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

RAIDs Consortium

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: identification of MACROD2 gene as HPV hot spot integration site

RAIDs Consortium

Université PSL
Antoni van Leeuwenhoek Hospital
Leiden University Medical Center
Erasmus MC
Oncology Institute of Vojvodina, Put doktora Goldmana, 421204, Sremska Kamenica, Serbia
Université Paris-Saclay
Hopital Privé Pays de Savoie, Service d’oncologie médicale, 19 avenue Pierre Mendès France, 74100, Annemasse, France
Institut national de la santé et de la recherche médicale
Gynecologic Oncology Department Clinic for Operative Oncology, Institute of Oncology of Vojvodina, Sremska, Serbia
Publica Institutul Oncologic, Chișinău, Republic of Moldova
Gustave Roussy, Paris, France
Arcagy-Gineco, Paris, France
Institut Pasteur Paris
Quanticsoft, Paris, France
Victor Babes University of Medicine and Pharmacy
Hannover Medical School
Centre Georges-François Leclerc
Centre Val d’Aurelle, Paris, France
Institut Curie
Erasmus University Rotterdam
Oncology Institute of Vojvodina
Service d’oncologie médicale
Institute of Oncology of Vojvodina
Publica Institutul Oncologic
Gustave Roussy
ARCAGY-GINECO
Quanticsoft
Centre Val d’Aurelle
Hôpital européen Georges Pompidou
Hôpital Tenon
Université de Lorraine
Institut de cancérologie de l’Ouest - site Paul Papin (ICO)
Technische Universität Dresden
René Gauducheau
Hannover Clinical Trial Center GmbH
SeqOmics Biotechnology Ltd.
Insitut Curie
Trinity College Dublin
Netherlands Cancer Institute
Sorbonne Université
Université Grenoble Alpes
University of Duisburg-Essen
University of Basel
University of Bonn
Spitalul Sfantul Constantin Brasov
University of Greifswald
AYMING
European Clinical Research Infrastructure Network
University of Novi Sad

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	777-785
Number of pages	9
Journal	British journal of cancer
Volume	124
Issue number	4
Early online date	2020
DOIs	https://doi.org/10.1038/s41416-020-01153-4
Publication status	Published - 16 Feb 2021

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1038/s41416-020-01153-4

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Cite this

@article{00d838064e6e44bc8f581fbb362110cb,

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

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.",

author = "\{RAIDs Consortium\} and Maud Kamal and Sonia Lameiras and Marc Deloger and Adeline Morel and Sophie Vacher and Charlotte Lecerf and Dupain, \{C. lia\} and Emmanuelle Jeannot and Elodie Girard and Sylvain Baulande and Coraline Dubot and Gemma Kenter and Jordanova, \{Ekaterina S.\} and Berns, \{Els M. J. J.\} and Guillaume Bataillon and Marina Popovic and Roman Rouzier and Wulfran Cacheux and \{le Tourneau\}, Christophe and Alain Nicolas and Nicolas Servant and Scholl, \{Suzy M.\} and Ivan Bi{\`e}che and \{de la Rochefordiere\}, Anne and Pierre Fumoleau and Aljosa Mandic and Nina Samet and Choumouss Kamoun and Windy Rondoff and Sebastien Armanet and Alexandra Rohel and Souhir Neffati and Marie-Emmanuelle Legrier and Mabiala, \{Sinette Ngoumou\} and Sylvain Dureau and Coralie Errera and Marius Craina and Madalin Margan and Sanne Samuels and Henry Zijlmans and Peter Hillemanns and Sorin Dema and Alis Dema and Goran Malenkovic and Branislav Djuran and Anne Floquet and Fr{\'e}d{\'e}ric Guyon and Colombo, \{Pierre Emmanuel\} and Michel Fabbro and Christine Kerr and Charlotte Ngo and Fabrice Lecuru and \{del Campo\}, \{Eleonor Rivin\} and Charles Coutant and Fr{\'e}d{\'e}ric Marchal and Nathalie Mesgouez-Nebout and Virginie Fourchotte and Feron, \{Jean Guillaume\} and Philippe Morice and Eric Deutsch and Pauline Wimberger and Classe, \{Jean Marc\} and \{von der Leyen\}, Heiko and Mathieu Minsat and Istvan Nagy and Balazs Balint and \{de Saint-Jorre\}, Nicolas and Alexia Savignoni and Franck Perez and Patricia Tresca and Noreen Gleeson and Philippe Hupe and Roman, \{Sergio Roman\} and Emmanuel Barillot and Fanny Coffin and Bastiaan Nuijen and Alexandre Boissonnas and Marc Billaud and Laurence Lafanechere and Jaap Verweij and Arjan Bandel and Jozien Hellemann and Kirsten Ruigrok-Ritstier and Philipp Harter and Christian Kurzeder and Alexander Mustea and Eugeniu Banu and Elisabeta Patcas and Victor Cernat and Andrea Slocker and Michele Mondini and Maud Bossard and Julie Chupin and Sjoerd Rodenhuis and Rene Medema and Anika Havemeier and Thomas Fink and Amelie Michon and Christine Kubiak and Corine Beaufort and Judit Cseklye and Dora Latinovics and Peter Bihari and Isabel Brito and B{\'e}reng{\`e}re Ouine and \{De Koning\}, Leanne and Vincent Puard and \{Del Nery\}, Elaine and Jos Beijnen and Dominique Koensgen and Daniela Bruennert and Milos Lucic and \{ter Haar\}, Natalja",

year = "2021",

month = feb,

day = "16",

doi = "10.1038/s41416-020-01153-4",

language = "English",

volume = "124",

pages = "777--785",

journal = "British journal of cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

number = "4",

}

Human papilloma virus (HPV) integration signature in Cervical Cancer: identification of MACROD2 gene as HPV hot spot integration site: identification of MACROD2 gene as HPV hot spot integration site. / RAIDs Consortium.
In: British journal of cancer, Vol. 124, No. 4, 16.02.2021, p. 777-785.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Human papilloma virus (HPV) integration signature in Cervical Cancer: identification of MACROD2 gene as HPV hot spot integration site

