Prospective study of human papillomavirus and risk of cervical adenocarcinoma

Human papillomaviruses (HPV) are established as a major cause of cervical carcinoma. However, causality inference is dependent on prospective evidence showing that exposure predicts risk for future disease. Such evidence is available for squamous cell carcinoma, but not for cervical adenocarcinoma. We followed a population‐based cohort of 994,120 women who participated in cytological screening in Sweden for a median of 6.7 years. Baseline smears from women who developed adenocarcinoma during follow‐up (118 women with in situ disease and 164 with invasive disease) and their individually matched controls (1,434 smears) were analyzed for HPV using PCR. Conditional logistic regression was used to estimate odds ratios (OR) of future adenocarcinoma with 95% confidence intervals (CI). Being positive for HPV 16 in the first cytologically normal smear was associated with increased risks for both future adenocarcinoma in situ (OR: 11.0, 95% CI: 2.6–46.8) and invasive adenocarcinoma (OR: 16.0, 95% CI: 3.8–66.7), compared to being negative for HPV 16. Similarly, an HPV 18 positive smear was associated with increased risks for adenocarcinoma in situ (OR: 26.0, 95% CI: 3.5–192) and invasive adenocarcinoma (OR: 28.0, 95% CI: 3.8–206), compared to an HPV 18 negative smear. Being positive for HPV 16/18 in 2 subsequent smears was associated with an infinite risk of both in situ and invasive adenocarcinoma. In conclusion, infections with HPV 16 and 18 are detectable up to at least 14 years before diagnosis of cervical adenocarcinoma. Our data provide prospective evidence that the association of HPV 16/18 with cervical adenocarcinoma is strong and causal.     

Regional distribution of human papillomavirus DNA and other risk factors for invasive cervical cancer in Panama

A population-based national cancer registry has documented strikingly different regional incidence rates of cervical cancer in the Republic of Panama. Such regional differences in disease rates could represent regional differences in the occurrence of risk factors, in particular, human genital papillomaviruses (HPV). This study enrolled newly diagnosed invasive cancer patients in the Republic of Panama over an 18-mo period. Behavioral risk factors were measured by interviewing cases and matched controls. In addition, DNA extracted from biopsies of the cancers was tested for HPV sequences. Early age at first coitus, multiple pregnancies, and nonparticipation in Pap smear screening programs were significant risk factors for cervical cancer in this population. These factors and low levels of education occurred more frequently among women residing in regions with higher cancer rates than women residing in the region with lower cancer rates. HPV DNA was detected most frequently (70%) among cases from the region with the lowest cancer rate (30 of 100,000) and least frequent (54%) among cases where the cancer rate was the highest (51 of 100,000). The observations suggest that risk factors other than HPV contribute to the differences in cervical cancer rates among women residing in various regions of Panama.     

Human papillomavirus infection and other risk factors for cervical neoplasia: a case-control study

A case control design has been used to investigate risk factors associated with the development of cervical squamous intraepithelial lesions (SIL) in a population of urban women in which non-affluent minority groups were heavily represented. Eighty-five women with histologically confirmed SIL were compared to a control group of 70 cytologically normal women. HPV infection was determined using both Southern blot hybridization and polymerase chain reaction (PCR) amplification specific for HPV types 16, 18, and 33. When Southern blot was used to detect HPV, logistic regression analysis identified HPV infection (odds ratio (OR) = 17.9, 95% confidence interval (CI) = 6.2-51.6) and low educational achievement (OR = 3.4, 95% CI = 1.2-10.1) as major independent risk factors. When PCR was employed to detect HPV, the logistic regression model suggested that HPV infection (OR = 10.4, 95% CI = 3.6-30.4) and Hispanic ethnicity (OR = 5.0, 95% CI = 1.2-20.5) represented independent risk factors; low educational achievement and Black ethnicity were risk factors of borderline significance. PCR detection of simultaneous co-infection with more than one HPV type was associated with a very high risk of SIL (OR for one type = 7.2, 95% CI = 2.4-21.9; OR for greater than I type = 43.0, 95% CI = 6.9-266.6). Furthermore, increased viral load determined by either method carried an increased risk of disease. HPV infection with viral types previously reported to be related to neoplastic or dysplastic lesions carried the highest risk of SIL. The association of HPV detected by Southern blot and SIL in women less than 35 years old had an OR of 10.1, whereas in women greater than or equal to 35 the OR was 74.5 (p = 0.09 for homogeneity of ORs). We conclude that infection with HPV is the major risk factor for cervical SIL and suggest that targeted HPV screening of women over age 35 may represent an innovative strategy to detect women at high risk of cervical neoplasia.     

