elwira Bakuła-Zalewska [Pologne] ; Janusz Kopczy Ski [Pologne] ; Kamil Kowalski [Pologne] ; Jakub Radziszewski [Pologne] ; Mariusz Bidzi Ski [Pologne] ; Stanisław G D [Pologne] ; Magdalena Kowalewska [Pologne]Source :
- Gynecologic oncology [ 1095-6859 ] ; 2018.
Descripteurs français
- KwdFr :
- ADN tumoral (analyse), Adulte (MeSH), Adulte d'âge moyen (MeSH), Analyse de mutations d'ADN (MeSH), Antibiotiques antinéoplasiques (pharmacologie), Antinéoplasiques (pharmacologie), Benzamides (MeSH), Carcinome épidermoïde (génétique), Carcinome épidermoïde (métabolisme), Carcinome épidermoïde (virologie), Femelle (MeSH), Humains (MeSH), Infections à papillomavirus (complications), Inhibiteur p16 de kinase cycline-dépendante (MeSH), Inhibiteur p18 de kinase cycline-dépendante (génétique), Inhibiteurs de protéines kinases (pharmacologie), Janus kinase 3 (génétique), Lignée cellulaire tumorale (MeSH), Morpholines (pharmacologie), Mutation (MeSH), Papillomaviridae (MeSH), Phosphatidylinositol 3-kinase (métabolisme), Phosphatidylinositol 3-kinases de classe I (génétique), Phosphohydrolase PTEN (génétique), Protein-Serine-Threonine Kinases (génétique), Protéine Smad-4 (génétique), Protéine p53 suppresseur de tumeur (génétique), Protéine-7 contenant une boite F et des répétitions WD (génétique), Protéines proto-oncogènes c-akt (génétique), Protéines proto-oncogènes c-akt (métabolisme), Protéines proto-oncogènes p21(ras) (génétique), Pyrimidines (MeSH), Récepteur de type 3 des facteurs de croissance fibroblastique (génétique), Sirolimus (pharmacologie), Sous-unités alpha Gq-G11 des protéines G (génétique), Sujet âgé (MeSH), Sujet âgé de 80 ans ou plus (MeSH), Survie cellulaire (effets des médicaments et des substances chimiques), Survie sans rechute (MeSH), Séquençage nucléotidique à haut débit (MeSH), Sérine-thréonine kinases TOR (métabolisme), Transduction du signal (effets des médicaments et des substances chimiques), Transduction du signal (génétique), Tumeurs de la vulve (génétique), Tumeurs de la vulve (métabolisme), Tumeurs de la vulve (virologie), Tyrosine kinase-3 de type fms (génétique), Évérolimus (pharmacologie).
- MESH :
- analyse : ADN tumoral.
- effets des médicaments et des substances chimiques : Survie cellulaire, Transduction du signal.
- génétique : Carcinome épidermoïde, Infections à papillomavirus, Inhibiteur p18 de kinase cycline-dépendante, Janus kinase 3, Phosphatidylinositol 3-kinases de classe I, Phosphohydrolase PTEN, Protein-Serine-Threonine Kinases, Protéine Smad-4, Protéine p53 suppresseur de tumeur, Protéine-7 contenant une boite F et des répétitions WD, Protéines proto-oncogènes c-akt, Protéines proto-oncogènes p21(ras), Récepteur de type 3 des facteurs de croissance fibroblastique, Sous-unités alpha Gq-G11 des protéines G, Transduction du signal, Tumeurs de la vulve, Tyrosine kinase-3 de type fms.
- métabolisme : Carcinome épidermoïde, Phosphatidylinositol 3-kinase, Protéines proto-oncogènes c-akt, Sérine-thréonine kinases TOR, Tumeurs de la vulve.
- pharmacologie : Antibiotiques antinéoplasiques, Antinéoplasiques, Inhibiteurs de protéines kinases, Morpholines, Sirolimus, Évérolimus.
- virologie : Carcinome épidermoïde, Tumeurs de la vulve.
- Adulte, Adulte d'âge moyen, Analyse de mutations d'ADN, Benzamides, Femelle, Humains, Inhibiteur p16 de kinase cycline-dépendante, Lignée cellulaire tumorale, Mutation, Papillomaviridae, Pyrimidines, Sujet âgé, Sujet âgé de 80 ans ou plus, Survie sans rechute, Séquençage nucléotidique à haut débit.
