© The Author 2006. Published by Oxford University Press.
ARTICLE |
Human Papillomavirus Infection and Incidence of Squamous Cell and Basal Cell Carcinomas of the Skin
Affiliations of authors: Department of Community and Family Medicine, Center for Environmental Health Sciences, and the Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH (MRK, TAS, AA, JRR, LAM); Department of Environmental Health, Harvard School of Public Health, Boston, MA (HHN); Division of Genome Modifications and Carcinogenesis, Research Program Infection and Cancer, German Cancer Research Center, Heidelberg, Germany (PS, TW, MP); Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada (TAS); Queensland Institute of Medical Research, Brisbane, Australia (ACG); Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands (JNBB); Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH (AP); Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH (SS)
Correspondence to: Margaret R. Karagas, PhD, Dartmouth Medical School, 7927 Rubin, One Medical Center Drive, Lebanon, NH 03756 (e-mail: margaret.karagas{at}dartmouth.edu).
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ABSTRACT |
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Background: Although infection with human papillomaviruses (HPVs) is a major risk factor for several epithelial cancers, an etiologic relationship between HPV and keratinocyte cancers, such as squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs), remains unclear. Methods: In a population-based case–control study of 252 SCC case patients, 525 BCC case patients, and 461 control subjects, we used multiplex serology to detect antibodies in plasma samples against 16 HPV types from phylogenetic genera alpha, beta, and mu. Multiplex serology is a new method that is based on fluorescent bead technology and allows simultaneous detection of antibodies against up to 100 different in situ affinity-purified recombinant HPV proteins. Data on sun sensitivity, outdoor exposure, and other risk factors for keratinocyte cancers were collected through personal interviews. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated via unconditional logistic regression models. Results: Overall, we detected HPV antibodies more frequently in SCC patients than in control subjects (OR = 1.6, 95% CI = 1.2 to 2.3), but we found no difference in HPV seropositivity between BCC case patients and control subjects (OR = 0.8, 95% CI = 0.6 to 1.1). Among HPV types, seropositivity to HPV types in genus beta (OR = 1.5, 95% CI = 1.0 to 2.1), particularly HPV 5 (OR = 1.8, 95% CI = 1.0 to 3.1), was associated with SCC risk. Individuals with tumors on chronically sun exposed sites were more likely to be seropositive for beta HPV types than individuals with SCC at other anatomic sites. The highest SCC risk was associated with positivity for multiple HPV types and, among individuals seropositive for HPV beta, a tendency to sunburn; however, the associations had limited statistical precision. Conclusions: Our findings support a role for HPV types from the genus beta in the pathogenesis of SCC.
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INTRODUCTION |
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TopNotesAbstractIntroductionSubjects and methodsResultsDiscussionReferences |
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Human papilloma viruses (HPVs) are highly prevalent among human populations and are characterized into phylogenetic genera alpha, beta, gamma, mu, and nu (1). Although an oncogenic role of HPVs in the genus alpha (i.e., alpha HPVs), especially HPV 16, has been clearly established for a number of epithelial cancers, most notably cancer of the cervix (2), an etiologic relationship for HPVs with keratinocyte cancers, such as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) of the skin, remains unclear. Beta HPVs are suspected in the etiology of these cancers because of estimates that up to 90% of keratinocyte cancers from immunocompromised individuals [for review, see (3)] and up to 50% of those from immunocompetent individuals [for review, see (4,5)] contain DNA from cutaneous HPV types or beta HPVs. These cutaneous beta HPVs include HPV 5 and 8 and other HPV types that were first identified in patients with epidermodysplasia verruciformis, a rare autosomal disorder that is characterized by cutaneous warts and extreme susceptibility to early onset of keratinocyte cancers (3).
All HPVs contain genes for the viral proteins E6 and E7. Among alpha HPVs, in particular HPV 16 and 18, the E6 and E7 proteins have strong transforming potentials because they inactivate both the Rb and p53 proteins. However, the E6 and E7 proteins from beta HPVs have not been extensively characterized, but initial findings indicate that their transforming potential may be weaker (5). However, E6 protein from HPV 8, a beta HPV type, has been shown to inhibit DNA repair (6). In addition, E6 proteins of some beta HPVs have been shown to target and abrogate Bak, a cellular protein involved in signaling apoptosis in the skin in response to UV-B damage (7). Because beta HPVs infect skin epithelial cells, they may increase the risk of developing skin cancer by promoting cell division with a concomitant reduction in DNA repair and resistance to UV-induced apoptosis.
