Human papilloma virus (HPV) integration signature in Cervical Cancer: identification of MACROD2 gene as HPV hot spot integration site

16 fév, 2021

British Journal of Cancer

Maud Kamal, , Sonia Lameiras, Marc Deloger, Adeline Morel, Sophie Vacher, Charlotte Lecerf, Célia Dupain, Emmanuelle Jeannot, Elodie Girard, Sylvain Baulande, Coraline Dubot, Gemma Kenter, Ekaterina S. Jordanova, Els M. J. J. Berns, Guillaume Bataillon, Marina Popovic, Roman Rouzier, Wulfran Cacheux, Christophe Le Tourneau, Alain Nicolas, Nicolas Servant, Suzy M. Scholl, Ivan Bièche

DOI

10.1038/s41416-020-01153-4

Abstract

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.