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1.
Cell ; 184(14): 3812-3828.e30, 2021 07 08.
Article in English | MEDLINE | ID: mdl-34214472

ABSTRACT

We study a patient with the human papilloma virus (HPV)-2-driven "tree-man" phenotype and two relatives with unusually severe HPV4-driven warts. The giant horns form an HPV-2-driven multifocal benign epithelial tumor overexpressing viral oncogenes in the epidermis basal layer. The patients are unexpectedly homozygous for a private CD28 variant. They have no detectable CD28 on their T cells, with the exception of a small contingent of revertant memory CD4+ T cells. T cell development is barely affected, and T cells respond to CD3 and CD2, but not CD28, costimulation. Although the patients do not display HPV-2- and HPV-4-reactive CD4+ T cells in vitro, they make antibodies specific for both viruses in vivo. CD28-deficient mice are susceptible to cutaneous infections with the mouse papillomavirus MmuPV1. The control of HPV-2 and HPV-4 in keratinocytes is dependent on the T cell CD28 co-activation pathway. Surprisingly, human CD28-dependent T cell responses are largely redundant for protective immunity.


Subject(s)
CD28 Antigens/deficiency , Inheritance Patterns/genetics , Papillomaviridae/physiology , Skin/virology , T-Lymphocytes/immunology , Adult , Amino Acid Sequence , Animals , Base Sequence , CD28 Antigens/genetics , CD28 Antigens/metabolism , CD4-Positive T-Lymphocytes/immunology , Child , Endopeptidases/metabolism , Female , Genes, Recessive , HEK293 Cells , Homozygote , Humans , Immunity, Humoral , Immunologic Memory , Jurkat Cells , Keratinocytes/pathology , Male , Mice, Inbred C57BL , Oncogenes , Papilloma/pathology , Papilloma/virology , Pedigree , Protein Sorting Signals , RNA, Messenger/genetics , RNA, Messenger/metabolism
2.
Annu Rev Immunol ; 29: 111-38, 2011.
Article in English | MEDLINE | ID: mdl-21166538

ABSTRACT

Cervical and other anogenital cancers are initiated by infection with one of a small group of human papillomaviruses (HPV). Virus-like particle-based vaccines have recently been developed to prevent infection with two cancer-associated HPV genotypes (HPV16, HPV18) and have been ∼95% effective at preventing HPV-associated disease caused by these genotypes in virus-naive subjects. Although immunization induces virus-neutralizing antibody sufficient to prevent infection, persistence of antibody as measured by current assays does not appear necessary to maintain protection over time. Investigators have not identified a reliable surrogate immunological marker of protection against disease following immunization. The prophylactic vaccines are not therapeutic for existing infection. Trials of HPV-specific immunotherapy have shown some efficacy for existing disease, although animal modeling suggests that a combination of immunization and local enhancement of innate immunity may be necessary for optimal therapeutic outcome. HPV prophylactic vaccines are the first vaccines designed to prevent a human cancer and are the practical outcome of a global collaborative effort between basic and applied scientists, clinicians, and industry.


Subject(s)
Cancer Vaccines/immunology , Neoplasms/immunology , Neoplasms/prevention & control , Papillomaviridae , Papillomavirus Infections/immunology , Papillomavirus Infections/prevention & control , Papillomavirus Vaccines/immunology , Animals , Humans , Neoplasms/virology , Papillomavirus Infections/virology
3.
Immunity ; 57(3): 600-611.e6, 2024 Mar 12.
Article in English | MEDLINE | ID: mdl-38447570

ABSTRACT

Plasma cells that emerge after infection or vaccination exhibit heterogeneous lifespans; most survive for days to months, whereas others persist for decades, providing antigen-specific long-term protection. We developed a mathematical framework to explore the dynamics of plasma cell removal and its regulation by survival factors. Analyses of antibody persistence following hepatitis A and B and HPV vaccination revealed specific patterns of longevity and heterogeneity within and between responses, implying that this process is fine-tuned near a critical "flat" state between two dynamic regimes. This critical state reflects the tuning of rates of the underlying regulatory network and is highly sensitive to variation in parameters, which amplifies lifespan differences between cells. We propose that fine-tuning is the generic outcome of competition over shared survival signals, with a competition-based mechanism providing a unifying explanation for a wide range of experimental observations, including the dynamics of plasma cell accumulation and the effects of survival factor deletion. Our theory is testable, and we provide specific predictions.


