Human Papillomavirus Concordance Between Parents and Their Newborn Offspring: Results From the Finnish Family Human Papillomavirus Study.

BACKGROUND: The knowledge on vertical human papillomavirus (HPV) transmission is limited. We aimed to determine whether HPV transmission from parents to their offspring occurs before or during birth. METHODS: Altogether, 321 mothers, 134 fathers, and their 321 newborn offspring from the Finnish Family HPV study cohort were included. Parents' genital and oral brush samples and semen samples were collected for HPV testing at baseline (36 weeks of pregnancy). Oral, genital, and umbilical samples from the newborn and placenta samples were collected for HPV testing immediately after delivery. HPV risk for the newborn was calculated from the mother's and father's HPV status by using logistic regression analyses. RESULTS: Concordances between mothers' and their newborns' HPV genotype at any site were statistically significant with HPV-6, -16, -18, -31, and -56; odds ratios (ORs) ranged from 3.41 (95% confidence interval [CI], 1.80-6.48) for HPV-16 to 634 (95% CI, 28.5-14 087) for HPV-31. Father-newborn HPV concordance was statistically significant with HPV-6 and HPV-31 (ORs, 4.89 [95% CI, 1.09-21.9] and 65.0 [95% CI, 2.92-1448], respectively). CONCLUSIONS: The genotype-specific HPV concordance between parents and their newborn is suggestive for vertical HPV transmission. However, transmission from the father to the newborn remains more uncertain.

HLA-G Alleles Impact the Perinatal Father-Child HPV Transmission.

The host factors that influence father-to-child human papillomavirus (HPV) transmission remain unknown. This study evaluated whether human leukocyte antigen (HLA)-G alleles are important in father-to-child HPV transmission during the perinatal period. Altogether, 134 father-newborn pairs from the Finnish Family HPV Study were included. Oral, semen and urethral samples from the fathers were collected before the delivery, and oral samples were collected from their offspring at delivery and postpartum on day 3 and during 1-, 2- and 6-month follow-up visits. HLA-G alleles were tested by direct sequencing. Unconditional logistic regression was used to determine the association of the father-child HLA-G allele and genotype concordance with the father-child HPV prevalence and concordance at birth and during follow-up. HLA-G allele G*01:01:03 concordance was associated with the father's urethral and child's oral high-risk (HR)-HPV concordance at birth (OR 17.00, 95% CI: 1.24-232.22). HLA-G allele G*01:04:01 concordance increased the father's oral and child's postpartum oral any- and HR-HPV concordance with an OR value of 7.50 (95% CI: 1.47-38.16) and OR value of 7.78 (95% CI: 1.38-43.85), respectively. There was no association between different HLA-G genotypes and HPV concordance among the father-child pairs at birth or postpartum. To conclude, the HLA-G allele concordance appears to impact the HPV transmission between the father and his offspring.

The association of HLA-G polymorphism with oral and genital HPV infection in men.

The host genetic factors that influence the natural history of human papillomavirus (HPV) infection in men are not well known. Our aim was to evaluate the role of human leukocyte antigen (HLA)-G polymorphism in oral and genital HPV infection in men. Altogether, 130 men from the Finnish Family HPV Study, with a 6-year follow-up, were included in the analyses. HLA-G alleles were tested by direct sequencing. Oral, urethral, and semen samples were collected and analyzed for 24 different HPV genotypes. Unconditional logistic regression was used to determine associations between HLA-G alleles and genotypes with HPV infection and its outcomes. Overall, eight different HLA-G alleles were identified with 15 different HLA-G genotype combinations. The most common HLA-G allele among the men was G*01:01:01 (86.2%, n = 112) followed by G*01:01:02 (36.2%, n = 47). Allele G*01:01:02 showed to be protective against any- and high-risk (HR) oral HPV (OR range of 0.20-0.24, 95% CI range of 0.06-0.85). Men having allele G*01:01:01 showed a reduced risk for incident (OR 0.30, 95% CI 0.11-0.84) and persistent (OR 0.24, 95% CI 0.08-0.69) oral infections. Allele G*01:01:03 was associated with increased risk for urethral HR-HPV infections (OR 4.94, 95% CI 1.34-18.27). Among self-reported demographic data, genotype G*01:01:01/01:01:03 was associated with an increased risk for oral warts (OR 8.00, 95% CI 1.23-51.89) and allele G*01:03:01 increased the risk of pollen and/or animal allergy (OR 13.59, 95% CI 1.57-117.25). To conclude, HLA-G polymorphism in men largely impacts the outcome of an oral HPV infection and seems to associate with self-reported allergies.

