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HPV E CNCER
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General Information: Ether-resistant, acid & heat stable Circular dsDNA ~8kb, non-enveloped Icosahedral,72 capsomeres, 55nm diameter Surface Antigen Over 100 genotypes*, High & Low Risk strains Causes warts; transforms cells Polycistronic (mRNA carrying information for the synthesis of more than one protein) , 8 ORF Genome: 3 Regions Replicates in Nucleus Plasmid-like state
PAPILLOMAVIRUSES Non-enveloped dsDNA viruses Circular genome ~8kb 55-nm spherical capsid coat Widely distributed in higher vertebrates Tigh species specificity Tropism for squamous epithelium Associated with verrugas & cancer
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O GENOMA DO HPV
O GENOMA DO HPV
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Classification of Papillomaviruses
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Family: Papillomaviridae
Genus: Polyomavirus
Mice Monkey SV40 Vacuolating Agent Man BK Virus, GU Tract, Renal Transplant Patients, JC Virus, Leucoencephalopathy
Genus: Papillomavirus
Zonotic PV
Animal Tumor Rabbit (Shope) Papilloma Bovine Papilloma Deer Sarcoma Human (Wart) Papilloma Associated Tumor Type Squamous Cell Carcinoma Squamous Cell Carcinoma Fibrosarcoma Squamous Cell Carcinoma
Pescoo de boi
Focinho de cavalo
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Anogenital lesions
Condyloma accuminata CIN, VIN, VAIN, PIN, PAIN
6,11 16,18,31
Malignancies
Cervical cancer Other anogenital cancers Laryngeal cancer Oral cancer
http://www.ashastd.org/hpvccrc/overview.html
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Common warts
Common warts
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Epidermodysplasia verruciformis
Rare inherited disease characterized by chronic infection with human papillomavirus (HPV). Widespread skin eruptions of flat-to-papillomatous, wart-like lesions and reddish-brown pigmented plaques on the trunk, the hands, the upper and lower extremities, and the face are typical.
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Classification of Papillomaviruses
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11
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In situ carcinoma
Benign lesion
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Anal Warts
SCC
Bowenoid papulosis
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Evento
Celsius (Roma) descreve as verrugas genitais Rigoni-Stern (Verona) associa o cancro genital a actividade sexual Verrugas disseminam-se por contacto Extractos infecciosos obtidos em clulas Progresso para malignidade requer co-factor (estudo em coelhos) Ayre descreve o Coilcito, chamando-o de Complexo pr cancro A natureza infecciosa das verrugas demonstrada epidemiologicamente Koss & Durfee introduzem o termo Koilocytosis (coilocitose) Sugere-se etiologia viral para o cancro de colo uterino: HSV Meisels & Fortin associam coilocitose e disqueratose como aco do HPV HPV demonstrado nas leses precursoras Infeco persistente pelo HPV precursora necessria para o cancro cervical. HPV causa 99.7% dos carcinomas cervicais.
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< 91.5
Source GLOBOCAN 2000; IARC
< 15.4
Trottier H, Franco EL. Vaccine. 2005. The epidemiology of genital human papillomavirus infection.
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0 1.9 4.9 9.7 17.3 42 rates per 100,000 0Age-standardised 1.9 4.9 9.7 mortality 17.3 42
GLOBOCAN 2008, International Agency for Research on Cancer
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25
20 18
20
16
Cncer
15
14 12 10
HPV
10
8 6
4 2
0 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 > 75
Idade (anos)
NCI SEER Data, 1990-94; Melkert et al., 1993. Int J Canc 53:919
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HPV & Cncer Cervical TIPO CARGA VIRAL INTERAO COM CLULA EPITELIAL RESPOSTA IMUNOLGICA
FACTORES DE RISCO
Comportamento sexual: mltiplos aumentam o risco de infeco por HPV. parceiros
Mulheres em clnicas de DST tem aumento de 4 a 13 vezes infeco por HPV. Indivduos com comprometimento do sistema imune tm chance 17 vzes maior de ter doenas associadas ao HPV. Estudo com 207 mulheres expostas ao HIV mostrou prevalncia de 23% em HIV- e 46% nas HIV + (Ho et al, 1994). Idade um factor de risco: mulheres de 15 a 25 anos tem o dobro de chance de infeco por HPV do que as mulheres acima dos 35. Outros factores (no concludentes): contraceptivo oral (reduo?), gravidez, cigarro, HSV, Chlamydia. Variveis scio-econmicas: pobreza, violncia domstica, abuso sexual, cuidados de sade inadequados.
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High risk HPV (oncogenic) types HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82
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Nature Reviews Cancer 2; 342-350 (2002); doi:10.1038/nrc798 PAPILLOMAVIRUSES AND CANCER: FROM BASIC STUDIES TO CLINICAL APPLICATION
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(+) (-)
ASCUS
NORMAL
HGSIL
CANCER
LGSIL
INTEGRAO ANEUPLOIDIA
ONCOGNESE CERVICAL
Clula Epitelial Madura
Padro Abortivo
Queratincito Imaturo
HPV
Padro Produtivo
HPV 6 ou 16 HPV 16
Coilcito
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Nature Reviews Cancer 2; 342-350 (2002); doi:10.1038/nrc798 PAPILLOMAVIRUSES AND CANCER: FROM BASIC STUDIES TO CLINICAL APPLICATION
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14.2 22.4 64
HPV HPV
Normal
CIN 3
Severe Dysplasia Carcinoma in situ
From Figure 6.13, DeMay RM. The Art and Science of Cytopathology. CD-ROM. ASCP. 1999. Wright TC, Kurman RJ, Ferenczy A: Precancerous Lesions of the Cervix. In Kurman RJ, ed: Blaustein's Pathology of the Female Genital Tract. 4th ed. New York: Springer-Verlag NY Inc, 1994.
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Progression scheme depicting the stages leading to the development cervical cancer from HPV infection to invasive disease.A. Functional progression model. B. Morphology based description of progression; arrows, HPV oncogene expression. C. Representative p16 staining patterns associated with morphologic and functional disease stages. Cancer Epidemiol Biomarkers Prev 2008;17(10):253645)
Pap test
IARC confirms efficacy of cervix cancer screening for women 25-65 in reducing mortality
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68 59 58 56 52 51 45 39 35 33 31 18 16
Tipo
HPV 16 HPV 18 HPV 45 HPV 31 HPV 52 HPV 33
Cncer
53% 11% 4% 3% 2% 2%
Controle
3.0% 1.0% 0.5% 0.6% 0.2% 0.2%
OR
434 248 197 123 200 373
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Detection of HPV Types in Cervix Cancers from Different Regions of the World
from Clifford Br J Cancer 2003;88:63
16 18 45 31 33 58 52 35 Others
Europe
0.5 0.5 13.5
Europe
Asia
0.5
HPV Types
2.9
17.2
1.4
Africa
3.4 2
Latin America
2 3.3 2.9 4 7 5.5 10.6 51.7 13
17.5
16 18 45
14.1 33
50.2
7.9 31
16 4.5 56 18 45 31 33 58 52 35 Others
16 18 45 31 33 58 52 35 15.3 Others
16 18
43.4
45 31 33 58 52 35
16 18 45 31 33 58 52 35 Others
Others
58 52 35 Others
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AIS: adenocarcinoma in situ; ATP: according to protocol; CIN: cervical intraepithelial neoplasia; CIN1+: CIN grade 1 or worse; CIN2+: CIN grade 2 or worse; FUTURE: Females united to unilaterally reduce endo/ectocervical disease; GSK: GlaxoSmithKline Biologicals, Rixensart, Belgium; ITT: intention to treat; Merck: Merck & Co., Inc., Whitehouse Station, NJ USA; MITT: modified intention to treat; NR: not reported; PATRICIA: Papilloma trial against cancer in young adults, CI: confidence interval. a 95% confidence intervals, except 97.9% confidence intervals used in PATRICIA. b A post-hoc analyses of PATRICIA including HPV -specific causal attribution in 3 CIN 2/3 cases with multiple HPV types generated efficacy estimates of 100%.
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Future options
Screening or triage by more accurate and less costly biomarkers (e.g., p16INK4a protein, DNA methylation markers) Prophylactic and therapeutic vaccine
Laura Koutsky, PhD Professor of Epidemiology University of Washington Seattle, WA, USA
<0.7
HPV: human papillomavirus; LSIL: low-grade squamous intraepithelial lesions; HSIL: high-grade squamous intraepithelial lesions.
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Epstein RJ Eur J Cancer. 2005 Nov;41(17):2595-600. Primary prevention of human papillomavirus-dependent neoplasia: no condom, no sex.
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