Abstract 4330: HPV double capture NGS method in cervical cancer: Identification of MACROD2 gene as HPV hot spot integration site and viral load status as a prognostic factor
Authors: Kamal Maud , Lameiras Sonia , Morel Adeline , Lecerf Charlotte , Vacher Sophie , Dupain Celia , Jeannot Emmanuelle , Deloger Marc , Servant Nicolas , Girard Elodie , Baulande Sylvain , Kenter Gemma , Jordanova Ekaterina , Berns Els , Rouzier Roman , Cacheux Wulfran , Le Tourneau Christophe , Nicolas Alain , Scholl Suzy , Bieche Ivan 
Published: September 2020

Abstract
BACKGROUND: Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality worldwide and constitutes the second most common malignancy in women. CC exhibits differences in clinical behavior; infection by high-risk Human Papilloma Virus (HPV) remains an important initiating event in tumorigenesis and the most important risk factors for CC. As HPV integration types may be specific biomarkers for prediction of clinical outcomes, we analyzed the association between the different viral integration signatures and clinic-pathological parameters in CC patients.
EXPERIMENTAL DESIGN: Patients included in this study were enrolled in the EU-funded RAIDs Network (Rational Molecular Assessment and Innovative Drug Selection, www.raids-fp7.eu) prospective CC BioRAIDs study [NCT02428842]. HPV double capture method followed by NGS was used to define the different integration signatures. Correlations between HPV integration signatures and clinical, biological and molecular features were assessed in a large series of 272 CC BioRAIDs patients.
RESULTS: The distribution of HPV signatures differed from that previously described in HPV-positive anal squamous cell carcinoma (p&lt;0.001). We identified more than 250 HPV insertions sites (inter-genic or intra-genic) and reported MACROD2 gene as the most frequent integration site followed by the MIPOL1/TTC6, TP63, ERBB2, KLF12. The seven patients with HPV integration in the MACROD2 gene tend to have a worse progression free survival (PFS) compared to other patients. HPV integration signatures were not associated with treatment type, histological subtype or FIGO staging, but were associated with PIK3CA mutational status (p=0.023) and HPV genotype status (p&lt;0.0001). HPV45 and HPV18 genotypes were always integrated in our patients' population, as compared to other HPV genotypes. There was no significant association between the different HPV integration signatures and PFS. High viral load was associated with longer PFS (p=0.011).
CONCLUSION: This is the first study assessing the prognostic value of HPV integration in a prospectively annotated CC patient cohort, which reports a hot-spot of HPV integrations at the MACROD2 gene, known to be implicated in impaired PARP1 activity and chromosome instability.
Citation Format: Maud Kamal, Sonia Lameiras, Adeline Morel, Charlotte Lecerf, Sophie Vacher, Celia Dupain, Emmanuelle Jeannot, Marc Deloger, Nicolas Servant, Elodie Girard, Sylvain Baulande, Gemma Kenter, Ekaterina Jordanova, Els Berns, Roman Rouzier, Wulfran Cacheux, Christophe Le Tourneau, Alain Nicolas, Suzy Scholl, Ivan Bieche. HPV double capture NGS method in cervical cancer: Identification of MACROD2 gene as HPV hot spot integration site and viral load status as a prognostic factor [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4330.