Human papillomavirus 16 E2-, E6- and E7-specific T-cell responses in children and their mothers who developed incident cervical intraepithelial neoplasia during a 14-year follow-up of the Finnish Family HPV cohort.

BACKGROUND: Human papillomavirus (HPV) infection has traditionally been regarded as a sexually transmitted disease (STD), but recent evidence implicates that an infected mother can transmit HPV to her newborn during pregnancy, at delivery, perinatal period or later. Given the lack of any studies on HPV-specific immune responses in children, we conducted HPV16-specific cell-mediated immune (CMI) monitoring of the mother-child pairs with known oral and genital HPV follow-up (FU) data since the delivery. In the Finnish Family HPV Study, 10 out of 331 mothers developed incident cervical intraepithelial neoplasia (CIN) during their 14-year FU. Our hypothesis according to the common dogma is that there is no HPV16 specific immune response in offspring of the CIN mother as she/he has not started the sexual life yet. METHODS: We used overlapping 30-35 mer peptides covering the entire HPV16 E2, E6 and E7 protein sequences. Assays for lymphocyte proliferation capacity, cytokine production and HPV16-specific Foxp3 + CD25 + CD4+ regulatory T-cells were performed. RESULTS: HPV16-specific proliferative T-cell responses were broader in children than in their mothers. Nine of 10 children had responses against both E2 peptide pools compared to only 4 of the 10 mothers. Six of the 10 children and only 2 mothers displayed reactivity to E6 and/or E7. The cytokine levels of IL-2 (p = 0.023) and IL-5 (p = 0.028) induced by all peptide pools, were also higher among children than their mothers. The children of the mothers with incident CIN3 had significantly higher IFN-γ (p = 0.032) and TNF-α (p = 0.008) levels than other children. CONCLUSIONS: Our study is the first to show that also children could have HPV-specific immunity. These data indicate that the children have circulating HPV16-specific memory T-cells which might have been induced by previous HPV16 exposure or ongoing HPV 16 infection.

High-risk human papillomavirus associated with incident cervical intraepithelial neoplasia developing in mothers in the Finnish Family HPV Study cohort.

BACKGROUND: Cofactors of high-risk (HR) human papillomavirus (HPV) in the progression of cervical intraepithelial neoplasia (CIN) are incompletely characterized. In this study these cofactors were investigated in a longitudinal setting. METHODS: A cohort of 329 women (mean age 25.5 y) were enrolled in the Finnish Family HPV Study, and followed-up for 6 y with serial cervical samples for HPV genotyping, virus integration status, and HPV serology. Hospital records were reviewed until March 2010 and linked with HPV detection data. All incident CIN lesions were subjected to HPV genotyping. HPV covariates were studied in an age- and HPV-matched nested case-control (1:4) setting. RESULTS: Twelve of the 329 women developed an incident CIN: 2 CIN1, 3 CIN2, and 7 CIN3. HPV16 was detected most frequently (7/12), followed by HPV58 (2/12), HPV18, HPV31, and HPV42. HPV integration was present in 4/12 cases. Long-lasting persistence of HPV31 and HPV16 preceded incident CIN2 and CIN3. In multivariate conditional logistic regression, the risk for incident CIN increased up to 4-fold with increasing number of deliveries (p = 0.024) and decreased with history of genital warts (p = 0.036). CONCLUSION: Baseline HR-HPV infections and their persistence precede incident CIN by several years. The 2 independent covariates of HR-HPV were (1) number of deliveries (increasing the risk), and (2) history of genital warts (protective effect).

Incident cervical infections with high- and low-risk human papillomavirus (HPV) infections among mothers in the prospective Finnish Family HPV Study.

BACKGROUND: The knowledge on type specificity and factors that increase or decrease the risk of incident HPV-infections is important to better understand the dynamics of HPV-infections. METHODS: A series of 329 pregnant women were enrolled in Finnish Family HPV Study at 3rd trimester of pregnancy and followed-up for 6 years, during which 203 baseline HPV-negative women acquired incident HPV infection. Incidence times and incidence rates (IR) were calculated for 24 low-and high-risk HPV-types detected by Multiplex-HPV-genotyping at each visit. Poison regression was used to estimate predictors of incident HPV infections of species 7 and 9 HPV-genotypes. RESULTS: HPV16 was the most frequent (47.8%) incident genotype followed by multiple-type infections (25.1%), and single infection with HPV18, 70, 6 and 45. Actuarial mean times to incident event were longest for HPV31 (34.5 months) and HPV45 (32.8 months), while crude mean times were longest for HPV56 (42.4 months) and HPV16 (23.1 months). Actuarial IR was highest for HPV16 and multiple-type infections. Independent protective factors against incident infections were 1) > 2 life-time sexual partners (p = 0.014), 2) later initiation of oral contraceptives (age > 20 years) (p = 0.017) and 3) pregnancy at FU visit (p = 0.0001). CONCLUSIONS: Among newly delivered mothers, higher number of life-time sexual partners, initiation of OC use after age 20 and becoming pregnant during FU decreased the risk for incident species 7/9 HPV infections.

