Insights into the Mechanisms and Structure of Breakage-Fusion-Bridge Cycles in Cervical Cancer using Long-Read Sequencing.

Autor: Rodriguez I; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA., Rossi NM; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA., Keskus A; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Rockville, MD, USA., Xie Y; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA., Ahmad T; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Rockville, MD, USA., Bryant A; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Rockville, MD, USA., Lou H; Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD., Paredes JG; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA., Milano R; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA., Rao N; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.; Department of Biology, Johns Hopkins University, Baltimore, MD, USA., Tulsyan S; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA., Boland JF; Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD., Luo W; Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD., Liu J; Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD., O'Hanlon T; Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD., Bess J; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA., Mukhina V; Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medical Center, Baltimore, MD, USA., Gaykalova D; Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA.; Marlene & Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical System, Baltimore, MD, USA.; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA., Yuki Y; Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD., Malik L; Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA and Center for Alzheimer's and Related Dementias, National Institute on Aging, Bethesda, Maryland, USA., Billingsley K; Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA and Center for Alzheimer's and Related Dementias, National Institute on Aging, Bethesda, Maryland, USA., Blauwendraat C; Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA and Center for Alzheimer's and Related Dementias, National Institute on Aging, Bethesda, Maryland, USA., Carrington M; Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD.; Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA., Yeager M; Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA and Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD., Mirabello L; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA., Kolmogorov M; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Rockville, MD, USA., Dean M; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.
Jazyk: angličtina
Zdroj: MedRxiv : the preprint server for health sciences [medRxiv] 2023 Aug 22. Date of Electronic Publication: 2023 Aug 22.
DOI: 10.1101/2023.08.21.23294276
Abstrakt: Cervical cancer is caused by human papillomavirus (HPV) infection, has few approved targeted therapeutics, and is the most common cause of cancer death in low-resource countries. We characterized 19 cervical and four head and neck cell lines using long-read DNA and RNA sequencing and identified the HPV types, HPV integration sites, chromosomal alterations, and cancer driver mutations. Structural variation analysis revealed telomeric deletions associated with DNA inversions resulting from breakage-fusion-bridge (BFB) cycles. BFB is a common mechanism of chromosomal alterations in cancer, and this is one of the first analyses of these events using long-read sequencing. Analysis of the inversion sites revealed staggered ends consistent with exonuclease digestion of the DNA after breakage. Some BFB events are complex, involving inter- or intra-chromosomal insertions or rearrangements. None of the BFB breakpoints had telomere sequences added to resolve the dicentric chromosomes and only one BFB breakpoint showed chromothripsis. Five cell lines have a Chr11q BFB event, with YAP1/BIRC2/BIRC3 gene amplification. Indeed, YAP1 amplification is associated with a 10-year earlier age of diagnosis of cervical cancer and is three times more common in African American women. This suggests that cervical cancer patients with YAP1 / BIRC2 / BIRC3 -amplification, especially those of African American ancestry, might benefit from targeted therapy. In summary, we uncovered new insights into the mechanisms and consequences of BFB cycles in cervical cancer using long-read sequencing.
Databáze: MEDLINE
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