Subject(s)
Longevity , Plasma Cells , Antibodies , Vaccination , Antigens
4.
Cell ; 172(6): 1163-1167, 2018 03 08.
Article in English | MEDLINE | ID: mdl-29522737

ABSTRACT

Evidence of the safety and protective benefits of human papillomavirus virus (HPV) vaccines as an anti-cancer measure is overwhelming. However, vaccine uptake varies widely across countries and falls short of levels needed to achieve population immunity. We highlight policy measures that would help ensure greater worldwide coverage and save lives.


Subject(s)
Alphapapillomavirus/immunology , Papillomavirus Infections/immunology , Papillomavirus Vaccines/immunology , Uterine Cervical Neoplasms/immunology , Alphapapillomavirus/drug effects , Female , Global Health/trends , Humans , Papillomavirus Infections/prevention & control , Papillomavirus Infections/virology , Papillomavirus Vaccines/economics , Papillomavirus Vaccines/therapeutic use , Uterine Cervical Neoplasms/prevention & control , Uterine Cervical Neoplasms/virology , Vaccination/economics , Vaccination/methods , Vaccination/trends
5.
Cell ; 174(6): 1465-1476.e13, 2018 09 06.
Article in English | MEDLINE | ID: mdl-30122350

ABSTRACT

Cell-penetrating peptides (CPPs) are short protein segments that can transport cargos into cells. Although CPPs are widely studied as potential drug delivery tools, their role in normal cell physiology is poorly understood. Early during infection, the L2 capsid protein of human papillomaviruses binds retromer, a cytoplasmic trafficking factor required for delivery of the incoming non-enveloped virus into the retrograde transport pathway. Here, we show that the C terminus of HPV L2 proteins contains a conserved cationic CPP that drives passage of a segment of the L2 protein through the endosomal membrane into the cytoplasm, where it binds retromer, thereby sorting the virus into the retrograde pathway for transport to the trans-Golgi network. These experiments define the cell-autonomous biological role of a CPP in its natural context and reveal how a luminal viral protein engages an essential cytoplasmic entry factor.


Subject(s)
Capsid Proteins/metabolism , Cell-Penetrating Peptides/metabolism , Oncogene Proteins, Viral/metabolism , Amino Acid Sequence , Capsid Proteins/chemistry , Capsid Proteins/genetics , Cell-Penetrating Peptides/chemistry , Cell-Penetrating Peptides/genetics , Endosomes/metabolism , Golgi Apparatus/virology , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , HEK293 Cells , HeLa Cells , Human papillomavirus 16/genetics , Human papillomavirus 16/physiology , Humans , Mutagenesis , Oncogene Proteins, Viral/chemistry , Oncogene Proteins, Viral/genetics , Protein Transport , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Sequence Alignment , Virus Attachment , Virus Internalization
6.
Cell ; 170(6): 1057-1059, 2017 09 07.
Article in English | MEDLINE | ID: mdl-28886377

ABSTRACT

Several human papillomavirus type 16 (HPV16) oncoproteins contribute to cellular transformation in vitro. In this issue of Cell, Mirabello and colleagues use high-throughput sequencing data to assess the diversity of HPV16 isolates from human patients. These data suggest that the E7 oncoprotein is the fundamental contributor to in vivo carcinogenesis.


Subject(s)
Human papillomavirus 16 , Oncogene Proteins, Viral , Humans , Neoplasms , Papillomavirus E7 Proteins , Repressor Proteins
7.
Cell ; 171(1): 14-17, 2017 Sep 21.
Article in English | MEDLINE | ID: mdl-28888324

ABSTRACT

This year's Lasker-DeBakey Prize for Clinical Research to Douglas Lowy and John Schiller celebrates the science behind one of the greatest advances in the history of cancer research: the development of vaccines that prevent infection and thus prevent tumor induction by pathogenic strains of human papilloma virus (HPV).