Human papillomavirus and predictors of cervical intraepithelial neoplasia among young mothers in a prospective follow-up study.

OBJECTIVE: To study the incidence times and rates for cervical intraepithelial neoplasia (CIN) and its predictors. MATERIAL AND METHODS: This is a prospective follow-up study at Turku University Hospital, Finland. The Finnish Family human papillomavirus (HPV) study comprised 329 pregnant women followed up for 3 years. In an extension of the follow-up period, 171 women participated in an additional 3 years follow-up. Cervical scrapings for HPV testing and cervical smears were collected at each follow-up visit (2, 12, 24 and 36 months and 6 years). Following two abnormal cervical smears, colposcopy with biopsies was done. The main outcome measures were actuarial and crude incidence times, incidence rates and predictors of incident CIN. RESULTS: During the follow-up period, 10 women (3.2%) developed biopsy-confirmed CIN, and four presented with incident atypical squamous cells suggesting high-grade squamous intraepithelial lesion cytology. The CIN/squamous intraepithelial lesion developed in 74.5 and 66.3 months, with crude incidence rates of 13.4/1,000 and 15.1/1,000 women months at risk, respectively. In multivariate Poisson regression, independent predictors of incident CIN were as follows: high-risk HPV positive at baseline (incidence rate ratio = 5.54; 95% confidence interval 1.02-30.14, p= 0.048); type-specific high-risk HPV persistence during follow-up (incidence rate ratio = 5.84; 95% confidence interval 2.28-17.93, p= 0.0001); cervical smear cytologically diagnosed for atypical squamous cells of undetermined significance or worse at any follow-up visit (incidence rate ratio = 4.56; 95% confidence interval 2.37-8.78, p= 0.0001); and new sexual partner during follow-up (incidence rate ratio = 9.45; 95% confidence interval 1.90-46.97, p= 0.006). CONCLUSION: The results indicate that combined use of cervical smear and HPV testing, with prompt referral to colposcopy, enables accurate detection of incident CIN well before progression to invasive cancer. In addition to baseline and persistent high-risk HPV, abnormal cervical smear and new sexual partner are key predictors of incident CIN.

Genotype-specific clearance of genital human papillomavirus (HPV) infections among mothers in the Finnish family HPV study.

The majority of cervical human papillomavirus (HPV) infections in young women are transient, but whether the clearance differs among different HPV genotypes and the different factors predicting genotype-specific clearance are partly unknown. In the Finnish Family HPV Study, 131 of 252 women (mean age, 25.5 years) cleared their infection during the prospective follow-up of 6 years (median, 62.4 months; range, 1.6 to 94.5 months). Cervical scrapings collected at each visit were tested for 24 low-risk and high-risk (HR) HPV types with multiplex HPV genotyping. Poison regression (panel data) was used to estimate predictors for the clearance of species 7 and 9 HPV genotypes. Of all HPV genotypes detected in these women, multiple-type and HPV type 16 (HPV16) infections showed clearance least frequently (46.1% and 50.5%, respectively). The actuarial and crude mean times to first clearance were variable among different genotypes. The actuarial clearance rate (events/person-time at risk) was highest for HPV16 and multiple-type infections, while HPV66 and -82 had the highest crude clearance rate. Independent predictors increasing type-specific clearance of species 7/9 HPV genotypes were older age (incidence rate ratio [IRR] = 1.1; 95% confidence interval [95% CI], 1.03 to 1.18; P = 0.002) and baseline oral HR HPV DNA-negative status (IRR = 2.94; 95% CI, 1.03 to 8.36; P = 0.042), while a higher number of sexual partners during the follow-up decreased the probability of clearance (IIR = 0.35; 95% CI, 0.15 to 0.83; P = 0.018). To conclude, HPV16 and multiple-type infections showed the lowest clearance among young mothers. Increasing age and negative oral HR HPV DNA status at baseline were associated with increased clearance, whereas a higher number of current sexual partners decreased the probability of species 7/9 HPV genotype clearance.