Initial serologic studies also provide compelling evidence that HPV was a potential etiologic factor in keratinocyte cancer (8–11). However, these studies were generally small and limited to a few HPV types. We therefore investigated 16 HPV types belonging to phylogenetic genera alpha, beta, and mu by use of multiplex serology (i.e., a method that allows the simultaneous detection of antibodies against many proteins) in a large ongoing population-based study of SCCs and BCCs in New Hampshire. In addition, we explored how sun exposure and sun sensitivity may interact with HPV in the etiology of keratinocyte cancers.
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SUBJECTS AND METHODS |
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Study Population
We established a population-based study of skin cancers through active surveillance of dermatologists and pathology laboratories throughout New Hampshire as described previously (12). We ascertained demographic and tumor information on all newly diagnosed skin cancer among residents of the state by reviewing medical records. We selected all case patients with invasive SCC and a two-to-one random sample of patients with BCC who were diagnosed between July 1, 1993, and June 30, 1995, among New Hampshire residents aged 25 to 74 years. As of March 1996, we had selected 1143 potential participants iagnosed with BCC or SCC. Among these potential participants, one patient was not contacted at the physician's request; 31 patients (3%) were reported as deceased by a household member or physician; 10 patients (1%) lived in households in which no one answered after 40 attempts to contact them by telephone, distributed over days, evenings, and weekends; 178 patients (16%) declined participation; and 27 patients (2%) were determined to be mentally incompetent or too ill to participate. Thus, we interviewed a total of 896 case patients, of whom 293 had been diagnosed with SCC and 603 had been diagnosed with BCC.
We identified control subjects from New Hampshire residents aged 25 to 74 years who were frequency matched on age (25–34, 35–44, 45–54, 55–64, 65–69, or 70–74 years) to the combined age distribution of the SCC and BCC case patients and on sex. We selected control subjects from lists of New Hampshire residents provided by the New Hampshire Department of Transportation (for those younger than 65 years old) and Centers for Medicare and Medicaid Services (for those 65 years and older). For the interview, each control subject was assigned a reference date that matched a case patient's diagnosis date. Of the 820 potential control subjects, 12 (2%) were reported as deceased by a member of the household; 12 (2%) were unreachable by telephone after 40 attempts distributed over days, evenings, and weekends; 228 (28%) declined participation; and 28 (3%) were determined to be mentally incompetent or too ill to participate. We thus interviewed 540 control subjects for the study.
Personal Interview
Participants provided written informed consent in accordance with the Committee for the Protection of Human Subjects at Dartmouth College, which approved the study. Study participants completed a personal interview by a trained interviewer, usually at their homes. Questions addressed sociodemographic information (level of education); lifestyle factors (e.g., cigarette smoking and use of alcohol); residential, occupational, medical, and family history; household exposures (e.g., type of drinking water); and sunlight-related factors. In particular, detailed information about sun exposure and skin sensitivity (i.e., tendency to sunburn) was collected. To estimate the amount of sun exposure, we used a modified version of the sun exposure questionnaire designed by Kricker et al. (13) for a population-based case–control study of nonmelanoma skin cancer from Australia. Subjects were sent a personal residence and work history calendar to complete before the interview. The calendar was used to identify periods of consistent outdoor activities, and then questions were asked about the amount of time spent outdoors during each of these periods (summer and rest of the year were estimated separately). Further, for each period of their life, subjects were asked about how many painful sunburns they had experienced (i.e., a sunburn that caused pain for 2 or more days).
Blood Collection
From all participants, we requested a venous blood sample of 20–30 mL in heparinized tubes. Blood was separated by centrifugation at 2500xg for 20 minutes at 4 °C. Plasma, red blood cells, and the buffy coat were stored separately at –80 °C until analysis. Each specimen was labeled with a type code (plasma, red blood cells, or buffy coat) and a unique identifier so that the staff was masked to the disease status associated with all samples.