English descriptors
- KwdEn :
- Adult (MeSH), Aged (MeSH), Aged, 80 and over (MeSH), Antibiotics, Antineoplastic (pharmacology), Antineoplastic Agents (pharmacology), Benzamides (MeSH), Carcinoma, Squamous Cell (genetics), Carcinoma, Squamous Cell (metabolism), Carcinoma, Squamous Cell (virology), Cell Line, Tumor (MeSH), Cell Survival (drug effects), Class I Phosphatidylinositol 3-Kinases (genetics), Cyclin-Dependent Kinase Inhibitor p16 (MeSH), Cyclin-Dependent Kinase Inhibitor p18 (genetics), DNA Mutational Analysis (MeSH), DNA, Neoplasm (analysis), Disease-Free Survival (MeSH), Everolimus (pharmacology), F-Box-WD Repeat-Containing Protein 7 (genetics), Female (MeSH), GTP-Binding Protein alpha Subunits, Gq-G11 (genetics), High-Throughput Nucleotide Sequencing (MeSH), Humans (MeSH), Janus Kinase 3 (genetics), Middle Aged (MeSH), Morpholines (pharmacology), Mutation (MeSH), PTEN Phosphohydrolase (genetics), Papillomaviridae (MeSH), Papillomavirus Infections (complications), Phosphatidylinositol 3-Kinase (metabolism), Protein Kinase Inhibitors (pharmacology), Protein-Serine-Threonine Kinases (genetics), Proto-Oncogene Proteins c-akt (genetics), Proto-Oncogene Proteins c-akt (metabolism), Proto-Oncogene Proteins p21(ras) (genetics), Pyrimidines (MeSH), Receptor, Fibroblast Growth Factor, Type 3 (genetics), Signal Transduction (drug effects), Signal Transduction (genetics), Sirolimus (pharmacology), Smad4 Protein (genetics), TOR Serine-Threonine Kinases (metabolism), Tumor Suppressor Protein p53 (genetics), Vulvar Neoplasms (genetics), Vulvar Neoplasms (metabolism), Vulvar Neoplasms (virology), fms-Like Tyrosine Kinase 3 (genetics).
- MESH :
- chemical , analysis : DNA, Neoplasm.
- chemical , genetics : Class I Phosphatidylinositol 3-Kinases, Cyclin-Dependent Kinase Inhibitor p18, F-Box-WD Repeat-Containing Protein 7, GTP-Binding Protein alpha Subunits, Gq-G11, Janus Kinase 3, PTEN Phosphohydrolase, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins p21(ras), Receptor, Fibroblast Growth Factor, Type 3, Smad4 Protein, Tumor Suppressor Protein p53, fms-Like Tyrosine Kinase 3.
- chemical , metabolism : Phosphatidylinositol 3-Kinase, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases.
- chemical , pharmacology : Antibiotics, Antineoplastic, Antineoplastic Agents, Everolimus, Morpholines, Protein Kinase Inhibitors, Sirolimus.
- complications : Papillomavirus Infections.
- drug effects : Cell Survival, Signal Transduction.
- genetics : Carcinoma, Squamous Cell, Signal Transduction, Vulvar Neoplasms.
- metabolism : Carcinoma, Squamous Cell, Vulvar Neoplasms.
- virology : Carcinoma, Squamous Cell, Vulvar Neoplasms.
- Adult, Aged, Aged, 80 and over, Benzamides, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p16, DNA Mutational Analysis, Disease-Free Survival, Female, High-Throughput Nucleotide Sequencing, Humans, Middle Aged, Mutation, Papillomaviridae, Pyrimidines.
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.
DOI: 10.1016/j.ygyno.2018.06.026
PubMed: 29980281
Affiliations:
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Department of General and Vascular Surgery, Multidisciplinary Hospital Warsaw-Miedzylesie, Warsaw, Poland.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Faculty of Nature, Siedlce University of Natural Sciences and Humanities, Poland; Department of General and Vascular Surgery, Multidisciplinary Hospital Warsaw-Miedzylesie, Warsaw</wicri:regionArea><wicri:noRegion>Warsaw</wicri:noRegion></affiliation></author><author><name sortKey="Bidzi Ski, Mariusz" sort="Bidzi Ski, Mariusz" uniqKey="Bidzi Ski M" first="Mariusz" last="Bidzi Ski">Mariusz Bidzi Ski</name><affiliation wicri:level="1"><nlm:affiliation>Gynecologic Oncology Department, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Gynecologic Oncology Department, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw</wicri:regionArea><wicri:noRegion>Warsaw</wicri:noRegion></affiliation></author><author><name sortKey="G D, Stanislaw" sort="G D, Stanislaw" uniqKey="G D S" first="Stanisław" last="G D">Stanisław G D</name><affiliation wicri:level="1"><nlm:affiliation>Oncology Clinic, Holycross Cancer Center, Kielce, Poland; Faculty of Heath Sciences, Jan Kochanowski University, Kielce, Poland.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Oncology Clinic, Holycross Cancer Center, Kielce, Poland; Faculty of Heath Sciences, Jan Kochanowski University, Kielce</wicri:regionArea><wicri:noRegion>Kielce</wicri:noRegion></affiliation></author><author><name sortKey="Kowalewska, Magdalena" sort="Kowalewska, Magdalena" uniqKey="Kowalewska M" first="Magdalena" last="Kowalewska">Magdalena Kowalewska</name><affiliation wicri:level="1"><nlm:affiliation>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.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland; Department of Immunology, Biochemistry and Nutrition, Medical University of Warsaw</wicri:regionArea><wicri:noRegion>Medical University of Warsaw</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2018">2018</date><idno type="RBID">pubmed:29980281</idno><idno type="pmid">29980281</idno><idno type="doi">10.1016/j.ygyno.2018.06.026</idno><idno type="wicri:Area/Main/Corpus">000509</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000509</idno><idno type="wicri:Area/Main/Curation">000509</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000509</idno><idno type="wicri:Area/Main/Exploration">000509</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Somatic mutation profiling of vulvar cancer: Exploring therapeutic targets.