. 2021 Feb;124(4):777-785.

doi: 10.1038/s41416-020-01153-4. Epub 2020 Nov 16.

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

Maud Kamal^{1

2}, Sonia Lameiras³, Marc Deloger⁴, Adeline Morel⁵, Sophie Vacher⁵, Charlotte Lecerf^{6

7}, Célia Dupain^{6

7}, Emmanuelle Jeannot^{5

8}, Elodie Girard⁴, Sylvain Baulande³, Coraline Dubot^{6

7}, Gemma Kenter⁹, Ekaterina S Jordanova^{9

10}, Els M J J Berns¹¹, Guillaume Bataillon⁸, Marina Popovic¹², Roman Rouzier^{13

14}, Wulfran Cacheux¹⁵, Christophe Le Tourneau^{6

7

4

14}, Alain Nicolas¹⁶, Nicolas Servant⁴, Suzy M Scholl^#^{6

7}, Ivan Bièche^#^{5

17}; RAIDs Consortium

Collaborators, Affiliations

Collaborators

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

Affiliations

¹ Department of Drug Development and Innovation, Institut Curie, PSL Research University, 75005 Paris & 92210, Saint-Cloud, France. maud.kamal@curie.fr.
² Department of Drug Development and Innovation, Institut Curie, PSL Research University, 92210, Saint-Cloud, France. maud.kamal@curie.fr.
³ Institut Curie, Genomics of Excellence (ICGex) Platform, PSL Research University, 75005, Paris, France.
⁴ Bioinformatics and Computational Systems Biology of Cancer, PSL Research University, Mines Paris Tech, INSERM U900, 75005, Paris, France.
⁵ Department of Genetics, Institut Curie, PSL Research University, 75005, Paris, France.
⁶ Department of Drug Development and Innovation, Institut Curie, PSL Research University, 75005 Paris & 92210, Saint-Cloud, France.
⁷ Department of Drug Development and Innovation, Institut Curie, PSL Research University, 92210, Saint-Cloud, France.
⁸ Department of Pathology, Institut Curie, PSL Research University, 75005, Paris, France.
⁹ Center for Gynaecologic Oncology Amsterdam, Amsterdam UMC and The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
¹⁰ Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
¹¹ Department of Medical Oncology, Erasmus MC, 3000 CA, Rotterdam, The Netherlands.
¹² Oncology Institute of Vojvodina, Put doktora Goldmana, 421204, Sremska Kamenica, Serbia.
¹³ Department of Surgery, Institut Curie, PSL Research University, 92210, Saint-Cloud, France.
¹⁴ Paris-Saclay University, Paris, France.
¹⁵ Hopital Privé Pays de Savoie, Service d'oncologie médicale, 19 avenue Pierre Mendès France, 74100, Annemasse, France.
¹⁶ Institut Curie, PSL Research University, CNRS UMR3244, 75248, Paris, France.
¹⁷ Faculty of Pharmaceutical and Biological Sciences, INSERM U1016, Paris Descartes University, 75005, Paris, France.

^# Contributed equally.

PMID: 33191407
PMCID: PMC7884736
DOI: 10.1038/s41416-020-01153-4

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

Maud Kamal et al. Br J Cancer. 2021 Feb.

. 2021 Feb;124(4):777-785.

doi: 10.1038/s41416-020-01153-4. Epub 2020 Nov 16.

Authors

Collaborators

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

Affiliations

¹ Department of Drug Development and Innovation, Institut Curie, PSL Research University, 75005 Paris & 92210, Saint-Cloud, France. maud.kamal@curie.fr.
² Department of Drug Development and Innovation, Institut Curie, PSL Research University, 92210, Saint-Cloud, France. maud.kamal@curie.fr.
³ Institut Curie, Genomics of Excellence (ICGex) Platform, PSL Research University, 75005, Paris, France.
⁴ Bioinformatics and Computational Systems Biology of Cancer, PSL Research University, Mines Paris Tech, INSERM U900, 75005, Paris, France.
⁵ Department of Genetics, Institut Curie, PSL Research University, 75005, Paris, France.
⁶ Department of Drug Development and Innovation, Institut Curie, PSL Research University, 75005 Paris & 92210, Saint-Cloud, France.
⁷ Department of Drug Development and Innovation, Institut Curie, PSL Research University, 92210, Saint-Cloud, France.
⁸ Department of Pathology, Institut Curie, PSL Research University, 75005, Paris, France.
⁹ Center for Gynaecologic Oncology Amsterdam, Amsterdam UMC and The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
¹⁰ Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
¹¹ Department of Medical Oncology, Erasmus MC, 3000 CA, Rotterdam, The Netherlands.
¹² Oncology Institute of Vojvodina, Put doktora Goldmana, 421204, Sremska Kamenica, Serbia.
¹³ Department of Surgery, Institut Curie, PSL Research University, 92210, Saint-Cloud, France.
¹⁴ Paris-Saclay University, Paris, France.
¹⁵ Hopital Privé Pays de Savoie, Service d'oncologie médicale, 19 avenue Pierre Mendès France, 74100, Annemasse, France.
¹⁶ Institut Curie, PSL Research University, CNRS UMR3244, 75248, Paris, France.
¹⁷ Faculty of Pharmaceutical and Biological Sciences, INSERM U1016, Paris Descartes University, 75005, Paris, France.

^# Contributed equally.

PMID: 33191407
PMCID: PMC7884736
DOI: 10.1038/s41416-020-01153-4

Erratum in

Correction to: Human papilloma virus (HPV) integration signature in Cervical Cancer: identification of MACROD2 gene as HPV hot spot integration site.
Kamal M, Lameiras S, Deloger M, Morel A, Vacher S, Lecerf C, Dupain C, Jeannot E, Girard E, Baulande S, Dubot C, Kenter G, Jordanova ES, Berns EMJJ, Bataillon G, Popovic M, Rouzier R, Cacheux W, Le Tourneau C, Nicolas A, Servant N, Scholl SM, Bièche I; RAIDs Consortium. Kamal M, et al. Br J Cancer. 2023 May;128(9):1790. doi: 10.1038/s41416-023-02261-7. Br J Cancer. 2023. PMID: 37055522 Free PMC article. No abstract available.

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.

PubMed Disclaimer

Conflict of interest statement

C.L.T. has participated in advisory boards of MSD, BMS, Merck Serono, Astra Zeneca, Roche and Nanobiotix, GSK, Celgene, Rakuten. All other authors report no conflict of interest.

Figures

**Fig. 1. Distribution of the HPV integration signatures according to the location of HPV-positive squamous cell carcinomas.**
a Cervical cancer; b anal cancer; p < 0.0001. 2J-COL 2 Junctions Colinear, 2J-NL 2 Junctions Non-Linear, MJ-CL Multiple Junctions Clustered, MJ-SC Multiple Junctions Scattered, EPI episomal and 2J 2 Junctions.

**Fig. 2**
Distribution of HPV insertion sites in the genome of patients with HPV-positive CC. Each dot represents an HPV integration site.

**Fig. 3**
Progression-free survival of the 272 HPV-positive cervical cancer patients according to HPV copy number.

See this image and copyright information in PMC

References

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

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Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

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