Subject(s)
Awards and Prizes , Human papillomavirus 16/physiology , Papillomavirus Infections/prevention & control , Papillomavirus Vaccines/immunology , Uterine Cervical Neoplasms/prevention & control , Female , History, 20th Century , History, 21st Century , Humans , Male , National Cancer Institute (U.S.) , Papillomavirus Infections/immunology , Papillomavirus Infections/virology , Papillomavirus Vaccines/history , United States , Uterine Cervical Neoplasms/immunology , Uterine Cervical Neoplasms/virology
8.
Cell ; 171(1): 23-27, 2017 Sep 21.
Article in English | MEDLINE | ID: mdl-28888323

ABSTRACT

When John Schiller first joined Douglas Lowy's lab at the National Cancer Institute of the NIH, he could have not predicted that their common interest in the molecular biology of oncogenes would set them in path for discoveries that ultimately enabled the development of a vaccine for the human papillomavirus, which causes the majority of cervical cancers worldwide. John and Doug, the recipients of the 2017 Lasker-DeBakey Clinical Award, have joined Cell editor João Monteiro in a Conversation about science, public health, and the joys and challenges of being basic scientists in a translational space. Annotated excerpts from this conversation are presented below.


Subject(s)
Papillomavirus Vaccines/immunology , Female , History, 20th Century , History, 21st Century , Humans , Male , National Cancer Institute (U.S.) , Papillomaviridae , Papillomavirus Vaccines/history , United States , Uterine Cervical Neoplasms/prevention & control , Uterine Cervical Neoplasms/virology
9.
Cell ; 170(6): 1164-1174.e6, 2017 Sep 07.
Article in English | MEDLINE | ID: mdl-28886384

ABSTRACT

Although most cervical human papillomavirus type 16 (HPV16) infections become undetectable within 1-2 years, persistent HPV16 causes half of all cervical cancers. We used a novel HPV whole-genome sequencing technique to evaluate an exceptionally large collection of 5,570 HPV16-infected case-control samples to determine whether viral genetic variation influences risk of cervical precancer and cancer. We observed thousands of unique HPV16 genomes; very few women shared the identical HPV16 sequence, which should stimulate a careful re-evaluation of the clinical implications of HPV mutation rates, transmission, clearance, and persistence. In case-control analyses, HPV16 in the controls had significantly more amino acid changing variants throughout the genome. Strikingly, E7 was devoid of variants in precancers/cancers compared to higher levels in the controls; we confirmed this in cancers from around the world. Strict conservation of the 98 amino acids of E7, which disrupts Rb function, is critical for HPV16 carcinogenesis, presenting a highly specific target for etiologic and therapeutic research.


Subject(s)
Alphapapillomavirus/genetics , Alphapapillomavirus/isolation & purification , Carcinoma/virology , Papillomavirus Infections/virology , Uterine Cervical Neoplasms/virology , Adult , Alphapapillomavirus/classification , Case-Control Studies , Female , Genome, Viral , Humans , Middle Aged , Papillomavirus E7 Proteins/genetics , Polymorphism, Single Nucleotide , Young Adult
10.
Mol Cell ; 84(2): 202-220.e15, 2024 Jan 18.
Article in English | MEDLINE | ID: mdl-38103559

ABSTRACT

Compounds binding to the bromodomains of bromodomain and extra-terminal (BET) family proteins, particularly BRD4, are promising anticancer agents. Nevertheless, side effects and drug resistance pose significant obstacles in BET-based therapeutics development. Using high-throughput screening of a 200,000-compound library, we identified small molecules targeting a phosphorylated intrinsically disordered region (IDR) of BRD4 that inhibit phospho-BRD4 (pBRD4)-dependent human papillomavirus (HPV) genome replication in HPV-containing keratinocytes. Proteomic profiling identified two DNA damage response factors-53BP1 and BARD1-crucial for differentiation-associated HPV genome amplification. pBRD4-mediated recruitment of 53BP1 and BARD1 to the HPV origin of replication occurs in a spatiotemporal and BRD4 long (BRD4-L) and short (BRD4-S) isoform-specific manner. This recruitment is disrupted by phospho-IDR-targeting compounds with little perturbation of the global transcriptome and BRD4 chromatin landscape. The discovery of these protein-protein interaction inhibitors (PPIi) not only demonstrates the feasibility of developing PPIi against phospho-IDRs but also uncovers antiviral agents targeting an epigenetic regulator essential for virus-host interaction and cancer development.


