Insertional oncogenesis by HPV70 revealed by multiple genomic analyses in a clinically HPV-negative cervical cancer

Anne Van Arsdale, Nicole E. Patterson, Elaine C. Maggi, Lorenzo Agoni, Koenraad Van Doorslaer, Bryan Harmon, Nicole Nevadunsky, Dennis Y.S. Kuo, Mark H. Einstein, Jack Lenz, Cristina Montagna

Research output: Contribution to journalArticle

Abstract

Cervical carcinogenesis, the second leading cause of cancer death in women worldwide, is caused by multiple types of human papillomaviruses (HPVs). To investigate a possible role for HPV in a cervical carcinoma that was HPV-negative by PCR testing, we performed HPV DNA hybridization capture plus massively parallel sequencing. This detected a subgenomic, URR-E6-E7-E1 segment of HPV70 DNA, a type not generally associated with cervical cancer, inserted in an intron of the B-cell lymphoma/leukemia 11B (BCL11B) gene in the human genome. Long range DNA sequencing confirmed the virus and flanking BCL11B DNA structures including both insertion junctions. Global transcriptomic analysis detected multiple, alternatively spliced, HPV70-BCL11B, fusion transcripts with fused open reading frames. The insertion and fusion transcripts were present in an intraepithelial precursor phase of tumorigenesis. These results suggest oncogenicity of HPV70, identify novel BCL11B variants with potential oncogenic implications, and underscore the advantages of thorough genomic analyses to elucidate insights into HPV-associated tumorigenesis.

Original languageEnglish (US)
Pages (from-to)84-95
Number of pages12
JournalGenes Chromosomes and Cancer
Volume59
Issue number2
DOIs
StatePublished - Feb 1 2020

Fingerprint

B-Cell Leukemia
Uterine Cervical Neoplasms
B-Cell Lymphoma
Carcinogenesis
DNA
High-Throughput Nucleotide Sequencing
Human Genome
DNA Sequence Analysis
Introns
Open Reading Frames
Cause of Death
Viruses
Carcinoma
Polymerase Chain Reaction
Genes
Neoplasms

All Science Journal Classification (ASJC) codes

  • Genetics
  • Cancer Research

Keywords

  • BCL11B
  • HPV DNA
  • HPV70
  • cancer
  • cervical carcinoma
  • fluorescent in situ hybridization
  • hybridization capture
  • insertional oncogenesis
  • long range sequencing
  • oncogene

Cite this

Van Arsdale, A., Patterson, N. E., Maggi, E. C., Agoni, L., Van Doorslaer, K., Harmon, B., ... Montagna, C. (2020). Insertional oncogenesis by HPV70 revealed by multiple genomic analyses in a clinically HPV-negative cervical cancer. Genes Chromosomes and Cancer, 59(2), 84-95. https://doi.org/10.1002/gcc.22799
Van Arsdale, Anne ; Patterson, Nicole E. ; Maggi, Elaine C. ; Agoni, Lorenzo ; Van Doorslaer, Koenraad ; Harmon, Bryan ; Nevadunsky, Nicole ; Kuo, Dennis Y.S. ; Einstein, Mark H. ; Lenz, Jack ; Montagna, Cristina. / Insertional oncogenesis by HPV70 revealed by multiple genomic analyses in a clinically HPV-negative cervical cancer. In: Genes Chromosomes and Cancer. 2020 ; Vol. 59, No. 2. pp. 84-95.
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abstract = "Cervical carcinogenesis, the second leading cause of cancer death in women worldwide, is caused by multiple types of human papillomaviruses (HPVs). To investigate a possible role for HPV in a cervical carcinoma that was HPV-negative by PCR testing, we performed HPV DNA hybridization capture plus massively parallel sequencing. This detected a subgenomic, URR-E6-E7-E1 segment of HPV70 DNA, a type not generally associated with cervical cancer, inserted in an intron of the B-cell lymphoma/leukemia 11B (BCL11B) gene in the human genome. Long range DNA sequencing confirmed the virus and flanking BCL11B DNA structures including both insertion junctions. Global transcriptomic analysis detected multiple, alternatively spliced, HPV70-BCL11B, fusion transcripts with fused open reading frames. The insertion and fusion transcripts were present in an intraepithelial precursor phase of tumorigenesis. These results suggest oncogenicity of HPV70, identify novel BCL11B variants with potential oncogenic implications, and underscore the advantages of thorough genomic analyses to elucidate insights into HPV-associated tumorigenesis.",
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Van Arsdale, A, Patterson, NE, Maggi, EC, Agoni, L, Van Doorslaer, K, Harmon, B, Nevadunsky, N, Kuo, DYS, Einstein, MH, Lenz, J & Montagna, C 2020, 'Insertional oncogenesis by HPV70 revealed by multiple genomic analyses in a clinically HPV-negative cervical cancer', Genes Chromosomes and Cancer, vol. 59, no. 2, pp. 84-95. https://doi.org/10.1002/gcc.22799

Insertional oncogenesis by HPV70 revealed by multiple genomic analyses in a clinically HPV-negative cervical cancer. / Van Arsdale, Anne; Patterson, Nicole E.; Maggi, Elaine C.; Agoni, Lorenzo; Van Doorslaer, Koenraad; Harmon, Bryan; Nevadunsky, Nicole; Kuo, Dennis Y.S.; Einstein, Mark H.; Lenz, Jack; Montagna, Cristina.

In: Genes Chromosomes and Cancer, Vol. 59, No. 2, 01.02.2020, p. 84-95.

Research output: Contribution to journalArticle

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AU - Van Arsdale, Anne

AU - Patterson, Nicole E.

AU - Maggi, Elaine C.

AU - Agoni, Lorenzo

AU - Van Doorslaer, Koenraad

AU - Harmon, Bryan

AU - Nevadunsky, Nicole

AU - Kuo, Dennis Y.S.

AU - Einstein, Mark H.

AU - Lenz, Jack

AU - Montagna, Cristina

PY - 2020/2/1

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N2 - Cervical carcinogenesis, the second leading cause of cancer death in women worldwide, is caused by multiple types of human papillomaviruses (HPVs). To investigate a possible role for HPV in a cervical carcinoma that was HPV-negative by PCR testing, we performed HPV DNA hybridization capture plus massively parallel sequencing. This detected a subgenomic, URR-E6-E7-E1 segment of HPV70 DNA, a type not generally associated with cervical cancer, inserted in an intron of the B-cell lymphoma/leukemia 11B (BCL11B) gene in the human genome. Long range DNA sequencing confirmed the virus and flanking BCL11B DNA structures including both insertion junctions. Global transcriptomic analysis detected multiple, alternatively spliced, HPV70-BCL11B, fusion transcripts with fused open reading frames. The insertion and fusion transcripts were present in an intraepithelial precursor phase of tumorigenesis. These results suggest oncogenicity of HPV70, identify novel BCL11B variants with potential oncogenic implications, and underscore the advantages of thorough genomic analyses to elucidate insights into HPV-associated tumorigenesis.

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