Utilization of the human genome sequence localizes human papillomavirus type 16 DNA integrated into the TNFAIP2 gene in a fatal cervical cancer from a 39-year-old woman.
OBJECTIVE
The purpose of our study was to characterize a human papillomavirus (HPV) 16 DNA integration in the genome of a rapidly progressive, lethal cervical cancer in a 39-year-old woman.


METHODS
An HPV 16 integration site from cervical cancer tissue was cloned and analyzed using Southern blot hybridization, nucleotide sequencing, fluorescence in situ hybridization analysis for chromosomal localization and comparison with the draft human genome sequence.


RESULTS
HPV 16 DNA (3826 bp) was integrated into the genome of the tumor sample and contained an intact upstream regulatory region and E6 and E7 open reading frames. Both 5' and 3' viral-cell junction regions contained direct repeat and palindrome sequences. The chromosomal location of the viral integration and cellular deletion was mapped to chromosome 14q32.3 using both a somatic cell hybrid panel and fluorescence in situ hybridization. Search of the draft human genome sequence confirmed the chromosomal location and revealed a disruption of the TNFAIP2 cytokine/retinoic acid-inducible gene.


CONCLUSIONS
On the basis of the lack of sequence homology between the viral and cellular site of integration and the structure of the viral-cell junctions, it seems that HPV 16 DNA integrates into the host genome by a mechanism of nonhomologous recombination. We suggest that, taken together, maintenance of E6 and E7 expression, loss of the E2 gene and disruption of the TNFAIP2 gene through viral integration contributed to the rapid progression of cervical cancer in this patient. Availability of the human genome sequence will facilitate identification of cellular genes involved in cervical cancer by high-throughput analysis of viral integration sites.
Einstein
Mark H
MH
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine/Montefiore Medical Center, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Cruz
Yvette
Y
El-Awady
Mustafa K
MK
Popescu
Nicolas C
NC
DiPaolo
Joseph A
JA
van Ranst
Marc
M
Kadish
Anna S
AS
Romney
Seymour
S
Runowicz
Carolyn D
CD
Burk
Robert D
RD
D000328:Adult; D015139:Blotting, Southern; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000821:virology*; D002874:Chromosome Mapping; D004279:DNA, Viral; D005260:Female; D015894:Genome, Human; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008856:Microscopy, Fluorescence; D027383:Papillomaviridae / Q000235:genetics*; D011995:Recombination, Genetic; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000821:virology*
D004279:DNA, Viral