</title><author><name sortKey="Zi Ba, Sebastian" sort="Zi Ba, Sebastian" uniqKey="Zi Ba S" first="Sebastian" last="Zi Ba">Sebastian Zi Ba</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Department of Molecular Diagnostics, Holycross Cancer Center, Kielce</wicri:regionArea><wicri:noRegion>Kielce</wicri:noRegion></affiliation></author><author><name sortKey="Kowalik, Artur" sort="Kowalik, Artur" uniqKey="Kowalik A" first="Artur" last="Kowalik">Artur Kowalik</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland. Electronic address: arturko@onkol.kielce.pl.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Department of Molecular Diagnostics, Holycross Cancer Center, Kielce</wicri:regionArea><wicri:noRegion>Kielce</wicri:noRegion></affiliation></author><author><name sortKey="Zalewski, Kamil" sort="Zalewski, Kamil" uniqKey="Zalewski K" first="Kamil" last="Zalewski">Kamil Zalewski</name><affiliation wicri:level="1"><nlm:affiliation>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.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Warsaw</wicri:noRegion></affiliation></author><author><name sortKey="Rusetska, Natalia" sort="Rusetska, Natalia" uniqKey="Rusetska N" first="Natalia" last="Rusetska">Natalia Rusetska</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw</wicri:regionArea><wicri:noRegion>Warsaw</wicri:noRegion></affiliation></author><author><name sortKey="Goryca, Krzysztof" sort="Goryca, Krzysztof" uniqKey="Goryca K" first="Krzysztof" last="Goryca">Krzysztof Goryca</name><affiliation wicri:level="1"><nlm:affiliation>Department of Genetics, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Department of Genetics, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw</wicri:regionArea><wicri:noRegion>Warsaw</wicri:noRegion></affiliation></author><author><name sortKey="Pia Cik, Agata" sort="Pia Cik, Agata" uniqKey="Pia Cik A" first="Agata" last="Pia Cik">Agata Pia Cik</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Department of Pathology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw</wicri:regionArea><wicri:noRegion>Warsaw</wicri:noRegion></affiliation></author><author><name sortKey="Misiek, Marcin" sort="Misiek, Marcin" uniqKey="Misiek M" first="Marcin" last="Misiek">Marcin Misiek</name><affiliation wicri:level="1"><nlm:affiliation>Department of Gynecologic Oncology, Holycross Cancer Center, Kielce, Poland.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Department of Gynecologic Oncology, Holycross Cancer Center, Kielce</wicri:regionArea><wicri:noRegion>Kielce</wicri:noRegion></affiliation></author><author><name sortKey="Bakula Zalewska, Elwira" sort="Bakula Zalewska, Elwira" uniqKey="Bakula Zalewska E" first="Elwira" last="Bakuła-Zalewska">Elwira Bakuła-Zalewska</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pathology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Department of Pathology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw</wicri:regionArea><wicri:noRegion>Warsaw</wicri:noRegion></affiliation></author><author><name sortKey="Kopczy Ski, Janusz" sort="Kopczy Ski, Janusz" uniqKey="Kopczy Ski J" first="Janusz" last="Kopczy Ski">Janusz Kopczy Ski</name><affiliation wicri:level="1"><nlm:affiliation>Department of Surgical Pathology, Holycross Cancer Center, Kielce, Poland.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Department of Surgical Pathology, Holycross Cancer Center, Kielce</wicri:regionArea><wicri:noRegion>Kielce</wicri:noRegion></affiliation></author><author><name sortKey="Kowalski, Kamil" sort="Kowalski, Kamil" uniqKey="Kowalski K" first="Kamil" last="Kowalski">Kamil Kowalski</name><affiliation wicri:level="1"><nlm:affiliation>Department of Cytology, Faculty of Biology, University of Warsaw, Poland.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Department of Cytology, Faculty of Biology, University of Warsaw</wicri:regionArea><wicri:noRegion>University of Warsaw</wicri:noRegion></affiliation></author><author><name sortKey="Radziszewski, Jakub" sort="Radziszewski, Jakub" uniqKey="Radziszewski J" first="Jakub" last="Radziszewski">Jakub Radziszewski</name><affiliation wicri:level="1"><nlm:affiliation>Faculty of Nature, Siedlce University of Natural Sciences and Humanities, Poland; Department of General and Vascular Surgery, Multidisciplinary Hospital Warsaw-Miedzylesie, Warsaw, Poland.