Human Papillomavirus and Cervical Cancer PDF

Human Papillomavirus and Cervical cancer Dr Vongani Muthambi Clinical virologist [email protected] Objectives To learn the epidemiology of HPV To list at least 3 oncogenic viruses To understand the pathways and features of tumorogenicity associated with vir...

Human Papillomavirus and Cervical cancer Dr Vongani Muthambi Clinical virologist [email protected] Objectives To learn the epidemiology of HPV To list at least 3 oncogenic viruses To understand the pathways and features of tumorogenicity associated with viral infections To learn the structure classification and replication of HPV To provide an overview of clinical spectrum of HPV infection To learn laboratory screening and diagnosis of HPV/cervical cancer To know how other STI influence HPV infection and progression to cervical cancer Terminology Transformation – is the process in which normal cells undergo to become malignant cells Mutation Activation of tumor genes Activation of tumor suppressors Oncogenesis – progression of cytological, genetic and cellular changes resulting in the development of a malignant tumor Continuous proliferation of a clone of cells Types of cancer & the cell type from which they are derived Type of cancer Cell type involved Carcinoma Epithelial cells Lymphoma Lymphocytes Sarcoma Connective tissue Leukaemia Blood-forming cells Mesothelioma Mesothelium  Oncogenic Viruses Viruses that are able to cause cancer are called – oncogenic viruses / tumor viruses Presence of viral DNA or viral proteins are detected in some tumors 20-25% of human cancer worldwide are estimated to have viral etiology NB: Cancer is a multistep process – Disease results from more than one mutation acquired over a period of time – Other role players: – Immunodeficiency – Human genetic predispositions – Environmental factors  Oncogenic Viruses DNA tumor viruses RNA tumor viruses Hepatitis B Hepatitis C Herpes viruses Epstein-Barr virus Human retroviruses Kaposisarcoma virus Human T-cell Human papillomavirus leukemia virus I Polyomaviruses (HTLV-I) JC virus BK virus Merkel cell polyomavirus Adenovirus  Oncogenesis Normal cell growth, cell differentiation and function are dependent on a complex regulatory system of cell cycle loss of normal cell-cycle restraints Tumor / Cancer (continuous proliferation of a clone of cells) Triggered by various carcinogens: – Nicotine, radiations, chemicals, hormones, mycotoxins – Viruses The characteristics of oncogenic viruses – Ability to causes chronic infection Directly or indirectly interfere with the cell’s function Viral proteins that interfere with normal cell cycle Integration of the viral genome randomly into the host cell’s DNA Normal Cell Cycle  Oncogenesis 2 classes of these genes that if altered expression can lead to loss of growth control: Tumor-suppressor genes / anti-oncogenes e.g: p53 (Nuclear protein); pRb (Retinoblastoma protein) genes that inhibit cell growth (induce apoptosis) cause cancer when they are turned off Proto-oncogenes e.g: c-myc This oncogene is activated under the control of a promotor → stimulating cell growth C-myc encodes a transcription factor  Human Papillomavirus Family: Papillomaviridae Papillomaviruses – Latin words – “Papilla” = nipple – “oma” = tumor It’s an non-enveloped, dsDNA Have over 200 of HPV and around 15 are linked to cancer – High risk( hr) types: associated with malignancy – Low risk types: warts hrHPV 16 & 18 responsible for most HPV associated cancers – ~90% of anal cancers – ~70% of all cervical cancer cases & oropharyngeal tumors – 40% of penile, vulvar & vaginal cancers hrHPV 31, 33, 45, 52, & 58 – minor contribution to cancers HPV High-risk types include: Transmission Type 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 Sexual transmission and 59. In utero or perinatal Others are classified as potential high-risk :53, Autoinoculation or 66,68, 70, 73, and 82 indirectly i.e fomites Currently, it is well known and proven that HPV16 and 18 are the most virulent high-risk genotypes causing about 70% of all invasive cervical cancer in the world Association between HPV and cervical cancer The vast majority of HPV infections are transitory and become undetectable in 12–24 months In some women whose infections continue to persist, the risk of developing precancerous conditions is significant. Many studies confirmed that persistent infection with an oncogenic HPV type is the main risk factor for detecting a cervical intraepithelial neoplasia (CIN) that may range from CIN1 to CIN3 and cancer DNA virus replication FEBS Letters, Volume: 593, Issue: 24, Pages: 3531-3550, First published: 25 November 2019, DOI: (10.1002/1873-3468.13695)  Virus replication HPV replicates exclusively in stratified squamous epithelium. It requires differentiating epithelium to undergo a complete replication cycle. HPV access basal epithelial cells through micro-abrasion In the basal layer Early non structural viral proteins are expressed such as E6 and E7 Early non structural proteins stimulate the infected cells to proliferate faster.  