Human papillomavirus,Chlamydia trachomatis, and other risk factors associated with cervical cancer in China

Background High prevalences of human papillomavirus (HPV) andChlamydia trachomatis infections, and their association with cervical cancer, have been reported in some parts of China. Other factors, including pregnancy and smoking, are reported to be associated with cervical cancer worldwide. Methods To determine significant risk factors for cervical cancer, we performed a case-control study in 43 women with cervical cancer and 370 women with normal findings from cervical cytologic analysis (controls), in the northeast of China. Scraped cervical cell samples were collected for examination of HPV andC. trachomatis DNA, using a polymerase chain reaction-based method for detection of low cancer risk and high cancer risk HPVs. Results Thirty-four of 370 controls, and 30 of 43 women with cervical cancer, were positive for HPV. None of the low-cancer risk HPV types were detected; HPV 16 was the predominant type in cervical cancers. The prevalence of HPV infection between pregnant and nonpregnant women did not differ, nor did it change over the course of pregnancy. The prevalence ofC. trachomatis infection was higher in HPV-positive than in HPV-negative control women, however, it did not differ between women with cervical cancer and the control group. Multivariate logistic analysis showed that neitherC. trachomatis infection, age at marriage, length of marriage, pregnancy, nor smoking were associated with cervical cancer. Conclusion Infection with HPV 16, 31, 33, or 58 was a significant risk determinant for cervical cancer, whereasC. trachomatis infection and other factors did not increase the risk of cervical cancer.     

Human papillomavirus infection and other risk factors for cervical intraepithelial neoplasia in Japan.

Various risk factors were investigated in 167 cervical intra-epithelial neoplasia (CIN) case and control pairs in Japan. CIN cases showed evidence of nine known risk factors including smoking and sexual behaviour. However, after adjustment for papillomavirus infection, the highest determinant, the only remaining risk factors were: being married, early age at first pregnancy and multiparity.     

Human papillomavirus and risk factors for cervical cancer in Chennai,India: a case-control study

To evaluate the role of human papillomavirus (HPV) and other risk factors in the aetiology of invasive cervical carcinoma (ICC), we conducted a hospital-based case-control study in Chennai, Southern India. A total of 205 ICC cases (including 12 adenocarcinomas) and 213 frequency age-matched control women were included. HPV DNA in cervical cells was evaluated by means of a polymerase chain-reaction assay. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were computed by means of unconditional multiple logistic regression models. HPV infection was detected in all but one ICC cases and in 27.7% of control women (OR = 498). Twenty-three different HPV types were found. HPV 16 was the most common type in either cases or controls, followed by HPV 18 and 33. The association of ICC with HPV 18 and HPV 16-associated types was somewhat stronger than the one with HPV 16. Multiple HPV infections did not show a higher OR for ICC than single infections. Other than HPV infection, high parity (OR for >4 vs. /=45 years = 4.2) were significantly associated with ICC, also after restricting the analysis to HPV-positive cases and controls. Poor hygienic conditions were associated with an increased risk of HPV infection among control women but not with ICC risk among HPV-positive women. A vaccine against HPV 16 and 18 may be effective in more than three-quarters of ICC in the study area.     

Asian-American variants of human papillomavirus 16 and risk for cervical cancer: a case-control study

BACKGROUND: Human papillomavirus 16 (HPV16) has a number of variants, each with a different geographic distribution and some that are associated more often with invasive neoplasias. We investigated whether the high incidence of cervical cancer in Mexico (50 cases per 100 000 women) may be associated with a high prevalence of oncogenic HPV16 variants. METHODS: Cervical samples were collected from 181 case patients with cervical cancer and from 181 age-matched control subjects, all from Mexico City. HPV16 was detected with an E6/E7 gene-specific polymerase chain reaction, and variant HPV classes and subclasses were identified by sequencing regions of the E6 and L1/MY genes. Clinical data and data on tumor characteristics were also collected. All statistical tests were two-sided. RESULTS: HPV16 was detected in cervical scrapes from 50.8% (92 of 181) of case patients and from 11% (20 of 181) of control subjects. All HPV16-positive samples, except one, contained European (E) or Asian-American (AA) variants. AA and E variants were found statistically significantly more often in case patients (AA = 23.2% [42 of 181]; E = 27.1% [49 of 181]) than in control subjects (AA = 1.1% [two of 181]; E = 10% [18 of 181]) (P<.001 for case versus control subjects for either E or AA variants, chi2 test). However, the frequency of AA variants was 21 times higher in cancer patients than in control subjects, whereas that ratio for E variants was only 2.7 (P =.006, chi2 test). The odds ratio (OR) for cervical cancer associated with AA variants (OR = 27.0; 95% confidence interval [CI] = 6.4 to 113.7) was higher than that associated with E variants (OR = 3.4; 95% CI = 1.9 to 6.0). AA-positive case patients (46.2 +/- 12.5 years [mean +/- standard deviation]) were 7.7 years younger than E-positive case patients (53.9 +/- 12.2 years) (P =.004, Student's t test). AA variants were associated with squamous cell carcinomas and adenocarcinomas, but E variants were associated with only squamous cell carcinomas (P =.014, Fisher's exact test). CONCLUSIONS: The high frequency of HPV16 AA variants, which appear to be more oncogenic than E variants, might contribute to the high incidence of cervical cancer in Mexico.     

