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

Mark H. Einstein, Yvette Cruz, Mustafa K. El-Awady, Nicolas C. Popescu, Joseph A. DiPaolo, Marc Van Ranst, Anna S. Kadish, Seymour Romney, Carolyn D. Runowicz, Robert D. Burk

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Purpose: 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. Experimental Design: 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.

Original languageEnglish (US)
Pages (from-to)549-554
Number of pages6
JournalClinical Cancer Research
Volume8
Issue number2
StatePublished - 2002

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Virus Integration
Human papillomavirus 16
Human Genome
Uterine Cervical Neoplasms
Intercellular Junctions
DNA
Genome
Fluorescence In Situ Hybridization
Genes
Inverted Repeat Sequences
Viral Structures
Hybrid Cells
Nucleic Acid Repetitive Sequences
Nucleic Acid Regulatory Sequences
Sequence Homology
Southern Blotting
Tretinoin
Genetic Recombination
Open Reading Frames
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Einstein, Mark H.; Cruz, Yvette; El-Awady, Mustafa K.; Popescu, Nicolas C.; DiPaolo, Joseph A.; Van Ranst, Marc; Kadish, Anna S.; Romney, Seymour; Runowicz, Carolyn D.; Burk, Robert D.

In: Clinical Cancer Research, Vol. 8, No. 2, 2002, p. 549-554.

Research output: Contribution to journalArticle

Einstein, MH, Cruz, Y, El-Awady, MK, Popescu, NC, DiPaolo, JA, Van Ranst, M, Kadish, AS, Romney, S, Runowicz, CD & Burk, RD 2002, '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', Clinical Cancer Research, vol. 8, no. 2, pp. 549-554.
Einstein, Mark H. ; Cruz, Yvette ; El-Awady, Mustafa K. ; Popescu, Nicolas C. ; DiPaolo, Joseph A. ; Van Ranst, Marc ; Kadish, Anna S. ; Romney, Seymour ; Runowicz, Carolyn D. ; Burk, Robert D. / 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. In: Clinical Cancer Research. 2002 ; Vol. 8, No. 2. pp. 549-554.
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abstract = "Purpose: 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. Experimental Design: 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.",
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AU - Cruz, Yvette

AU - El-Awady, Mustafa K.

AU - Popescu, Nicolas C.

AU - DiPaolo, Joseph A.

AU - Van Ranst, Marc

AU - Kadish, Anna S.

AU - Romney, Seymour

AU - Runowicz, Carolyn D.

AU - Burk, Robert D.

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