Multiplex Serology
Frozen plasma samples from 252 SCC case patients, 525 BCC case patients, and 461 control subjects were analyzed for antibodies to the major capsid protein L1 of HPV types 1, 2, 3, 5, 6, 8, 9, 10, 15, 16, 20, 24, 32, 36, 38, and 57. We used multiplex serology, an antibody detection method that is based on a glutathione S-transferase capture enzyme-linked immunosorbent assay, as previously described (14,15), in combination with fluorescent bead technology (16). Briefly, full-length viral proteins fused with a N-terminal glutathione S-transferase domain and a C-terminal peptide derived from the large T antigen of simian virus 40 (14) were expressed in bacteria. Glutathione–casein (14) was coupled to internally fluorescence-labeled polystyrene beads (Luminex, Austin, TX), and glutathione S-transferase fusion proteins were affinity purified on the beads directly in a one-step procedure. Beads with glutathione S-transferase alone were prepared for background determination. Binding of the antigen (i.e., the glutathione S-transferase fusion proteins) to various beads was verified with a monoclonal antibody against the common C-terminal peptide (14). All antigens were expressed as glutathione S-transferase fusion proteins, and binding of all GST fusion proteins was verified with the monoclonal antibody against the common C-terminal peptide. The differently labeled beads carrying different antigens were then mixed and incubated in 96-well plates with human serum that had been diluted 1 : 100 in blocking buffer, as described previously (16). Antibodies bound to the beads via the viral antigens were then stained with biotinylated anti-human immunoglobulin and a fluorescent reporter conjugate streptavidin–R-phycoerythrin (Molecular Probes, Eugene, OR). Antibodies bound to antigens on beads were quantified in the Luminex analyzer, which also identified the internal bead color and thus the antigen carried by the bead. Antibody quantity was determined as the median R-phycoerythrin fluorescence intensity from at least 100 beads of the same internal color. Reactions with a median R-phycoerythrin fluorescence intensity of more than 400 U, after subtraction of background reactivity (glutathione S-transferase alone) were considered seropositive.
For quality control, serum from an HPV-positive human blood donor that contained antibodies against a subset of HPV antigens was also assayed on each 96-well plate. The positive reactions of this serum were used to estimate interplate variation (median coefficient of variation [CV] = 13.6%) and interday variation (median CV = 3.8%). As an additional quality control measure, a panel of 129 randomly selected sera from the study was tested twice on successive days (median CV = 6.6%). With this serum panel, 227 positive reactions to the 16 viral antigens were obtained on day 1 and 256 positive reactions were obtained on day 2. With one exception, the 33 discordant reactions were all close to the cutoff value; that is, the median R-phycoerythrin fluorescence intensity of the discordant negative reactions was 335 U, and the median R-phycoerythrin fluorescence intensity of the discordant positive reactions was 451 U.
Statistical Analysis
We first examined the association between HPV seropositivity (i.e., any type positive and, more specifically, any beta HPV type) and known skin cancer risk factors. These risk factors included age (as a continuous variable), sex, level of education (less than college, college, graduate, or professional school), cigarette smoking status at 1 year before the reference date (never smoker, former smoker, or current smoker), skin sensitivity as measured by skin reaction after 1 hour of sun exposure the first time in summer (severe sunburn with blistering or painful sunburn with peeling or mild sunburn with some tanning, or tanning with no sunburn), and the number of lifetime painful sunburns (none, one or two, three to nine, or 10 or more).
Unconditional logistic regression models were used to estimate the associations between HPV seropositivity (yes or no), number of types positive (none, one, or more than one), genus (alpha—HPV 2, 3, 6, 10, 16, 32, and 57; beta—HPV 5, 8, 9, 15, 20, 24, 36, and 38), or specific HPV types (including HPV 1 from genus mu) and the risk of SCC or BCC (17). The multivariable model included age, sex, and skin sensitivity. Ninety-eight percent of the study population reported being Caucasian; therefore, we did not adjust the analysis by race. In the analysis of keratinocyte cancer risks associated with beta HPV types, we compared risks in those who were seropositive for these types with those who were seronegative for them. We also calculated risks for those who were exclusively seropositive for a specific HPV type versus those who were seronegative for all HPV types.