Subject(s)
Papillomavirus Infections , Transcription Factors , Humans , Transcription Factors/genetics , Transcription Factors/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Human Papillomavirus Viruses , Papillomavirus Infections/drug therapy , Papillomavirus Infections/genetics , Proteomics , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Papillomaviridae/genetics , Papillomaviridae/metabolism , Viral Proteins/genetics , Virus Replication/physiology , DNA Repair , Bromodomain Containing Proteins
11.
Immunity ; 54(12): 2842-2858.e5, 2021 12 14.
Article in English | MEDLINE | ID: mdl-34813775

ABSTRACT

People living with HIV (PLWH) are at increased risk for developing skin and mucosal malignancies despite systemic reconstitution of CD4+ T cells upon antiretroviral therapy (ART). The underlying mechanism of chronic tissue-related immunodeficiency in HIV is unclear. We found that skin CD4+ tissue-resident memory T (Trm) cells were depleted after HIV infection and replenished only upon early ART initiation. TCR clonal analysis following early ART suggested a systemic origin for reconstituting CD4+ Trm cells. Single-cell RNA sequencing in PLWH that received late ART treatment revealed a loss of CXCR3+ Trm cells and a tolerogenic skin immune environment. Human papilloma virus-induced precancerous lesion biopsies showed reduced CXCR3+ Trm cell frequencies in the mucosa in PLWH versus HIV- individuals. These results reveal an irreversible loss of CXCR3+ Trm cells confined to skin and mucosa in PLWH who received late ART treatment, which may be a precipitating factor in the development of HPV-related cancer.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , HIV Infections/immunology , HIV-1/physiology , Immunologic Deficiency Syndromes/immunology , Memory T Cells/immunology , Mucous Membrane/immunology , Skin/immunology , Adult , Antiretroviral Therapy, Highly Active , Female , HIV Infections/drug therapy , HIV Long-Term Survivors , Humans , Immunologic Deficiency Syndromes/drug therapy , Male , Middle Aged , Receptors, CXCR3/metabolism , Sequence Analysis, RNA , Single-Cell Analysis , Time-to-Treatment , Young Adult
12.
CA Cancer J Clin ; 73(2): 164-197, 2023 03.
Article in English | MEDLINE | ID: mdl-36305841

ABSTRACT

The most common cancer caused by human papillomavirus (HPV) infection in the United States is oropharyngeal cancer (OPC), and its incidence has been rising since the turn of the century. Because of substantial long-term morbidities with chemoradiation and the favorable prognosis of HPV-positive OPC, identifying the optimal deintensification strategy for this group has been a keystone of academic head-and-neck surgery, radiation oncology, and medical oncology for over the past decade. However, the first generation of randomized chemotherapy deintensification trials failed to change the standard of care, triggering concern over the feasibility of de-escalation. National database studies estimate that up to one third of patients receive nonstandard de-escalated treatments, which have subspecialty-specific nuances. A synthesis of the multidisciplinary deintensification data and current treatment standards is important for the oncology community to reinforce best practices and ensure optimal patient outcomes. In this review, the authors present a summary and comparison of prospective HPV-positive OPC de-escalation trials. Chemotherapy attenuation compromises outcomes without reducing toxicity. Limited data comparing transoral robotic surgery (TORS) with radiation raise concern over toxicity and outcomes with TORS. There are promising data to support de-escalating adjuvant therapy after TORS, but consensus on treatment indications is needed. Encouraging radiation deintensification strategies have been reported (upfront dose reduction and induction chemotherapy-based patient selection), but level I evidence is years away. Ultimately, stage and HPV status may be insufficient to guide de-escalation. The future of deintensification may lie in incorporating intratreatment response assessments to harness the powers of personalized medicine and integrate real-time surveillance.


Subject(s)
Oropharyngeal Neoplasms , Papillomavirus Infections , Humans , Human Papillomavirus Viruses , Consensus , Prospective Studies , Oropharyngeal Neoplasms/surgery
13.
Nature ; 631(8021): 544-548, 2024 Jul.
Article in English | MEDLINE | ID: mdl-39020036