T2 - identification of MACROD2 gene as HPV hot spot integration site

AU - RAIDs Consortium

AU - Kamal, Maud

AU - Lameiras, Sonia

AU - Deloger, Marc

AU - Morel, Adeline

AU - Vacher, Sophie

AU - Lecerf, Charlotte

AU - Dupain, C. lia

AU - Jeannot, Emmanuelle

AU - Girard, Elodie

AU - Baulande, Sylvain

AU - Dubot, Coraline

AU - Kenter, Gemma

AU - Jordanova, Ekaterina S.

AU - Berns, Els M. J. J.

AU - Bataillon, Guillaume

AU - Popovic, Marina

AU - Rouzier, Roman

AU - Cacheux, Wulfran

AU - le Tourneau, Christophe

AU - Nicolas, Alain

AU - Servant, Nicolas

AU - Scholl, Suzy M.

AU - Bièche, Ivan

AU - de la Rochefordiere, Anne

AU - Fumoleau, Pierre

AU - Mandic, Aljosa

AU - Samet, Nina

AU - Kamoun, Choumouss

AU - Rondoff, Windy

AU - Armanet, Sebastien

AU - Rohel, Alexandra

AU - Neffati, Souhir

AU - Legrier, Marie-Emmanuelle

AU - Mabiala, Sinette Ngoumou

AU - Dureau, Sylvain

AU - Errera, Coralie

AU - Craina, Marius

AU - Margan, Madalin

AU - Samuels, Sanne

AU - Zijlmans, Henry

AU - Hillemanns, Peter

AU - Dema, Sorin

AU - Dema, Alis

AU - Malenkovic, Goran

AU - Djuran, Branislav

AU - Floquet, Anne

AU - Guyon, Frédéric

AU - Colombo, Pierre Emmanuel

AU - Fabbro, Michel

AU - Kerr, Christine

AU - Ngo, Charlotte

AU - Lecuru, Fabrice

AU - del Campo, Eleonor Rivin

AU - Coutant, Charles

AU - Marchal, Frédéric

AU - Mesgouez-Nebout, Nathalie

AU - Fourchotte, Virginie

AU - Feron, Jean Guillaume

AU - Morice, Philippe

AU - Deutsch, Eric

AU - Wimberger, Pauline

AU - Classe, Jean Marc

AU - von der Leyen, Heiko

AU - Minsat, Mathieu

AU - Nagy, Istvan

AU - Balint, Balazs

AU - de Saint-Jorre, Nicolas

AU - Savignoni, Alexia

AU - Perez, Franck

AU - Tresca, Patricia

AU - Gleeson, Noreen

AU - Hupe, Philippe

AU - Roman, Sergio Roman

AU - Barillot, Emmanuel

AU - Coffin, Fanny

AU - Nuijen, Bastiaan

AU - Boissonnas, Alexandre

AU - Billaud, Marc

AU - Lafanechere, Laurence

AU - Verweij, Jaap

AU - Bandel, Arjan

AU - Hellemann, Jozien

AU - Ruigrok-Ritstier, Kirsten

AU - Harter, Philipp

AU - Kurzeder, Christian

AU - Mustea, Alexander

AU - Banu, Eugeniu

AU - Patcas, Elisabeta

AU - Cernat, Victor

AU - Slocker, Andrea

AU - Mondini, Michele

AU - Bossard, Maud

AU - Chupin, Julie

AU - Rodenhuis, Sjoerd

AU - Medema, Rene

AU - Havemeier, Anika

AU - Fink, Thomas

AU - Michon, Amelie

AU - Kubiak, Christine

AU - Beaufort, Corine

AU - Cseklye, Judit

AU - Latinovics, Dora

AU - Bihari, Peter

AU - Brito, Isabel

AU - Ouine, Bérengère

AU - De Koning, Leanne

AU - Puard, Vincent

AU - Del Nery, Elaine

AU - Beijnen, Jos

AU - Koensgen, Dominique

AU - Bruennert, Daniela

AU - Lucic, Milos

AU - ter Haar, Natalja

PY - 2021/2/16

Y1 - 2021/2/16

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85096001348

UR - https://www.ncbi.nlm.nih.gov/pubmed/33191407

UR - https://www.scopus.com/pages/publications/85096001348

U2 - 10.1038/s41416-020-01153-4

DO - 10.1038/s41416-020-01153-4

M3 - Article

C2 - 33191407

SN - 0007-0920

VL - 124

SP - 777

EP - 785

JO - British journal of cancer

JF - British journal of cancer

IS - 4

ER -

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

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