We assessed the potential modifying effects of sunlight-related factors on the associations of beta HPV seropositivity (yes or no) and keratinocyte cancer risk by examining the effects of skin sensitivity (severe sunburn with blistering or painful sunburn with peeling, or mild sunburn with some tanning or tanning with no sunburn) and number of severe sunburns (none, one or two, three to nine, or 10 or more), according to HPV seropositivity. We also estimated the strata-specific odds ratios associated with genus beta seropositivity for these factors. In addition, we conducted a case–case analysis according to anatomic subsite as an indicator of chronic sun exposure. In this analysis, we compared HPV seroprevalence rates among those who had tumors exclusively on the head and neck with HPV seroprevalence rates among those who had tumors on other sites; as in the case–control analysis, we used unconditional logistic regression analysis with adjustment for age, sex, and skin sensitivity. Interactions with skin sensitivity, sunburns, and demographic factors (e.g., sex) were tested by the addition of an interaction term to the logistic regression model, and P values were derived with the log likelihood ratio test. All statistical tests were two-sided. All analyses were performed with the SAS statistical software package (version 9.1; SAS Institute, Cary, NC).
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RESULTS |
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TopNotesAbstractIntroductionSubjects and methodsResultsDiscussionReferences |
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Among control subjects, the rate of HPV seropositivity did not differ by age, level of education, smoking status, skin sensitivity, or number of sunburns (Table 1). A higher prevalence of HPV antibodies was observed in men than in women, and the difference was statistically significant for beta HPV types (28.2% in men versus 19.3% in women; P = .03).
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Overall, individuals who were seropositive for any HPV type had a statistically significant elevated risk of SCC (odds ratio [OR] = 1.6, 95% confidence interval [CI] = 1.2 to 2.3) but not in BCC (OR = 0.8, 95% CI = 0.6 to 1.1) compared with individuals who were seronegative for any HPV (Table 2). The overall risk of SCC was slightly higher among those who were seropositive for multiple HPV types (OR = 1.8, 95% CI = 1.3 to 2.7) than among those who were seropositive for a single HPV type (OR = 1.4, 95% CI = 1.0 to 2.1) (Table 2). The association with SCC was statistically significant for seropositivity to a beta HPV (OR = 1.5, 95% CI = 1.0 to 2.1) but not for seropositivity to an alpha HPV (OR = 1.2, 95% CI = 0.8 to 1.7) (Table 2). Results were similar when the analysis was restricted to those who were seropositive to just one HPV type (i.e., seropositive to a beta HPV versus seronegative for all HPV types, OR = 1.8, 95% CI = 0.9 to 3.4). We also investigated whether seropositivity to any individual HPV beta type was associated with SCC or BCC risk. We observed an elevated risk for SCC among individuals who were seropositive for HPV 5 (OR = 1.8, 95% CI = 1.0 to 3.1) or for HPV 20 (OR = 1.7, 95% = 0.9 to 3.0), compared with those who were seronegative for all beta HPV types, but the latter was not statistically significant (Table 3). We also found stronger associations with seropositivity for any beta HPV type and the risk of SCC among women (OR = 2.2, 95% CI = 1.3 to 3.9) than among men (OR = 1.4, 95% CI = 0.9 to 2.1), but the interaction was not statistically significant (P = .30). We found no association between seropositivity for any beta HPV type and BCC (Table 3). Further, we did not detect an association between HPV 1, the one mu HPV type that we examined, and risk of either BCC (OR = 0.9, 95% CI = 0.7 to 1.2) or SCC (OR = 1.3, 95% CI = 0.9 to 1.9).
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We next examined whether the association between seropositivity for any beta HPV type and risk of SCC varied by sunlight-related factors, such as anatomic site of the tumor, skin sensitivity, and number of sunburns. In the case–case analysis, individuals with SCC tumors on their head or neck were more likely to be seropositive for beta HPV types than individuals with SCC at other body sites (OR = 1.6, 95% CI = 0.9 to 3.0). The anatomic site difference was statistically significant for seropositivity to HPV 20 (case–case OR = 3.1, 95% CI = 1.0 to 9.6). There were no statistically significant differences between the alpha HPV types and SCC risk by anatomic site or between any HPV type and BCC risk by anatomic site (data not shown).
