Frequent genomic structural alterations at HPV insertion sites in cervical carcinoma.
To investigate whether integration of HPV DNA in cervical carcinoma is responsible for structural alterations of the host genome at the insertion site, a series of 34 primary cervical carcinomas and eight cervical cancer-derived cell lines were analysed. DNA copy number profiles were assessed using the Affymetrix GeneChip Human Mapping 250K Sty array. HPV 16, 18 or 45 integration sites were determined using the DIPS-PCR technique. The genome status at integration sites was classified as follows: no change, amplification, transition normal/gain, normal/loss or gain/LOH. A single HPV integration site was found in 34 cases; two sites were found in seven cases; and three sites in one case (51 sites). Comparison between integration sites and DNA copy number profiles showed that the genome status was altered at 17/51 (33%) integration sites, corresponding to 16/42 cases (38%). Alterations detected were amplification in nine cases, transition normal/loss in four cases, normal/gain in three cases, and gain/LOH in one case. A highly significant association was found between genomic rearrangement and integration of HPV DNA (p < 10(-10)). Activation of the replication origin located in viral integrated sequences in a cell line derived from one of the primary cervical carcinomas induced an increase of the amplification level of both viral and cellular DNA sequences flanking the integration locus. This mechanism may be implicated in the triggering of genome amplification at the HPV integration site in cervical carcinoma. Structural alterations of the host genome are frequently observed at the integration site of HPV DNA in cervical cancer and may act in oncogenesis.
Department of Tumour Biology, Institut Curie, F-75248 Paris, France.
Martine
M
Peter
Nicolas
N
Stransky
Jérôme
J
Couturier
Philippe
P
Hupé
Emmanuel
E
Barillot
Patricia
P
de Cremoux
Paul
P
Cottu
Francois
F
Radvanyi
Xavier
X
Sastre-Garau
D000230:Adenocarcinoma / Q000235:genetics / Q000821:virology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000821:virology; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods; D005814:Genes, Viral; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D027383:Papillomaviridae / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D030361:Papillomavirus Infections / Q000150:complications / Q000235:genetics* / Q000821:virology; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000821:virology; D016662:Virus Integration / Q000235:genetics*
D004279:DNA, Viral; D009856:Oncogene Proteins, Viral; C084762:oncogene protein E1, Human papillomavirus type 18; C069102:oncogene protein E2, Human papillomavirus type 18