ABSTRACT

A long-standing challenge is how to formulate proteins and vaccines to retain function during storage and transport and to remove the burdens of cold-chain management. Any solution must be practical to use, with the protein being released or applied using clinically relevant triggers. Advanced biologic therapies are distributed cold, using substantial energy, limiting equitable distribution in low-resource countries and placing responsibility on the user for correct storage and handling. Cold-chain management is the best solution at present for protein transport but requires substantial infrastructure and energy. For example, in research laboratories, a single freezer at -80 °C consumes as much energy per day as a small household1. Of biological (protein or cell) therapies and all vaccines, 75% require cold-chain management; the cost of cold-chain management in clinical trials has increased by about 20% since 2015, reflecting this complexity. Bespoke formulations and excipients are now required, with trehalose2, sucrose or polymers3 widely used, which stabilize proteins by replacing surface water molecules and thereby make denaturation thermodynamically less likely; this has enabled both freeze-dried proteins and frozen proteins. For example, the human papilloma virus vaccine requires aluminium salt adjuvants to function, but these render it unstable against freeze-thaw4, leading to a very complex and expensive supply chain. Other ideas involve ensilication5 and chemical modification of proteins6. In short, protein stabilization is a challenge with no universal solution7,8. Here we designed a stiff hydrogel that stabilizes proteins against thermal denaturation even at 50 °C, and that can, unlike present technologies, deliver pure, excipient-free protein by mechanically releasing it from a syringe. Macromolecules can be loaded at up to 10 wt% without affecting the mechanism of release. This unique stabilization and excipient-free release synergy offers a practical, scalable and versatile solution to enable the low-cost, cold-chain-free and equitable delivery of therapies worldwide.


Subject(s)
Drug Storage , Hydrogels , Protein Denaturation , Protein Stability , Proteins , Syringes , Humans , Excipients , Freeze Drying , Hydrogels/chemistry , Proteins/administration & dosage , Proteins/chemistry , Proteins/economics , Trehalose , Freezing , Refrigeration , Papillomavirus Vaccines/chemistry , Drug Storage/economics , Drug Storage/methods
14.
Immunity ; 52(1): 183-199.e9, 2020 01 14.
Article in English | MEDLINE | ID: mdl-31924475

ABSTRACT

Head and neck squamous cell carcinoma (HNSCC) arises through exposure to environmental carcinogens or malignant transformation by human papillomavirus (HPV). Here, we assessed the transcriptional profiles of 131,224 single cells from peripheral and intra-tumoral immune populations from patients with HPV- and HPV+ HNSCC and healthy donors. Immune cells within tumors of HPV- and HPV+ HNSCC displayed a spectrum of transcriptional signatures, with helper CD4+ T cells and B cells being relatively divergent and CD8+ T cells and CD4+ regulatory T cells being relatively similar. Transcriptional results were contextualized through multispectral immunofluorescence analyses and evaluating putative cell-cell communication based on spatial proximity. These analyses defined a gene expression signature associated with CD4+ T follicular helper cells that is associated with longer progression-free survival in HNSCC patients. The datasets and analytical approaches herein provide a resource for the further study of the impact of immune cells on viral- and carcinogen-induced cancers.


Subject(s)
B-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Head and Neck Neoplasms/immunology , Squamous Cell Carcinoma of Head and Neck/immunology , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Regulatory/immunology , Alphapapillomavirus/immunology , Cell Differentiation/immunology , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/virology , Humans , Immunotherapy , Progression-Free Survival , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/virology
15.
CA Cancer J Clin ; 72(6): 561-569, 2022 11.
Article in English | MEDLINE | ID: mdl-35969145

ABSTRACT

Human papillomavirus (HPV) is currently linked to almost 35,000 new cases of cancer in women and men each year in the United States. Gardasil-9 (Merck & Company), the only HPV vaccine now available in the United States, is nearly 100% effective at preventing precancers caused by oncogenic HPV types. In the United States, however, only about one half of adolescents are up to date with HPV vaccination. It is well known that health care clinicians' recommendations play a significant role in parents' decisions regarding HPV vaccination. A growing body of literature examines specific communication strategies for promoting uptake of the HPV vaccine. A comprehensive review of the evidence for each of these strategies is needed. The authors searched the PubMed, EMBASE, Cochrane Central Register of Controlled Trials, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, and Web of Science Complete databases for original articles with a defined clinician communication strategy and an outcome of HPV vaccine uptake or intention to vaccinate (PROSPERO registry no. CRD42020107602). In total, 46 studies were included. The authors identified two main strategies with strong evidence supporting their positive impact on vaccine uptake: strong recommendation and presumptive recommendation. Determinations about a causal relationship were limited by the small numbers of randomized controlled trials. There is also opportunity for more research to determine the effects of motivational interviewing and cancer-prevention messaging.