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Faculty of Nature, Siedlce University of Natural Sciences and Humanities, Poland; Department of General and Vascular Surgery, Multidisciplinary Hospital Warsaw-Miedzylesie, Warsaw</wicri:regionArea><wicri:noRegion>Warsaw</wicri:noRegion></affiliation></author><author><name sortKey="Bidzi Ski, Mariusz" sort="Bidzi Ski, Mariusz" uniqKey="Bidzi Ski M" first="Mariusz" last="Bidzi Ski">Mariusz Bidzi Ski</name><affiliation wicri:level="1"><nlm:affiliation>Gynecologic Oncology Department, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Gynecologic Oncology Department, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw</wicri:regionArea><wicri:noRegion>Warsaw</wicri:noRegion></affiliation></author><author><name sortKey="G D, Stanislaw" sort="G D, Stanislaw" uniqKey="G D S" first="Stanisław" last="G D">Stanisław G D</name><affiliation wicri:level="1"><nlm:affiliation>Oncology Clinic, Holycross Cancer Center, Kielce, Poland; Faculty of Heath Sciences, Jan Kochanowski University, Kielce, Poland.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Oncology Clinic, Holycross Cancer Center, Kielce, Poland; Faculty of Heath Sciences, Jan Kochanowski University, Kielce</wicri:regionArea><wicri:noRegion>Kielce</wicri:noRegion></affiliation></author><author><name sortKey="Kowalewska, Magdalena" sort="Kowalewska, Magdalena" uniqKey="Kowalewska M" first="Magdalena" last="Kowalewska">Magdalena Kowalewska</name><affiliation wicri:level="1"><nlm:affiliation>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.</nlm:affiliation><country xml:lang="fr">Pologne</country><wicri:regionArea>Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland; Department of Immunology, Biochemistry and Nutrition, Medical University of Warsaw</wicri:regionArea><wicri:noRegion>Medical University of Warsaw</wicri:noRegion></affiliation></author></analytic><series><title level="j">Gynecologic oncology</title><idno type="eISSN">1095-6859</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult (MeSH)</term><term>Aged (MeSH)</term><term>Aged, 80 and over (MeSH)</term><term>Antibiotics, Antineoplastic (pharmacology)</term><term>Antineoplastic Agents (pharmacology)</term><term>Benzamides (MeSH)</term><term>Carcinoma, Squamous Cell (genetics)</term><term>Carcinoma, Squamous Cell (metabolism)</term><term>Carcinoma, Squamous Cell (virology)</term><term>Cell Line, Tumor (MeSH)</term><term>Cell Survival (drug effects)</term><term>Class I Phosphatidylinositol 3-Kinases (genetics)</term><term>Cyclin-Dependent Kinase Inhibitor p16 (MeSH)</term><term>Cyclin-Dependent Kinase Inhibitor p18 (genetics)</term><term>DNA Mutational Analysis (MeSH)</term><term>DNA, Neoplasm (analysis)</term><term>Disease-Free Survival (MeSH)</term><term>Everolimus (pharmacology)</term><term>F-Box-WD Repeat-Containing Protein 7 (genetics)</term><term>Female (MeSH)</term><term>GTP-Binding Protein alpha Subunits, Gq-G11 (genetics)</term><term>High-Throughput Nucleotide Sequencing (MeSH)</term><term>Humans (MeSH)</term><term>Janus Kinase 3 (genetics)</term><term>Middle Aged (MeSH)</term><term>Morpholines (pharmacology)</term><term>Mutation (MeSH)</term><term>PTEN Phosphohydrolase (genetics)</term><term>Papillomaviridae (MeSH)</term><term>Papillomavirus Infections (complications)</term><term>Phosphatidylinositol 3-Kinase (metabolism)</term><term>Protein Kinase Inhibitors (pharmacology)</term><term>Protein-Serine-Threonine Kinases (genetics)</term><term>Proto-Oncogene Proteins c-akt (genetics)</term><term>Proto-Oncogene Proteins c-akt (metabolism)</term><term>Proto-Oncogene Proteins p21(ras) (genetics)</term><term>Pyrimidines (MeSH)</term><term>Receptor, Fibroblast Growth Factor, Type 3 (genetics)</term><term>Signal Transduction (drug effects)</term><term>Signal Transduction (genetics)</term><term>Sirolimus (pharmacology)</term><term>Smad4 Protein (genetics)</term><term>TOR Serine-Threonine Kinases (metabolism)</term><term>Tumor Suppressor Protein p53 (genetics)</term><term>Vulvar Neoplasms (genetics)</term><term>Vulvar Neoplasms (metabolism)</term><term>Vulvar Neoplasms (virology)</term><term>fms-Like Tyrosine Kinase 3 (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ADN tumoral (analyse)</term><term>Adulte (MeSH)</term><term>Adulte d'âge moyen (MeSH)</term><term>Analyse de mutations d'ADN (MeSH)</term><term>Antibiotiques antinéoplasiques (pharmacologie)</term><term>Antinéoplasiques (pharmacologie)</term><term>Benzamides (MeSH)</term><term>Carcinome épidermoïde (génétique)</term><term>Carcinome épidermoïde (métabolisme)</term><term>Carcinome épidermoïde (virologie)</term><term>Femelle (MeSH)</term><term>Humains (MeSH)</term><term>Infections à papillomavirus (complications)</term><term>Inhibiteur p16 de kinase cycline-dépendante (MeSH)</term><term>Inhibiteur p18 de kinase cycline-dépendante (génétique)</term><term>Inhibiteurs de protéines kinases (pharmacologie)</term><term>Janus kinase 3 (génétique)</term><term>Lignée cellulaire tumorale (MeSH)</term><term>Morpholines (pharmacologie)</term><term>Mutation (MeSH)</term><term>Papillomaviridae (MeSH)</term><term>Phosphatidylinositol 3-kinase (métabolisme)</term><term>Phosphatidylinositol 3-kinases de classe I (génétique)</term><term>Phosphohydrolase PTEN (génétique)</term><term>Protein-Serine-Threonine Kinases (génétique)</term><term>Protéine Smad-4 (génétique)</term><term>Protéine p53 suppresseur de tumeur (génétique)</term><term>Protéine-7 contenant une boite F et des répétitions WD (génétique)</term><term>Protéines proto-oncogènes c-akt (génétique)</term><term>Protéines proto-oncogènes c-akt (métabolisme)</term><term>Protéines proto-oncogènes p21(ras) (génétique)</term><term>Pyrimidines (MeSH)</term><term>Récepteur de type 3 des facteurs de croissance fibroblastique (génétique)</term><term>Sirolimus (pharmacologie)</term><term>Sous-unités alpha Gq-G11 des protéines G (génétique)</term><term>Sujet âgé (MeSH)</term><term>Sujet âgé de 80 ans ou plus (MeSH)</term><term>Survie cellulaire (effets des médicaments et des substances chimiques)</term><term>Survie sans rechute (MeSH)</term><term>Séquençage nucléotidique à haut débit (MeSH)</term><term>Sérine-thréonine kinases TOR (métabolisme)</term><term>Transduction du signal (effets des médicaments et des substances chimiques)</term><term>Transduction du signal (génétique)</term><term>Tumeurs de la vulve (génétique)</term><term>Tumeurs de la vulve (métabolisme)</term><term>Tumeurs de la vulve (virologie)</term><term>Tyrosine kinase-3 de type fms (génétique)</term><term>Évérolimus (pharmacologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analysis" xml:lang="en"><term>DNA, Neoplasm</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Class I Phosphatidylinositol 3-Kinases</term><term>Cyclin-Dependent Kinase Inhibitor p18</term><term>F-Box-WD Repeat-Containing Protein 7</term><term>GTP-Binding Protein alpha Subunits, Gq-G11</term><term>Janus Kinase 3</term><term>PTEN Phosphohydrolase</term><term>Protein-Serine-Threonine Kinases</term><term>Proto-Oncogene Proteins c-akt</term><term>Proto-Oncogene Proteins p21(ras)</term><term>Receptor, Fibroblast Growth Factor, Type 3</term><term>Smad4 Protein</term><term>Tumor Suppressor Protein p53</term><term>fms-Like Tyrosine Kinase 3</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Phosphatidylinositol 3-Kinase</term><term>Proto-Oncogene Proteins c-akt</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antibiotics, Antineoplastic</term><term>Antineoplastic Agents</term><term>Everolimus</term><term>Morpholines</term><term>Protein Kinase Inhibitors</term><term>Sirolimus</term></keywords><keywords scheme="MESH" qualifier="analyse" xml:lang="fr"><term>ADN tumoral</term></keywords><keywords scheme="MESH" qualifier="complications" xml:lang="en"><term>Papillomavirus Infections</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Survival</term><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Survie cellulaire</term><term>Transduction du signal</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Carcinoma, Squamous Cell</term><term>Signal Transduction</term><term>Vulvar Neoplasms</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Carcinome épidermoïde</term><term>Infections à papillomavirus</term><term>Inhibiteur p18 de kinase cycline-dépendante</term><term>Janus kinase 3</term><term>Phosphatidylinositol 3-kinases de classe I</term><term>Phosphohydrolase PTEN</term><term>Protein-Serine-Threonine Kinases</term><term>Protéine Smad-4</term><term>Protéine p53 suppresseur de tumeur</term><term>Protéine-7 contenant une boite F et des répétitions WD</term><term>Protéines proto-oncogènes c-akt</term><term>Protéines proto-oncogènes p21(ras)</term><term>Récepteur de type 3 des facteurs de croissance fibroblastique</term><term>Sous-unités alpha Gq-G11 des protéines G</term><term>Transduction du signal</term><term>Tumeurs de la vulve</term><term>Tyrosine kinase-3 de type fms</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Carcinoma, Squamous Cell</term><term>Vulvar Neoplasms</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Carcinome épidermoïde</term><term>Phosphatidylinositol 3-kinase</term><term>Protéines proto-oncogènes c-akt</term><term>Sérine-thréonine kinases TOR</term><term>Tumeurs de la vulve</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antibiotiques antinéoplasiques</term><term>Antinéoplasiques</term><term>Inhibiteurs de protéines kinases</term><term>Morpholines</term><term>Sirolimus</term><term>Évérolimus</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Carcinome épidermoïde</term><term>Tumeurs de la vulve</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Carcinoma, Squamous Cell</term><term>Vulvar Neoplasms</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Aged</term><term>Aged, 80 and over</term><term>Benzamides</term><term>Cell Line, Tumor</term><term>Cyclin-Dependent Kinase Inhibitor p16</term><term>DNA Mutational Analysis</term><term>Disease-Free Survival</term><term>Female</term><term>High-Throughput Nucleotide Sequencing</term><term>Humans</term><term>Middle Aged</term><term>Mutation</term><term>Papillomaviridae</term><term>Pyrimidines</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adulte</term><term>Adulte d'âge moyen</term><term>Analyse de mutations d'ADN</term><term>Benzamides</term><term>Femelle</term><term>Humains</term><term>Inhibiteur p16 de kinase cycline-dépendante</term><term>Lignée cellulaire tumorale</term><term>Mutation</term><term>Papillomaviridae</term><term>Pyrimidines</term><term>Sujet âgé</term><term>Sujet âgé de 80 ans ou plus</term><term>Survie sans rechute</term><term>Séquençage nucléotidique à haut débit</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><b>BACKGROUND</b></p><p>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.