Human papilloma virus (HPV) integration signature in Cervical Cancer: identification of MACROD2 gene as HPV hot spot integration site
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 ,   RAIDs Consortium, de la Rochefordiere Anne , Fumoleau Pierre , Mandic Aljosa , Samet Nina , Kamoun Choumouss , Rondoff Windy , Armanet Sebastien , Rohel Alexandra , Neffati Souhir , Legrier Marie-Emmanuelle , Mabiala Sinette Ngoumou , Dureau Sylvain , Errera Coralie , Craina Marius , Margan Madalin , Samuels Sanne , Zijlmans Henry , Hillemanns Peter , Dema Sorin , Dema Alis , Malenkovic Goran , Djuran Branislav , Floquet Anne , Guyon Frédéric , Colombo Pierre Emmanuel , Fabbro Michel , Kerr Christine , Ngo Charlotte , Lecuru Fabrice , del Campo Eleonor Rivin , Coutant Charles , Marchal Frédéric , Mesgouez-Nebout Nathalie , Fourchotte Virginie , Feron Jean Guillaume , Morice Philippe , Deutsch Eric , Wimberger Pauline , Classe Jean-Marc , von der Leyen Heiko , Minsat Mathieu , Nagy Istvan , Balint Balazs , de Saint-Jorre Nicolas , Savignoni Alexia , Perez Franck , Tresca Patricia , Gleeson Noreen , Hupe Philippe , Roman Sergio Roman , Barillot Emmanuel , Coffin Fanny , Nuijen Bastiaan , Boissonnas Alexandre , Billaud Marc , Lafanechere Laurence , Verweij Jaap , Bandel Arjan , Hellemann Jozien , Ruigrok-Ritstier Kirsten , Harter Philipp , Kurzeder Christian , Mustea Alexander , Banu Eugeniu , Patcas Elisabeta , Cernat Victor , Slocker Andrea , Mondini Michele , Bossard Maud , Chupin Julie , Rodenhuis Sjoerd , Medema Rene , Havemeier Anika , Fink Thomas , Michon Amelie , Kubiak Christine , Beaufort Corine , Cseklye Judit , Latinovics Dora , Bihari Peter , Brito Isabel , Ouine Bérengère , De Koning Leanne , Puard Vincent , Del Nery Elaine , Beijnen Jos , Koensgen Dominique , Bruennert Daniela , Lucic Milos , ter Haar Natalja 
Published: November 2020

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.