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

Genes Chromosomes Cancer. 2020 Feb;59(2):84-95. doi: 10.1002/gcc.22799. Epub 2019 Sep 4.


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.

Keywords: BCL11B; HPV DNA; HPV70; cancer; cervical carcinoma; fluorescent in situ hybridization; hybridization capture; insertional oncogenesis; long range sequencing; oncogene.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism
  • DNA, Viral / analysis
  • Female
  • Genomics
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Middle Aged
  • Papillomaviridae / genetics*
  • Papillomaviridae / pathogenicity
  • Papillomavirus Infections / diagnosis*
  • Papillomavirus Infections / genetics
  • Polymerase Chain Reaction
  • RNA, Messenger / genetics
  • Repressor Proteins / genetics
  • Tumor Suppressor Proteins / genetics
  • Uterine Cervical Neoplasms / genetics*
  • Uterine Cervical Neoplasms / metabolism


  • BCL11B protein, human
  • DNA, Viral
  • RNA, Messenger
  • Repressor Proteins
  • Tumor Suppressor Proteins