</p></div><div type="abstract" xml:lang="en"><p><b>METHODS</b></p><p>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).</p></div><div type="abstract" xml:lang="en"><p><b>RESULTS</b></p><p>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.</p></div><div type="abstract" xml:lang="en"><p><b>CONCLUSIONS</b></p><p>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.</p></div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">29980281</PMID><DateCompleted><Year>2018</Year><Month>10</Month><Day>26</Day></DateCompleted><DateRevised><Year>2019</Year><Month>12</Month><Day>10</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1095-6859</ISSN><JournalIssue CitedMedium="Internet"><Volume>150</Volume><Issue>3</Issue><PubDate><Year>2018</Year><Month>09</Month></PubDate></JournalIssue><Title>Gynecologic oncology</Title><ISOAbbreviation>Gynecol Oncol</ISOAbbreviation></Journal><ArticleTitle>Somatic mutation profiling of vulvar cancer: Exploring therapeutic targets.</ArticleTitle><Pagination><MedlinePgn>552-561</MedlinePgn></Pagination><ELocationID EIdType="pii" ValidYN="Y">S0090-8258(18)31008-4</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.ygyno.2018.06.026</ELocationID><Abstract><AbstractText Label="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.</AbstractText><AbstractText Label="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).</AbstractText><AbstractText Label="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.</AbstractText><AbstractText Label="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.</AbstractText><CopyrightInformation>Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Zięba</LastName><ForeName>Sebastian</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kowalik</LastName><ForeName>Artur</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland. Electronic address: arturko@onkol.kielce.pl.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zalewski</LastName><ForeName>Kamil</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rusetska</LastName><ForeName>Natalia</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Goryca</LastName><ForeName>Krzysztof</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Department of Genetics, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Piaścik</LastName><ForeName>Agata</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Pathology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Misiek</LastName><ForeName>Marcin</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Gynecologic Oncology, Holycross Cancer Center, Kielce, Poland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bakuła-Zalewska</LastName><ForeName>Elwira</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Department of Pathology, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kopczyński</LastName><ForeName>Janusz</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Surgical Pathology, Holycross Cancer Center, Kielce, Poland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kowalski</LastName><ForeName>Kamil</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Department of Cytology, Faculty of Biology, University of Warsaw, Poland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Radziszewski</LastName><ForeName>Jakub</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Faculty of Nature, Siedlce University of Natural Sciences and Humanities, Poland; Department of General and Vascular Surgery, Multidisciplinary Hospital Warsaw-Miedzylesie, Warsaw, Poland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bidziński</LastName><ForeName>Mariusz</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Gynecologic Oncology Department, Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Góźdź</LastName><ForeName>Stanisław</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Oncology Clinic, Holycross Cancer Center, Kielce, Poland; Faculty of Heath Sciences, Jan Kochanowski University, Kielce, Poland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kowalewska</LastName><ForeName>Magdalena</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>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.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2018</Year><Month>07</Month><Day>03</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Gynecol Oncol</MedlineTA><NlmUniqueID>0365304</NlmUniqueID><ISSNLinking>0090-8258</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000903">Antibiotics, Antineoplastic</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000970">Antineoplastic Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D001549">Benzamides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C000614131">CDKN2A protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D019941">Cyclin-Dependent Kinase Inhibitor p16</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D050763">Cyclin-Dependent Kinase Inhibitor p18</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004273">DNA, Neoplasm</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000073979">F-Box-WD Repeat-Containing Protein 7</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C513273">FBXW7 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C554061">GNAQ protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D009025">Morpholines</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D047428">Protein Kinase Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011743">Pyrimidines</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C497796">SMAD4 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D051901">Smad4 Protein</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D016159">Tumor Suppressor Protein p53</NameOfSubstance></Chemical><Chemical><RegistryNumber>0BSC3P4H5X</RegistryNumber><NameOfSubstance UI="C585537">vistusertib</NameOfSubstance></Chemical><Chemical><RegistryNumber>9HW64Q8G6G</RegistryNumber><NameOfSubstance UI="D000068338">Everolimus</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.-</RegistryNumber><NameOfSubstance UI="C109790">STK11 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="C546842">MTOR protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber><NameOfSubstance UI="D058570">TOR Serine-Threonine Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.137</RegistryNumber><NameOfSubstance UI="D058534">Class I Phosphatidylinositol 3-Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.137</RegistryNumber><NameOfSubstance UI="C484760">PIK3CA protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.137</RegistryNumber><NameOfSubstance UI="D058539">Phosphatidylinositol 3-Kinase</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.10.1</RegistryNumber><NameOfSubstance UI="C496365">FGFR3 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.10.1</RegistryNumber><NameOfSubstance UI="C497970">FLT3 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.10.1</RegistryNumber><NameOfSubstance UI="D051498">Receptor, Fibroblast Growth Factor, Type 3</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.10.1</RegistryNumber><NameOfSubstance UI="D051941">fms-Like Tyrosine Kinase 3</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.10.2</RegistryNumber><NameOfSubstance UI="C507933">JAK3 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.10.2</RegistryNumber><NameOfSubstance UI="D053616">Janus Kinase 3</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="C494918">AKT1 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D017346">Protein-Serine-Threonine Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D051057">Proto-Oncogene Proteins c-akt</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.1.3.67</RegistryNumber><NameOfSubstance UI="D051059">PTEN Phosphohydrolase</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.1.3.67</RegistryNumber><NameOfSubstance UI="C494929">PTEN protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.6.5.1</RegistryNumber><NameOfSubstance UI="D043802">GTP-Binding Protein alpha Subunits, Gq-G11</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.6.5.2</RegistryNumber><NameOfSubstance UI="C501009">HRAS protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.6.5.2</RegistryNumber><NameOfSubstance UI="D016283">Proto-Oncogene Proteins p21(ras)</NameOfSubstance></Chemical><Chemical><RegistryNumber>W36ZG6FT64</RegistryNumber><NameOfSubstance UI="D020123">Sirolimus</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000328" MajorTopicYN="N">Adult</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000368" MajorTopicYN="N">Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000369" MajorTopicYN="N">Aged, 80 and over</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000903" MajorTopicYN="N">Antibiotics, Antineoplastic</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000970" MajorTopicYN="N">Antineoplastic Agents</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001549" MajorTopicYN="N">Benzamides</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002294" MajorTopicYN="N">Carcinoma, Squamous Cell</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002470" MajorTopicYN="N">Cell Survival</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058534" MajorTopicYN="N">Class I Phosphatidylinositol 3-Kinases</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D019941" MajorTopicYN="N">Cyclin-Dependent Kinase Inhibitor p16</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D050763" MajorTopicYN="N">Cyclin-Dependent Kinase Inhibitor p18</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004252" MajorTopicYN="N">DNA Mutational Analysis</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004273" MajorTopicYN="N">DNA, Neoplasm</DescriptorName><QualifierName UI="Q000032" MajorTopicYN="Y">analysis</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018572" MajorTopicYN="N">Disease-Free Survival</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000068338" MajorTopicYN="N">Everolimus</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000073979" MajorTopicYN="N">F-Box-WD Repeat-Containing Protein 7</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D043802" MajorTopicYN="N">GTP-Binding Protein alpha Subunits, Gq-G11</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D059014" MajorTopicYN="N">High-Throughput Nucleotide Sequencing</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D053616" MajorTopicYN="N">Janus Kinase 