Suzy M Scholl1,2, Ivan Bièche3,4, Maud Kamal5,6, Sonia Lameiras7, Marc Deloger8, Adeline Morel3, Sophie Vacher3, Charlotte Lecerf1,2, Célia Dupain1,2, Emmanuelle Jeannot3,9, Elodie Girard8, Sylvain Baulande7, Coraline Dubot1,2, Gemma Kenter10, Ekaterina S Jordanova10,11, Els M J J Berns12, Guillaume Bataillon9, Marina Popovic13, Roman Rouzier14,15, Wulfran Cacheux16, Christophe Le Tourneau1,2,8,15, Alain Nicolas17, Nicolas Servant8. 1. Department of Drug Development and Innovation, Institut Curie, PSL Research University, 75005 Paris & 92210, Saint-Cloud, France. 2. Department of Drug Development and Innovation, Institut Curie, PSL Research University, 92210, Saint-Cloud, France. 3. Department of Genetics, Institut Curie, PSL Research University, 75005, Paris, France. 4. Faculty of Pharmaceutical and Biological Sciences, INSERM U1016, Paris Descartes University, 75005, Paris, France. 5. Department of Drug Development and Innovation, Institut Curie, PSL Research University, 75005 Paris & 92210, Saint-Cloud, France. maud.kamal@curie.fr. 6. Department of Drug Development and Innovation, Institut Curie, PSL Research University, 92210, Saint-Cloud, France. maud.kamal@curie.fr. 7. Institut Curie, Genomics of Excellence (ICGex) Platform, PSL Research University, 75005, Paris, France. 8. Bioinformatics and Computational Systems Biology of Cancer, PSL Research University, Mines Paris Tech, INSERM U900, 75005, Paris, France. 9. Department of Pathology, Institut Curie, PSL Research University, 75005, Paris, France. 10. Center for Gynaecologic Oncology Amsterdam, Amsterdam UMC and The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. 11. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. 12. Department of Medical Oncology, Erasmus MC, 3000 CA, Rotterdam, The Netherlands. 13. Oncology Institute of Vojvodina, Put doktora Goldmana, 421204, Sremska Kamenica, Serbia. 14. Department of Surgery, Institut Curie, PSL Research University, 92210, Saint-Cloud, France. 15. Paris-Saclay University, Paris, France. 16. Hopital Privé Pays de Savoie, Service d'oncologie médicale, 19 avenue Pierre Mendès France, 74100, Annemasse, France. 17. Institut Curie, PSL Research University, CNRS UMR3244, 75248, Paris, France.
Abstract
BACKGROUND: Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality with infection by human papilloma virus (HPV) being the most important risk factor. We analysed the association between different viral integration signatures, clinical parameters and outcome in pre-treated CCs. METHODS: Different integration signatures were identified using HPV double capture followed by next-generation sequencing (NGS) in 272 CC patients from the BioRAIDs study [NCT02428842]. Correlations between HPV integration signatures and clinical, biological and molecular features were assessed. RESULTS: Episomal HPV was much less frequent in CC as compared to anal carcinoma (p < 0.0001). We identified >300 different HPV-chromosomal junctions (inter- or intra-genic). The most frequent integration site in CC was in MACROD2 gene followed by MIPOL1/TTC6 and TP63. HPV integration signatures were not associated with histological subtype, FIGO staging, treatment or PFS. HPVs were more frequently episomal in PIK3CA mutated tumours (p = 0.023). Viral integration type was dependent on HPV genotype (p < 0.0001); HPV18 and HPV45 being always integrated. High HPV copy number was associated with longer PFS (p = 0.011). CONCLUSIONS: This is to our knowledge the first study assessing the prognostic value of HPV integration in a prospectively annotated CC cohort, which detects a hotspot of HPV integration at MACROD2; involved in impaired PARP1 activity and chromosome instability.
BACKGROUND: Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality with infection by human papilloma virus (HPV) being the most important risk factor. We analysed the association between different viral integration signatures, clinical parameters and outcome in pre-treated CCs. METHODS: Different integration signatures were identified using HPV double capture followed by next-generation sequencing (NGS) in 272 CC patients from the BioRAIDs study [NCT02428842]. Correlations between HPV integration signatures and clinical, biological and molecular features were assessed. RESULTS: Episomal HPV was much less frequent in CC as compared to anal carcinoma (p < 0.0001). We identified >300 different HPV-chromosomal junctions (inter- or intra-genic). The most frequent integration site in CC was in MACROD2 gene followed by MIPOL1/TTC6 and TP63. HPV integration signatures were not associated with histological subtype, FIGO staging, treatment or PFS. HPVs were more frequently episomal in PIK3CA mutated tumours (p = 0.023). Viral integration type was dependent on HPV genotype (p < 0.0001); HPV18 and HPV45 being always integrated. High HPV copy number was associated with longer PFS (p = 0.011). CONCLUSIONS: This is to our knowledge the first study assessing the prognostic value of HPV integration in a prospectively annotated CC cohort, which detects a hotspot of HPV integration at MACROD2; involved in impaired PARP1 activity and chromosome instability.
Authors: Alix Warburton; Tovah E Markowitz; Joshua P Katz; James M Pipas; Alison A McBride Journal: NPJ Genom Med Date: 2021-11-30 Impact factor: 8.617
Authors: Andris M Evans; Mikhail Salnikov; Steven F Gameiro; Saman Maleki Vareki; Joe S Mymryk Journal: J Clin Med Date: 2022-08-18 Impact factor: 4.964