Finally, we examined the associations between SCC risk and skin sensitivity and history of sunburns according to beta HPV seropositivity (i.e., the main effects of these factors according to beta HPV seropositivity) and evaluated the relation between beta HPV seropositivity stratified in subgroups defined by these factors (i.e., the association between beta HPV seropositivity among those who experience a severe sunburn with blistering upon first exposure to the sun in summer for 1 hour or who had 10 or more painful sunburns in their lifetime). We found elevated risks for SCC associated with beta HPV seropositivity primarily among those with a more sun-sensitive phenotype (among those who got a painful sunburn with peeling, OR = 1.9, 95% CI = 1.0 to 3.8; and among those who got a severe burn with blistering, OR = 2.3, 95% CI = 0.7 to 7.7) (Table 4). SCC risk was also increased among those who reported having had 10 or more sunburns (e.g., for beta HPV seropositivity, OR = 1.7, 95% CI = 0.9 to 3.3) (Table 4). However, neither of the interactions (i.e., between skin sensitivity, beta HPV seropositivity, and SCC or between number of sunburns, beta HPV seropositivity, and SCC) was statistically significant.
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DISCUSSION |
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TopNotesAbstractIntroductionSubjects and methodsResultsDiscussionReferences |
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We used a recently developed multiplex serologic assay (16) to test for antibodies against 16 different HPV types in a population-based case–control study of SCC and BCC. We found that the risk of SCC but not that of BCC was associated with seropositivity to HPV. In particular, individuals who were seropositive for beta HPVs were at higher risk of developing SCC than those who were seronegative for beta HPVs. Moreover, individuals with SCC were more likely to test seropositive to multiple HPV types than were control subjects. Among the individual HPV types examined, SCC risk was specifically associated with HPV 5 and, to a lesser extent, with HPV 20. We had limited statistical power to detect an excess risk, especially for rarer HPV types, and we also cannot exclude the possibility of detecting associations due to chance because of multiple comparisons.
Our finding of an association specifically with the beta HPV types is not surprising, however. Infection with beta HPV types was first characterized in patients with epidermodysplasia verruciformis, who experience diminished cell-mediated immunity and predisposition to multiple, early-onset keratinocyte cancers, in which various beta HPV types were detected. Although several beta HPV types have been detected in these patients, HPV 5 and HPV 8 are the most common and appear to be present in up to 90% of the SCC tumors of these patients (3). Organ transplant recipients who receive immunosuppressive drugs to prevent allograft rejection also develop cutaneous warts, keratoacanthomas, and kertinocyte tumors (18). As with patients with epidermodysplasia verruciformis, approximately 90% of the SCC tumors from these patients contain beta HPV DNA (19–21). By contrast, among immunocompetent individuals, the percentage of tumors containing DNA from beta HPV types is lower but as yet poorly defined (5,21).
Our results generally are consistent with previous smaller clinic-based case–control investigations that have evaluated seropositivity to beta HPV types among immunocompetent individuals. The largest study to date tested serum samples from case patients with skin cancer and control subjects identified from regional hospital/clinics in The Netherlands (i.e., 161 SCC case patients, 454 BCC case patients, and 386 control subjects). Among seven HPV types investigated (HPV 5, 8, 15, 20, 24, 38, and 16), an increase in risk of SCC with several types was observed. The strongest associations with SCC were observed for HPV 8 and 38 (9), but an elevated risk of BCC associated with HPV 8 and 20 was also reported (9). Other small dermatology clinic–based investigations found an excess risk of SCC associated with HPV 8, with odds ratios of from 3 to 30 (8–11). One study (10) also evaluated HPV 15, 36, and 23 and found an approximately threefold increase in SCC risk associated with HPV 36. Another study described a higher prevalence of HPV 8 antibodies in BCC patients than in general population control subjects (11), but another study did not find this association (8). In our study, the overall association with SCC risk was strongest for HPV 5; the odds ratio for HPV 20 was of a similar magnitude to HPV 5, but it had a wider confidence interval. In light of the relatively low prevalence of some of individual HPV types, imprecise estimation of risk has been an issue for all prior studies of cutaneous HPVs and skin cancer, as well as this study, because of the limited sample size. Nonetheless, the data in aggregate do not indicate that a specific beta HPV type is consistently associated with skin cancer risk in immunocompetent individuals.