3</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008875" MajorTopicYN="N">Middle Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009025" MajorTopicYN="N">Morpholines</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D009154" MajorTopicYN="N">Mutation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051059" MajorTopicYN="N">PTEN Phosphohydrolase</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D027383" MajorTopicYN="N">Papillomaviridae</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D030361" MajorTopicYN="N">Papillomavirus Infections</DescriptorName><QualifierName UI="Q000150" MajorTopicYN="N">complications</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058539" MajorTopicYN="N">Phosphatidylinositol 3-Kinase</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D047428" MajorTopicYN="N">Protein Kinase Inhibitors</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017346" MajorTopicYN="N">Protein-Serine-Threonine Kinases</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051057" MajorTopicYN="N">Proto-Oncogene Proteins c-akt</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016283" MajorTopicYN="N">Proto-Oncogene Proteins p21(ras)</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011743" MajorTopicYN="N">Pyrimidines</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051498" MajorTopicYN="N">Receptor, Fibroblast Growth Factor, Type 3</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020123" MajorTopicYN="N">Sirolimus</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051901" MajorTopicYN="N">Smad4 Protein</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058570" MajorTopicYN="N">TOR Serine-Threonine Kinases</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016159" MajorTopicYN="N">Tumor Suppressor Protein p53</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014846" MajorTopicYN="N">Vulvar Neoplasms</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000821" MajorTopicYN="N">virology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051941" MajorTopicYN="N">fms-Like Tyrosine Kinase 3</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">CDKN2A</Keyword><Keyword MajorTopicYN="Y">HPV</Keyword><Keyword MajorTopicYN="Y">NGS</Keyword><Keyword MajorTopicYN="Y">TP53</Keyword><Keyword MajorTopicYN="Y">Vulvar cancer</Keyword><Keyword MajorTopicYN="Y">mTOR</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2018</Year><Month>02</Month><Day>20</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2018</Year><Month>05</Month><Day>30</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2018</Year><Month>06</Month><Day>23</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2018</Year><Month>7</Month><Day>8</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2018</Year><Month>10</Month><Day>27</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2018</Year><Month>7</Month><Day>8</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">29980281</ArticleId><ArticleId IdType="pii">S0090-8258(18)31008-4</ArticleId><ArticleId IdType="doi">10.1016/j.ygyno.2018.06.026</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Pologne</li></country></list><tree><country name="Pologne"><noRegion><name sortKey="Zi Ba, Sebastian" sort="Zi Ba, Sebastian" uniqKey="Zi Ba S" first="Sebastian" last="Zi Ba">Sebastian Zi Ba</name></noRegion><name sortKey="Bakula Zalewska, Elwira" sort="Bakula Zalewska, Elwira" uniqKey="Bakula Zalewska E" first="Elwira" last="Bakuła-Zalewska">Elwira Bakuła-Zalewska</name><name sortKey="Bidzi Ski, Mariusz" sort="Bidzi Ski, Mariusz" uniqKey="Bidzi Ski M" first="Mariusz" last="Bidzi Ski">Mariusz Bidzi Ski</name><name sortKey="G D, Stanislaw" sort="G D, Stanislaw" uniqKey="G D S" first="Stanisław" last="G D">Stanisław G D</name><name sortKey="Goryca, Krzysztof" sort="Goryca, Krzysztof" uniqKey="Goryca K" first="Krzysztof" last="Goryca">Krzysztof Goryca</name><name sortKey="Kopczy Ski, Janusz" sort="Kopczy Ski, Janusz" uniqKey="Kopczy Ski J" first="Janusz" last="Kopczy Ski">Janusz Kopczy Ski</name><name sortKey="Kowalewska, Magdalena" sort="Kowalewska, Magdalena" uniqKey="Kowalewska M" first="Magdalena" last="Kowalewska">Magdalena Kowalewska</name><name sortKey="Kowalik, Artur" sort="Kowalik, Artur" uniqKey="Kowalik A" first="Artur" last="Kowalik">Artur Kowalik</name><name sortKey="Kowalski, Kamil" sort="Kowalski, Kamil" uniqKey="Kowalski K" first="Kamil" last="Kowalski">Kamil Kowalski</name><name sortKey="Misiek, Marcin" sort="Misiek, Marcin" uniqKey="Misiek M" first="Marcin" last="Misiek">Marcin Misiek</name><name sortKey="Pia Cik, Agata" sort="Pia Cik, Agata" uniqKey="Pia Cik A" first="Agata" last="Pia Cik">Agata Pia Cik</name><name sortKey="Radziszewski, Jakub" sort="Radziszewski, Jakub" uniqKey="Radziszewski J" first="Jakub" last="Radziszewski">Jakub Radziszewski</name><name sortKey="Rusetska, Natalia" sort="Rusetska, Natalia" uniqKey="Rusetska N" first="Natalia" last="Rusetska">Natalia Rusetska</name><name sortKey="Zalewski, Kamil" sort="Zalewski, Kamil" uniqKey="Zalewski K" first="Kamil" last="Zalewski">Kamil Zalewski</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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