The association of human papillomavirus antibodies with cervical cancer risk.

The association between viral human papillomavirus (HPV) DNA and cervical carcinoma has been well documented. However, less is known about the immune response to HPV infections and its relationship to cervical cancer risk. A higher prevalence of antibodies to HPV16 E7 among women with cervical cancer compared with controls has been reported, but reactivity to other antigens has not been systematically examined. Prevalence of serum IgG antibody reactivities to HPV6-encoded L1 and L2 and to HPV16- and HPV18-encoded E2, E4, E6, E7, L1, and L2 bacterial fusion proteins in a Western immunoblot assay were measured among cases with invasive cervical cancer (n = 69) and control women (n = 81). The intensities of the Western blot bands were graded as +1, +2, or +3 (0 = negative). Antibodies to HPV6 L1 and L2, HPV16 E7 and L2, and HPV18 L2 fusion proteins were observed among 39-62% of cases and 33-71% of controls. After systematic sampling for antibody reactivity to this range of fusion proteins, the sample was expanded to include 150 cases and 145 controls tested exclusively for reaction to HPV6 L1 and L2, HPV16 E7, and HPV16 and HPV18 L2. Relative risk was estimated for > or = +1, +1, and > or = +2 levels of reactivity after adjustment for confounding factors. Except for HPV16 E7, reactivity at the > or = +1 level did not distinguish cases from controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prospective study on metabolic factors and risk of prostate cancer

BACKGROUND:

There are inconsistent data regarding the association between metabolic factors, separately and combined, and the risk of prostate cancer and death from prostate cancer.

METHODS:

In the Metabolic Syndrome and Cancer Project (Me‐Can), data on body mass index (BMI); blood pressure; and blood levels of glucose, cholesterol, and triglycerides were collected for 289,866 men. Cox proportional hazard models were used to calculate relative risks (RRs) by exposures in quintiles as well as for z scores (with a mean of 0 and a standard deviation of 1) together with a composite sum of scores to assess the combined effect of metabolic factors. RRs were corrected for random errors in measurement.

RESULTS:

During a mean follow‐up of 12 years, 6673 men were diagnosed with prostate cancer and 961 died of the disease. Men with high levels of glucose and triglycerides were found to have a decreased risk of prostate cancer: top versus bottom quintile of glucose: RR, 0.82 (95% confidence interval [95% CI], 0.62‐1.08; P value for trend = .03) and top versus bottom quintile of triglycerides: RR, 0.88 (95% CI, 0.74‐1.04; P value for trend = .001). High BMI, elevated blood pressure, and a high composite z score were found to be associated with an increased risk of death from prostate cancer: top versus bottom quintile of BMI: RR, 1.36 (95% CI, 1.08‐1.71); systolic blood pressure: RR, 1.62 (95% CI, 1.07‐2.45); and per 1‐unit increase of the composite z score: RR, 1.13 (95% CI, 1.03‐1.25).

CONCLUSIONS:

The authors found no evidence of an association between high levels of metabolic factors and the risk of prostate cancer, but high BMI, elevated blood pressure, and a composite score of all metabolic factors were associated with an increased risk of death from prostate cancer. Cancer 2012. © 2012 American Cancer Society.     

Differences in the risk of cervical cancer and human papillomavirus infection by education level

Background:

Cervical cancer risk is associated with low education even in an unscreened population, but it is not clear whether human papillomavirus (HPV) infection follows the same pattern.

Methods:

Two large multicentric studies (case–control studies of cervical cancer and HPV prevalence survey) including nearly 20 000 women. GP5+/GP6+ PCR was used to detect HPV.