Subject(s)
Alphapapillomavirus , Neoplasms , Papillomavirus Infections , Papillomavirus Vaccines , Adolescent , Male , Female , Humans , United States , Papillomavirus Infections/prevention & control , Papillomavirus Infections/complications , Papillomavirus Vaccines/therapeutic use , Vaccination , Communication , Parents , Neoplasms/prevention & control
16.
CA Cancer J Clin ; 71(6): 505-526, 2021 11.
Article in English | MEDLINE | ID: mdl-34499351

ABSTRACT

Despite being highly preventable, cervical cancer is the fourth most common cancer and cause of cancer death in women globally. In low-income countries, cervical cancer is often the leading cause of cancer-related morbidity and mortality. Women living with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome are at a particularly high risk of cervical cancer because of an impaired immune response to human papillomavirus, the obligate cause of virtually all cervical cancers. Globally, approximately 1 in 20 cervical cancers is attributable to HIV; in sub-Saharan Africa, approximately 1 in 5 cervical cancers is due to HIV. Here, the authors provide a critical appraisal of the evidence to date on the impact of HIV disease on cervical cancer risk, describe key methodologic issues, and frame the key outstanding research questions, especially as they apply to ongoing global efforts for prevention and control of cervical cancer. Expanded efforts to integrate HIV care with cervical cancer prevention and control, and vice versa, could assist the global effort to eliminate cervical cancer as a public health problem.


Subject(s)
HIV Infections/epidemiology , Uterine Cervical Neoplasms/epidemiology , Uterine Cervical Neoplasms/prevention & control , Early Detection of Cancer , Female , Humans , Immunocompromised Host , Papillomavirus Infections , Papillomavirus Vaccines , Precancerous Conditions/therapy , Primary Prevention , Secondary Prevention
17.
Nature ; 612(7940): 495-502, 2022 12.
Article in English | MEDLINE | ID: mdl-36450981

ABSTRACT

Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage1-3. The FA repair pathway protects against endogenous and exogenous carcinogenic aldehydes4-7. Individuals with FA are hundreds to thousands fold more likely to develop head and neck (HNSCC), oesophageal and anogenital squamous cell carcinomas8 (SCCs). Molecular studies of SCCs from individuals with FA (FA SCCs) are limited, and it is unclear how FA SCCs relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or infection with human papillomavirus9 (HPV). Here, by sequencing genomes and exomes of FA SCCs, we demonstrate that the primary genomic signature of FA repair deficiency is the presence of high numbers of structural variants. Structural variants are enriched for small deletions, unbalanced translocations and fold-back inversions, and are often connected, thereby forming complex rearrangements. They arise in the context of TP53 loss, but not in the context of HPV infection, and lead to somatic copy-number alterations of HNSCC driver genes. We further show that FA pathway deficiency may lead to epithelial-to-mesenchymal transition and enhanced keratinocyte-intrinsic inflammatory signalling, which would contribute to the aggressive nature of FA SCCs. We propose that the genomic instability in sporadic HPV-negative HNSCC may arise as a result of the FA repair pathway being overwhelmed by DNA interstrand crosslink damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA-crosslinking damage.


Subject(s)
DNA Repair , Fanconi Anemia , Genomics , Head and Neck Neoplasms , Humans , Aldehydes/adverse effects , Aldehydes/metabolism , DNA Repair/genetics , Fanconi Anemia/genetics , Fanconi Anemia/metabolism , Fanconi Anemia/pathology , Head and Neck Neoplasms/chemically induced , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/pathology , Papillomavirus Infections , Squamous Cell Carcinoma of Head and Neck/chemically induced , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/metabolism , Squamous Cell Carcinoma of Head and Neck/pathology , DNA Damage/drug effects
18.
Am J Hum Genet ; 111(3): 544-561, 2024 03 07.
Article in English | MEDLINE | ID: mdl-38307027

ABSTRACT

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.


