Insights into the mechanisms and structure of breakage-fusion-bridge cycles in cervical cancer using long-read sequencing.

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 cancer 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 our study applies long-read sequencing to this important chromosomal rearrangement type. 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 chromosomal region 11q BFB event, with YAP1-BIRC3-BIRC2 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 individuals with cervical cancer and YAP1-BIRC3-BIRC2 amplification, especially those of African ancestry, might benefit from targeted therapy. In summary, we uncovered valuable insights into the mechanisms and consequences of BFB cycles in cervical cancer using long-read sequencing.

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

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.

Extrachromosomal Amplification of Human Papillomavirus Episomes Is a Mechanism of Cervical Carcinogenesis.

SIGNIFICANCE: Multimers of the HPV genome are generated in cervical tumors replicating as extrachromosomal episomes, which is associated with deletion and rearrangement of the HPV genome and provides a mechanism for oncogenesis without integration.

Management of Bipolar Disorder During the Perinatal Period.

Bipolar disorder (BPD) is a lifelong mental health condition characterized by symptoms of mania, depression, and often anxiety. BPD can have detrimental consequences for individuals during pregnancy and the postpartum period, as well as for their offspring. This is often due to underdiagnosis and/or misdiagnosis as unipolar depression. There is a high incidence of first episodes of BPD in pregnant and postpartum persons. Perinatal care providers need to routinely screen for BPD and assess for relapse among those with a previous diagnosis during the pregnancy and postpartum periods. Medication management is complex and must be considered in the context of an individual's risk factors and perceptions about treatment as well as the limited evidence regarding fetal safety, using a shared decision-making model. Collaboration, consultation, and/or referral to mental health care providers are essential for managing acute and chronic BPD symptoms.

αVß8 integrin targeting to prevent posterior capsular opacification.

Fibrotic posterior capsular opacification (PCO), a major complication of cataract surgery, is driven by transforming growth factor-ß (TGF-ß). Previously, αV integrins were found to be critical for the onset of TGF-ß-mediated PCO in vivo; however, the functional heterodimer was unknown. Here, ß8 integrin-conditional knockout (ß8ITG-cKO) lens epithelial cells (LCs) attenuated their fibrotic responses, while both ß5 and ß6 integrin-null LCs underwent fibrotic changes similar to WT at 5 days post cataract surgery (PCS). RNA-Seq revealed that ß8ITG-cKO LCs attenuated their upregulation of integrins and their ligands, as well as known targets of TGF-ß-induced signaling, at 24 hours PCS. Treatment of ß8ITG-cKO eyes with active TGF-ß1 at the time of surgery rescued the fibrotic response. Treatment of WT mice with an anti-αVß8 integrin function blocking antibody at the time of surgery ameliorated both canonical TGF-ß signaling and LC fibrotic response PCS, and treatment at 5 days PCS, after surgically induced fibrotic responses were established, largely reversed this fibrotic response. These data suggest that αVß8 integrin is a major regulator of TGF-ß activation by LCs PCS and that therapeutics targeting αVß8 integrin could be effective for fibrotic PCO prevention and treatment.