Much of our knowledge of the association between HPV and the risk of skin cancers has been obtained from skin tumors arising in renal transplant recipients. Among these patients, SCC tumors, in particular, have DNA from multiple beta HPV types (22). If the total number of HPV types present is a greater determinant of skin cancer risk than the specific type of HPV, then part of the inconsistencies in the current literature may thus be explained. We found evidence that a higher SCC risk was associated with seropositivity for more than one HPV type. However, much larger studies are needed to evaluate the nature of this association—that is, whether specific combinations of HPV types are associated with an increased risk.
Exposure to UV radiation is the major environmental risk factor for keratinocyte cancer, and there is biologic evidence that HPV E6 may modify the cellular response to UV exposure. We detected a stronger association between beta HPV seropositivity and risk of developing SCC on chronically sun exposed sites, such as the head and neck, than on other parts of the body, and the association was statistically significant for HPV 20. Also, an association between SCC and seropositivity to beta HPV types was observed among those with a sun-sensitive phenotype, compared with those who tan, and was stronger among those with a greater number of sunburns. Our epidemiologic results are consistent with results from in vitro studies that suggest the E6 protein from several cutaneous HPVs reduces DNA repair of UV-B damage by altering the G1-phase cell cycle checkpoint (23). In addition, the E6 protein from beta HPV types also modifies DNA repair by interacting with the single-strand break repair protein XRCC1 to reduce its repair activity (6). Tumors from patients with epidermodysplasia verruciformis also contain mutations in TP53 that are specific to UV exposure (24), which suggests that HPV may have a role in the UV-induced carcinogenic pathway. Skin carcinomas associated with HPV infection may also develop through a similar pathway—that is, through an interaction between the epidermodysplasia verruciformis–related types of HPV and UV radiation, i.e., by altering DNA repair activity (6,23,25). This mechanism differs from that used by the high-risk alpha HPV types associated with other malignancies, in which viral proteins directly inactivate critical tumor suppressor proteins. For skin cancer, HPV may thus operate more as a susceptibility factor that interacts with other exposures and host traits (e.g., DNA repair capacity) to increase disease risk. The possible modifying effects of UV radiation and individual susceptibility for HPV-related skin cancers require additional research.
Although we have identified an association between seropositivity to HPV and SCC risk, a direct causal link has yet to be established. Establishing this association for skin cancers is particularly challenging because, unlike the situation for cervical cancer, in which sampling of cervical mucosa is possible, obtaining comparable tissue from unaffected individuals is less apparent, i.e., precisely from where on the body surface should the sample be taken? For this reason, studies have attempted to use hair follicles from eyebrows, a known reservoir of HPV virus. In the two epidemiologic studies that have used this approach, an increased risk of SCC but not of BCC was associated with beta HPV DNA (26,27). Further investigations that incorporate measures of HPV DNA in hair follicle, skin, or tumor tissue samples, in addition to obtaining serologic data on HPV types, may provide a more complete understanding of the etiologic role of HPV in these keratinocyte cancers.
In conclusion, it is becoming increasingly evident that HPV acts as a carcinogen in malignancies other than cervical cancer. Keratinocyte cancers are by far the most common malignancies in the United States. Although generally not fatal, they carry appreciable morbidity and are a growing economic and health care burden on our population. Although sun exposure and sun sensitivity are the major risk factors for keratinocyte cancers (28), our data support a role of HPV, particularly beta HPVs, in the development of SCC.
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NOTES |
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The study was funded in part by grant CA57494 from the National Cancer Institute, National Institutes of Health (NIH), and grant QLK2-CT-2002–01179 from the European Community (EC). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or the EC.
The authors are indebted to the dermatologists comprising the New Hampshire Skin Cancer Study Group and to the study investigators and staff of the New Hampshire Health Study. We thank G. Orth and E. M. de Villiers for the gift of HPV plasmids.
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Manuscript received July 16, 2005; revised December 23, 2005; accepted January 24, 2006.
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J Natl Cancer Inst 2006 98: 1425-1426.
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