Replication of the viral genome  Epithelial cells mature move up the epithelial layer  expression of the viral structural genes L1 and L2. Production of structural viral proteins and new virus particles assemble and are Shedding of virus as the infected cells desquamate. Epithelium is an immune-privileged site and the virus evades immune recognition and may persist for many months to years in the same individual. Pathogenesis  Clinical spectrum of HPV infection Most HPV infections are clinically silent Only minority of people develop clinically apparent lesions Warts Cutaneous warts are caused by HPV types 1, 2, 3, 4, 5 and 8. Benign painless proliferative lesions occurring on the skin at sites of abrasion such as hands, feet, knees and elbows Common, especially in children over the age of five years. Typically persist for months, but eventually regress in immuno- competent people.  Clinical spectrum of HPV infection Mucosal warts mainly due to HPV 6 and 11. Lesions are most commonly seen in genital mucosa usually sexually transmitted may occur in oropharynx ( see next slide) may persist for months or years benign but can cause much distress due to disfigurement of the genital area.  Clinical spectrum of HPV infection Laryngeal papillomatosis commonly seen in infants and young children Caused by infection with HPV 6 or 11 Warts develop in the larynx, especially on the vocal cords. usually acquired during passage through infected birth canal. Affected children develop hoarseness and stridor and airway obstruction. Treatment involves repeated surgical removal of the growths  Clinical spectrum of HPV infection Epidermodysplasia verruciformis Occurs with a rare immunodeficiency state Mutations in the EVER1 or EVER2 genes on chromosome 17q2defect in cell-mediated immunity Patients are highly susceptible to HPV infection Disease characterized by chronic infection with multiple HPV types Widespread skin eruptions of flat-to-papillomatous, wartlike lesions and reddish-brown pigmented plaques on the trunk, the hands, the upper and lower extremities, and the face are typical. Some skin lesions may undergo malignant transformation  HPV Oncogenesis Integration of HPV DNA into the host chromosomes Viral proteins interfere with the control of cell cycle – E6 binds to p53 – E7 binds to pRb Other endogenous factors associated with malignant transformation – Activation of c-myc by nearby integration of HPVDNA  HPV and STI HIV Causes immunodeficiency Decreased ability of immune system to clear HPV associated with persistence HPV and increased incidence of low grade and high grade cervical intraepithelial lesion(CIN) HIV infected females with CD4 cell count of < 200 have a 7 fold increased incidence of cervical Ca ART  immune reconstitution reduces HPV persistence  HPV clearance and regression of low grade CIN  HPV and STI HSV 1& 2 Latency in nerve ganglion Reactivation can be symptomatic or asymptomatic with shedding of virus HSV infection allows better accses to basal cell layer directly or indirectly influence persistence and oncogenic activities of HPV HSV 2 seropositive women have 2-9 fold increased risk of developing cervical Ca  Risk factors for persistent infection & cervical cancer  Cigarette  Smoking  Long-term oral contraceptive use,  High parity,  Early age at first delivery  Immunosuppressive states  Multiple sexual partners Diagnosis – Cytology and colposcopy – Molecular assays DNA PCR Cervical fluid E6 & E7 mRNA Vaginal tampon  Prevention of Cx cancer Vaccination Behavior change – Limiting high risk exposure Treatment of HIV and other STI Cervical cytology screening – Reduces incidence of cervical cancer by 70% Cervarix (serotypes 6 and 11 ) Virus-like particle vaccine 2 doses – Administered 6 months apart Indication – Females: 9 through 26 years Gardasil 4 (serotypes 6,11, 16 & 18)  References https://3pw8zx30ta4c3jegjv14ssuv-wpengine.netdna- ssl.com/wp-content/uploads/sites/2/2019/05/table-1.jpg https://consultqd.clevelandclinic.org/human-papillomavirus- in-2019-an-update-on-vaccines-and-dosing-recommendations/ https://emedicine.medscape.com/article/1131981-overview