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Genes Chromosomes Cancer. 2019 Aug 13. doi: 10.1002/gcc.22799. [Epub ahead of print]

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

Author information

1
Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York.
2
Department of Genetics, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York.
3
Department of Women's and Children's Health, Obstetrics & Gynecology Unit, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy.
4
School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences BIO5 Institute University of Arizona, Tuscon, Arizona, USA.
5
Department of Pathology, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York.
6
Department of Obstetrics, Gynecology, and Women's Health, Rutgers New Jersey Medical School, Newark, New Jersey.

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.

KEYWORDS:

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

PMID:
31407403
DOI:
10.1002/gcc.22799

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