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

• Published in: British journal of cancer Vol. 124; no. 4; pp. 777 - 785
• Main Authors: Kamal, Maud, Lameiras, Sonia, Deloger, Marc, Morel, Adeline, Vacher, Sophie, Lecerf, Charlotte, Dupain, Célia, Jeannot, Emmanuelle, Girard, Elodie, Baulande, Sylvain, Dubot, Coraline, Kenter, Gemma, Jordanova, Ekaterina S., Berns, Els M. J. J., Bataillon, Guillaume, Popovic, Marina, Rouzier, Roman, Cacheux, Wulfran, Le Tourneau, Christophe, Nicolas, Alain, Servant, Nicolas, Scholl, Suzy M., Bièche, Ivan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-02-2021; Nature Publishing Group; Cancer Research UK
• Subjects: 631/337; 692/4017; 692/4028; 692/53; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - virology; Cervical cancer; Cervix; Class I Phosphatidylinositol 3-Kinases - genetics; Copy number; Disease hot spots; DNA Repair Enzymes - genetics; Drug Resistance; Epidemiology; Female; Genotypes; Human papillomavirus; Humans; Hydrolases - genetics; Integration; Kallikreins - genetics; Life Sciences; Middle Aged; Molecular Medicine; Next-generation sequencing; Oncology; Papillomaviridae - genetics; Papillomaviridae - physiology; Papillomavirus Infections - genetics; Papillomavirus Infections - virology; Poly(ADP-ribose) polymerase; Progression-Free Survival; Prostate-Specific Antigen - genetics; Risk factors; Tumors; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - virology; Virus Integration - genetics
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-01153-4

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.