Results:

Education level was consistently associated with cervical cancer risk (odds ratio (OR) for 0 and >5 years vs 1–5 years=1.50, 95% confidence interval (CI): 1.25–1.80 and 0.69, 95% CI: 0.57–0.82, respectively, P for trend <0.0001). In contrast, no association emerged between education level and HPV infection in either of the two IARC studies. A majority of the women studied had never had a Pap smear. The association between low education level and cervical cancer was most strongly attenuated by adjustment for age at first sexual intercourse and first pregnancy. Parity and screening history (but not lifetime number of sexual partners, husband''s extramarital sexual relationships, and smoking) also seemed to be important confounding factors.

Conclusion:

The excess of cervical cancer found in women with a low socio-economic status seems, therefore, not to be explained by a concomitant excess of HPV prevalence, but rather by early events in a woman''s sexually active life that may modify the cancer-causing potential of HPV infection.     

人乳头瘤病毒检测阴性子宫颈癌的研究进展

子宫颈癌是妇科最常见的恶性肿瘤,研究证实99.7%的宫颈癌是因感染人乳头瘤病毒（human papillomavirus,HPV）造成的,但几乎所有的研究中都发现有HPV检测阴性的子宫颈癌存在。HPV检测阴性的子宫颈癌可以概括为假阴性和真阴性两种情况,造成假阴性的原因有病变小、取材有限、病毒载量低、非高危人乳头瘤病毒基因型、技术错误或检测灵敏度不足等。现有的筛查方式具有一定局限性,一些具有高灵敏度和特异性的新型分子标记物如微小核糖核酸、FAM19A4基因甲基化等已被证明有望作为子宫颈癌早期检测和诊断的指标。近年来关于HPV阴性子宫颈癌的研究越来越多,但对HPV阴性子宫颈癌患者临床特点的分析存在差异。本文主要对HPV阴性子宫颈癌假阴性的原因、筛查诊断及临床特点方面进行综述。     

Association of human papillomavirus type 58 variant with the risk of cervical cancer

Human papillomavirus (HPV) type 58 has been found to be prevalent among Chinese patients with cervical cancer. This study examined the oncogenic risk of HPV58 variants in Hong Kong, a southern part of China. Altogether, 1924 women were studied: 42.8% with a normal cervix, 16.2% with cervical intraepithelial neoplasia (CIN) I, 12.7% with CIN II, 20.8% with CIN III, and 7.6% with invasive cervical cancer (ICC). The overall prevalence of HPV58 was 11.4% (220) and increased statistically significantly with the severity of neoplasia (P(trend)<.001, chi(2) test for trend). Among HPV58-positive women, the occurrence of E7 632C-->T (T20I) and E7 760G-->A (G63S) variants (T20I/G63S) showed a positive trend of association with the severity of neoplasia (P(trend)<.001, chi(2) test for trend). HPV58 variants carrying these two substitutions showed an odds ratio (OR) for ICC of 26.79 (95% confidence interval = 10.14 to 74.72), and this OR was 6.9-fold higher than the ORs of variants without these substitutions. Patients with CIN III or ICC who were also infected with T20I/G63S variants had a statistically significant younger age at diagnosis than those infected with other variants (median age = 37 years versus 48 years; P =.038, two-sided Mann-Whitney U test). Thus, HPV58 variants carrying E7 T20I/G63S substitutions may be associated with an increased risk for cervical cancer.     

Genetic variations in human papillomavirus and cervical cancer outcomes

Cervical cancer is driven by persistent infection of human papillomavirus (HPV), which is influenced by HPV type and intratypic variants, yet the impact of HPV type and intratypic variants on patient outcomes is far less understood. Here, we examined the association of cervical cancer stage and survival with HPV type, clade, lineage, and intratypic variants within the HPV E6 locus. Of 1,028 HPV-positive cases recruited through the CerGE study, 301 were in-situ and 727 were invasive cervical cancer (ICC), with an average post-diagnosis follow-up of 4.8 years. HPV sequencing was performed using tumor-isolated DNA to assign HPV type, HPV 16 lineage, clade, and intratypic variants within the HPV 16 E6 locus, of which nonsynonomous variants were functionally annotated by molecular modeling. HPV 18-related types were more prevalent in ICC compared to in-situ disease and associated with significantly worse recurrence-free survival (RFS) compared to HPV 16-related types. The HPV 16 Asian American lineage D3 and Asian lineage A4 associated more frequently with ICC than with in situ disease and women with an intratypic HPV 16 lineage B exhibited a trend toward worse RFS than those with A, C, or D lineages. Participants with intratypic E6 variants predicted to stabilize the E6–E6AP–p53 complex had worse RFS. Variants within the highly immunogenic HPV 16 E6 region (E14–I34) were enriched in ICC compared to in-situ lesions but were not associated with survival. Collectively, our results suggest that cervical cancer outcome is associated with HPV variants that affect virus-host interactions.     

