Human papilloma virus (HPV) integration signature in Cervical Cancer: identification of MACROD2 gene as HPV hot spot integration site.
Carcinoma, Squamous Cell
/ genetics
Class I Phosphatidylinositol 3-Kinases
/ genetics
DNA Repair Enzymes
/ genetics
Female
Humans
Hydrolases
/ genetics
Kallikreins
/ genetics
Middle Aged
Papillomaviridae
/ genetics
Papillomavirus Infections
/ genetics
Progression-Free Survival
Prostate-Specific Antigen
/ genetics
Uterine Cervical Neoplasms
/ genetics
Virus Integration
/ genetics
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
18
03
2020
accepted:
15
10
2020
revised:
02
10
2020
pubmed:
17
11
2020
medline:
15
7
2021
entrez:
16
11
2020
Statut:
ppublish
Résumé
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. 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. 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). 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.
Sections du résumé
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.
Identifiants
pubmed: 33191407
doi: 10.1038/s41416-020-01153-4
pii: 10.1038/s41416-020-01153-4
pmc: PMC7884736
doi:
Substances chimiques
MACROD2 protein, human
0
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
PIK3CA protein, human
EC 2.7.1.137
Hydrolases
EC 3.-
KLK3 protein, human
EC 3.4.21.-
Kallikreins
EC 3.4.21.-
Prostate-Specific Antigen
EC 3.4.21.77
DNA Repair Enzymes
EC 6.5.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
777-785Subventions
Organisme : EC | EC Seventh Framework Programm | FP7 People: Marie-Curie Actions (FP7-PEOPLE - Specific Programme "People" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013))
ID : No 304810
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : France Génomique ANR-10-INBS-09-08
Organisme : Agence Nationale de la Recherche (French National Research Agency)
ID : ICGEx ANR-10-EQPX-03
Investigateurs
Anne de la Rochefordiere
(A)
Pierre Fumoleau
(P)
Aljosa Mandic
(A)
Nina Samet
(N)
Choumouss Kamoun
(C)
Windy Rondoff
(W)
Sebastien Armanet
(S)
Alexandra Rohel
(A)
Souhir Neffati
(S)
Marie-Emmanuelle Legrier
(ME)
Sinette Ngoumou Mabiala
(SN)
Sylvain Dureau
(S)
Coralie Errera
(C)
Marius Craina
(M)
Madalin Margan
(M)
Sanne Samuels
(S)
Henry Zijlmans
(H)
Peter Hillemanns
(P)
Sorin Dema
(S)
Alis Dema
(A)
Goran Malenkovic
(G)
Branislav Djuran
(B)
Anne Floquet
(A)
Frédéric Guyon
(F)
Pierre Emmanuel Colombo
(PE)
Michel Fabbro
(M)
Christine Kerr
(C)
Charlotte Ngo
(C)
Fabrice Lecuru
(F)
Eleonor Rivin Del Campo
(ER)
Charles Coutant
(C)
Frédéric Marchal
(F)
Nathalie Mesgouez-Nebout
(N)
Virginie Fourchotte
(V)
Jean Guillaume Feron
(JG)
Philippe Morice
(P)
Eric Deutsch
(E)
Pauline Wimberger
(P)
Jean-Marc Classe
(JM)
Heiko von der Leyen
(H)
Mathieu Minsat
(M)
Istvan Nagy
(I)
Balazs Balint
(B)
Nicolas de Saint-Jorre
(N)
Alexia Savignoni
(A)
Franck Perez
(F)
Patricia Tresca
(P)
Noreen Gleeson
(N)
Philippe Hupe
(P)
Sergio Roman Roman
(SR)
Emmanuel Barillot
(E)
Fanny Coffin
(F)
Bastiaan Nuijen
(B)
Alexandre Boissonnas
(A)
Marc Billaud
(M)
Laurence Lafanechere
(L)
Jaap Verweij
(J)
Arjan Bandel
(A)
Jozien Hellemann
(J)
Kirsten Ruigrok-Ritstier
(K)
Philipp Harter
(P)
Christian Kurzeder
(C)
Alexander Mustea
(A)
Eugeniu Banu
(E)
Elisabeta Patcas
(E)
Victor Cernat
(V)
Andrea Slocker
(A)
Michele Mondini
(M)
Maud Bossard
(M)
Julie Chupin
(J)
Sjoerd Rodenhuis
(S)
Rene Medema
(R)
Anika Havemeier
(A)
Thomas Fink
(T)
Amelie Michon
(A)
Christine Kubiak
(C)
Corine Beaufort
(C)
Judit Cseklye
(J)
Dora Latinovics
(D)
Peter Bihari
(P)
Isabel Brito
(I)
Bérengère Ouine
(B)
Leanne De Koning
(L)
Vincent Puard
(V)
Elaine Del Nery
(E)
Jos Beijnen
(J)
Dominique Koensgen
(D)
Daniela Bruennert
(D)
Milos Lucic
(M)
Natalja Ter Haar
(N)
Commentaires et corrections
Type : ErratumIn
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