Subject(s)
Papillomavirus Infections , Uterine Cervical Neoplasms , Female , Humans , Uterine Cervical Neoplasms/genetics , Chromosome Aberrations , Telomere/genetics , DNA
19.
CA Cancer J Clin ; 70(4): 274-280, 2020 07.
Article in English | MEDLINE | ID: mdl-32639044

ABSTRACT

The American Cancer Society (ACS) presents an adaptation of the current Advisory Committee on Immunization Practices recommendations for human papillomavirus (HPV) vaccination. The ACS recommends routine HPV vaccination between ages 9 and 12 years to achieve higher on-time vaccination rates, which will lead to increased numbers of cancers prevented. Health care providers are encouraged to start offering the HPV vaccine series at age 9 or 10 years. Catch-up HPV vaccination is recommended for all persons through age 26 years who are not adequately vaccinated. Providers should inform individuals aged 22 to 26 years who have not been previously vaccinated or who have not completed the series that vaccination at older ages is less effective in lowering cancer risk. Catch-up HPV vaccination is not recommended for adults aged older than 26 years. The ACS does not endorse the 2019 Advisory Committee on Immunization Practices recommendation for shared clinical decision making for some adults aged 27 through 45 years who are not adequately vaccinated because of the low effectiveness and low cancer prevention potential of vaccination in this age group, the burden of decision making on patients and clinicians, and the lack of sufficient guidance on the selection of individuals who might benefit.


Subject(s)
Immunization Schedule , Mass Vaccination/standards , Neoplasms/prevention & control , Papillomavirus Infections/prevention & control , Papillomavirus Vaccines/administration & dosage , Adolescent , Adult , Advisory Committees/standards , Alphapapillomavirus/immunology , Alphapapillomavirus/pathogenicity , American Cancer Society/organization & administration , Child , Clinical Competence , Female , Health Personnel/education , Health Plan Implementation/organization & administration , Health Plan Implementation/standards , Humans , Intersectoral Collaboration , Mass Vaccination/organization & administration , Middle Aged , Neoplasms/pathology , Neoplasms/virology , Papillomavirus Infections/pathology , Papillomavirus Infections/virology , United States , Vaccination Coverage/organization & administration , Vaccination Coverage/standards , Young Adult
20.
CA Cancer J Clin ; 70(5): 321-346, 2020 09.
Article in English | MEDLINE | ID: mdl-32729638

ABSTRACT

The American Cancer Society (ACS) recommends that individuals with a cervix initiate cervical cancer screening at age 25 years and undergo primary human papillomavirus (HPV) testing every 5 years through age 65 years (preferred); if primary HPV testing is not available, then individuals aged 25 to 65 years should be screened with cotesting (HPV testing in combination with cytology) every 5 years or cytology alone every 3 years (acceptable) (strong recommendation). The ACS recommends that individuals aged >65 years who have no history of cervical intraepithelial neoplasia grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening (qualified recommendation). These new screening recommendations differ in 4 important respects compared with the 2012 recommendations: 1) The preferred screening strategy is primary HPV testing every 5 years, with cotesting and cytology alone acceptable where access to US Food and Drug Administration-approved primary HPV testing is not yet available; 2) the recommended age to start screening is 25 years rather than 21 years; 3) primary HPV testing, as well as cotesting or cytology alone when primary testing is not available, is recommended starting at age 25 years rather than age 30 years; and 4) the guideline is transitional, ie, options for screening with cotesting or cytology alone are provided but should be phased out once full access to primary HPV testing for cervical cancer screening is available without barriers. Evidence related to other relevant issues was reviewed, and no changes were made to recommendations for screening intervals, age or criteria for screening cessation, screening based on vaccination status, or screening after hysterectomy. Follow-up for individuals who screen positive for HPV and/or cytology should be in accordance with the 2019 American Society for Colposcopy and Cervical Pathology risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors.


Subject(s)
Early Detection of Cancer/standards , Mass Screening/standards , Papillomaviridae/isolation & purification , Uterine Cervical Neoplasms/diagnosis , Adult , Aged , American Cancer Society , Female , Humans , Middle Aged , Papillomavirus Infections/diagnosis , Papillomavirus Vaccines , United States , Uterine Cervical Neoplasms/prevention & control , Uterine Cervical Neoplasms/virology , Vaginal Smears , Uterine Cervical Dysplasia/diagnosis , Uterine Cervical Dysplasia/prevention & control , Uterine Cervical Dysplasia/virology
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