Prevalence of human papillomavirus in cervical cancer: a multicenter study in China

A large-scale epidemiologic survey on the prevalence of different types of human papillomavirus (HPV) in cervical cancer in China is indicated because of the implications for the development of diagnostic probes and vaccines against cervical cancer. A total of 809 cervical cancer specimens were collected from 5 regions in China including Shanghai, Guangzhou, Sichuan, Beijing and Hong Kong. HPV DNA was detected in 83.7% of the specimens. HPV-16 was present in 79.6%, HPV-18 in 7.5%, HPV-52 in 2.6% and HPV-58 in 3.8% of all HPV-positive specimens. The prevalences of HPV-16 and HPV-18 in Hong Kong were 61.7 and 14.8%, respectively, representing a lower HPV-16 and a higher HPV-18 proportion compared with the other regions. HPV-16 remained the most common HPV infection in both squamous cell carcinoma (SCC) and adenocarcinoma (AC). The proportion of HPV-18 infection was significantly higher in AC than in SCC.     

Viral characteristics of human papillomavirus infection and antioxidant levels as risk factors for cervical dysplasia

Genital human papillomavirus (HPV) infection is the major causal factor of cervical intraepithelial neoplasia (CIN). The potential role of nutrition as an additional, independent risk factor for CIN has not been appropriately addressed in the context of HPV. This case-control study evaluated the etiologic role of HPV in terms of viral type and load and examined the association between CIN and plasma levels of micronutrients adjusting for HPV. Cases (n = 378) with histo-pathologically confirmed CIN and controls (n = 366) with no history of abnormal Pap smears were recruited from colposcopy and gynecology clinics, respectively. Risk of CIN was significantly increased among women who were infected with multiple HPV types (odds ratio [OR] = 21.06), a high viral load (OR = 13.08) and HPV 16 (OR = 62.49). After adjusting for HPV positivity and demographic factors, there was an inverse correlation between plasma α-tocopherol and risk of CIN (OR = 0.15). Plasma ascorbic acid was protective at a high level of ≥ 0.803 mg/ dl (OR = 0.46). CIN was not associated with plasma retinol and β-carotene levels. The effect of genital HPV infection on CIN development is highly influenced by oncogenic viral type and high viral load. Vitamins C and E may play an independent protective role in development of CIN that needs to be confirmed in prospective studies. Int. J. Cancer 78:594–599, 1998. © 1998 Wiley-Liss, Inc.     

HPV在宫颈癌发病中的作用机制研究

宫颈癌是多因素协同作用引发的疾病,人乳头瘤病毒(HPV)在宫颈癌发病中起重要作用.现从流行病学、分子生物学、免疫学等方面对HPV在宫颈癌发病中的作用机制作一综述.     

Long-term risk of recurrent cervical human papillomavirus infection and precancer and cancer following excisional treatment

Risk of recurrent CIN2+ (including cervical intraepithelial neoplasia grade 2 [CIN2], CIN3, carcinoma and in situ, adenocarcinoma in situ or cancer) remains elevated for years following treatment. The role of long-term post-treatment human papillomavirus (HPV) presence on subsequent risk of CIN2+ was evaluated in the 10,049-women Guanacaste cohort. Six hundred eighty-one women were referred to colposcopy because of high-grade cytology, positive cervicography and/or suspicion of cancer based on visual assessment; 486 were judged to require treatment. After excluding women with <12 months of follow-up (N = 88), prior cancer or hysterectomy (N = 37) or other reasons (N = 14), 347 were included in the analysis. Infections were categorized as persistent if present at both pre- and post-treatment visits and new if detected only post-treatment. Median time between the treatment and post-treatment visits was 6.7 years (interquartile range 3.8-7.8). At the post-treatment visit, 8 (2.4%), 2 (0.6%) and 8 (2.4%) of the 347 treated women had persistent HPV16, HPV18 or other carcinogenic HPV, respectively. Two (0.8%), 3 (1.0%) and 13 (4.0%) had new HPV16, HPV18 and other carcinogenic HPV, respectively. Six CIN2+ cases were identified at the post-treatment visit, all with persistent infections (three HPV16, one HPV18 and two other carcinogenic HPV). No recurrent disease was observed among women with new HPV infections during the follow-up period. Thus, persistence of HPV infection a median of six years after treatment was uncommon but, when present, posed a substantial risk of subsequent CIN2+. Serial follow-up data from other studies would further strengthen these conclusions.