HPV: Sex, cancer and a virus
November 22, 2013 4:25 PM Subscribe
"On a sunny day in 1998, Maura Gillison was walking across the campus of Johns Hopkins University in Baltimore, Maryland, thinking about a virus. The young oncologist bumped into the director of the university's cancer centre, who asked politely about her work. Gillison described her discovery of early evidence that human papillomavirus (HPV) — a ubiquitous pathogen that infects nearly every human at some point in their lives — could be causing tens of thousands of cases of throat cancer each year in the United States. The senior doctor stared down at Gillison, not saying a word. “That was the first clue that what I was doing was interesting to others and had potential significance,” recalls Gillison."
Human papillomavirus is causing a new form of head and neck cancer— leaving researchers scrambling to understand risk factors, tests and treatments.
Case–Control Study of Human Papillomavirus and Oropharyngeal Cancer
BACKGROUND: Substantial molecular evidence suggests a role for human papillomavirus (HPV) in the pathogenesis of oropharyngeal squamous-cell carcinoma, but epidemiologic data have been inconsistent.
METHODS: We performed a hospital-based, case–control study of 100 patients with newly diagnosed oropharyngeal cancer and 200 control patients without cancer to evaluate associations between HPV infection and oropharyngeal cancer. Multivariate logistic-regression models were used for case–control comparisons.
RESULTS: A high lifetime number of vaginal-sex partners (26 or more) was associated with oropharyngeal cancer (odds ratio, 3.1; 95% confidence interval [CI], 1.5 to 6.5), as was a high lifetime number of oral-sex partners (6 or more) (odds ratio, 3.4; 95% CI, 1.3 to 8.8). The degree of association increased with the number of vaginal-sex and oral-sex partners (P values for trend, 0.002 and 0.009, respectively). Oropharyngeal cancer was significantly associated with oral HPV type 16 (HPV-16) infection (odds ratio, 14.6; 95% CI, 6.3 to 36.6), oral infection with any of 37 types of HPV (odds ratio, 12.3; 95% CI, 5.4 to 26.4), and seropositivity for the HPV-16 L1 capsid protein (odds ratio, 32.2; 95% CI, 14.6 to 71.3). HPV-16 DNA was detected in 72% (95% CI, 62 to 81) of 100 paraffin-embedded tumor specimens, and 64% of patients with cancer were seropositive for the HPV-16 oncoprotein E6, E7, or both. HPV-16 L1 seropositivity was highly associated with oropharyngeal cancer among subjects with a history of heavy tobacco and alcohol use (odds ratio, 19.4; 95% CI, 3.3 to 113.9) and among those without such a history (odds ratio, 33.6; 95% CI, 13.3 to 84.8). The association was similarly increased among subjects with oral HPV-16 infection, regardless of their tobacco and alcohol use. By contrast, tobacco and alcohol use increased the association with oropharyngeal cancer primarily among subjects without exposure to HPV-16.
CONCLUSIONS: Oral HPV infection is strongly associated with oropharyngeal cancer among subjects with or without the established risk factors of tobacco and alcohol use.
Evidence for a Causal Association Between Human Papillomavirus and a Subset of Head and Neck Cancers
Background: High-risk human papillomaviruses (HPVs) are etiologic agents for anogenital tract cancers and have been detected in head and neck squamous cell carcinomas (HNSCCs). We investigated, retrospectively, an etiologic role for HPVs in a large series of patients with HNSCC.
Methods: Tumor tissues from 253 patients with newly diagnosed or recurrent HNSCC were tested for the presence of HPV genome by use of polymerase chain reaction (PCR)-based assays, Southern blot hybridization, and in situ hybridization. The viral E6 coding region was sequenced to confirm the presence of tumor-specific viral isolates. Exons 5–9 of the TP53 gene were sequenced from 166 specimens. The hazard of death from HNSCC in patients with and without HPV-positive tumors was determined by proportional hazards regression analysis.
Results: HPV was detected in 62 (25%) of 253 cases (95% confidence interval [CI] = 19%–30%). High-risk, tumorigenic type HPV16 was identified in 90% of the HPV-positive tumors. HPV16 was localized specifically by in situ hybridization within the nuclei of cancer cells in preinvasive, invasive, and lymph node disease. Southern blot hybridization patterns were consistent with viral integration. Poor tumor grade (odds ratio [OR] = 2.4; 95% CI = 1.2– 4.9) and oropharyngeal site (OR = 6.2; 95% CI = 3.1–12.1) independently increased the probability of HPV presence. As compared with HPV-negative oropharyngeal cancers, HPV-positive oropharyngeal cancers were less likely to occur among moderate to heavy drinkers (OR = 0.17; 95% CI = 0.05–0.61) and smokers (OR = 0.16; 95% CI = 0.02–1.4), had a characteristic basaloid morphology (OR = 18.7; 95% CI = 2.1–167), were less likely to have TP53 mutations (OR = 0.06; 95% CI = 0.01–0.36), and had improved disease-specific survival (hazard ratio [HR] = 0.26; 95% CI = 0.07–0.98). After adjustment for the presence of lymph node disease (HR = 2.3; 95% CI = 1.4– 3.8), heavy alcohol consumption (HR = 2.6; 95% CI = 1.4–4.7), and age greater than 60 years old (HR = 1.4; 95% CI = 0.8–2.3), all patients with HPV-positive tumors had a 59% reduction in risk of death from cancer when compared with HPV-negative HNSCC patients (HR = 0.41; 95% CI = 0.20–0.88).
Conclusions: These data extend recent molecular and epidemiologic studies and strongly suggest that HPV-positive oropharyngeal cancers comprise a distinct molecular, clinical, and pathologic disease entity that is likely causally associated with HPV infection and that has a markedly improved prognosis.
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