Biomaterial and implant induced ossification: in vitro and in vivo findings.

Material-induced ossification is suggested as a suitable approach to heal large bone defects. Fiber-reinforced composite-bioactive glasses (FRC-BGs) display properties that could enhance the ossification of calvarial defects. Here, we analyzed the healing processes of a FRC-BG implant in vivo from the perspective of material-induced ossification. Histological analysis of the implant, which was removed 5 months after insertion, showed the formation of viable, noninflammatory mesenchymal tissue with newly-formed mineralized woven bone, as well as nonmineralized connective tissue with capillaries and larger blood vessels. The presence of osteocytes was detected within the newly generated bone matrix. To expand our understanding on the osteogenic properties of FRC-BG, we cultured human adipose tissue-derived mesenchymal stromal cells (AD-MSCs) in the presence of two different BGs (45S5 and S53P4) and Al2 O3 control. AD-MSCs grew and proliferated on all the scaffolds tested, as well as secreted abundant extracellular matrix, when osteogenic differentiation was appropriately stimulated. 45S5 and S53P4 induced enhanced expression of COL2A1, COL10A1, COL5A1 collagen subunits, and pro-osteogenic genes BMP2 and BMP4. The concomitant downregulation of BMP3 was also detected. Our findings show that FRC-BG can support the vascularization of the implant and the formation of abundant connective tissue in vivo. Specifically, BG 45S5 and BG S53P4 are suited to evoke the osteogenic potential of host mesenchymal stromal cells. In conclusion, FRC-BG implant demonstrated material-induced ossification both in vitro and in vivo.

Effect of second pregnancy on maternal carriage and outcome of high-risk human papillomavirus (HPV). Experience from the prospective finnish family HPV study.

OBJECTIVES: The effect of second pregnancy on human papillomavirus (HPV) carriage and outcome is modelled in longitudinal setting covering two subsequent pregnancies. STUDY DESIGN: Among 329 (baseline pregnant) women prospectively followed up in the Finnish Family HPV Study, two subcohorts were compiled: (i) 78 women (Group B) who became pregnant for the second time during the follow-up, and (ii) 100 women (Group A) who did not develop 2nd pregnancy. The effect of pregnancy on high-risk HPV (HR-HPV) carriage and outcome was analysed using Kaplan-Meier and Cox survival analyses and generalized estimating equation (GEE) modelling of the longitudinal data. RESULTS: Women in the two groups were similar in their baseline HR-HPV status but significantly different in several known risk factors of HR-HPV infection. Group A women showed higher point prevalence of cervical and oral HR-HPV at the 36-month (p = 0.015) and 6-month (p = 0.024) follow-up visit, respectively. Among Group B women, prevalence of both cervical and oral HR-HPV significantly decreased during 2nd pregnancy (p = 0.005 and p = 0.002) as compared with inter-pregnancy period, but increased again after 2nd pregnancy. There was no difference in acquisition or clearance of cervical or oral HR-HPV between the two groups in univariate (Kaplan-Meier) or multivariate (Cox) survival analysis. In the GEE approach, 2nd pregnancy was not significantly associated with cervical or oral HR-HPV carriage or persistence when adjusted for all other covariates. CONCLUSIONS: Second pregnancy is of little impact on carriage and persistence of oral and cervical HR-HPV infections in a longitudinal setting over time.

The performance of the HPV16 real-time PCR integration assay.

OBJECTIVES: Integration of high risk human papillomavirus (HPV) into the host genome leads to viral oncogene deregulation predisposing to neoplastic progression. Integration can be detected from pap smear or biopsy and use as marker of progressive disease. DESIGN AND METHODS: We have previously developed a highly sensitive real-time PCR method to determine HPV integration frequency and viral load of HPV16 in clinical samples. The test is accurate and sensitive detecting approx. 50 copies of integrated HPV in the sample. RESULTS: We found that a tenfold excess of episomal form to integrated form interferes with the test, regardless the amount of viral DNA. The same was true with background DNA more than 1500 ng in reaction. CONCLUSIONS: Overall, this method is reproducible and suitable for high-throughput screening of clinical samples, but excess episomal copies might mask the integrated form.

Human papillomavirus in the placenta and umbilical cord blood.

OBJECTIVE: To analyze human papillomavirus (HPV) DNA in umbilical cord blood and in placenta, including its cellular localization. DESIGN: Longitudinal prospective study. SETTING: Maternity Unit of Turku University Hospital, and MediCity, University of Turku. SAMPLES: Placental and cord blood samples obtained at delivery from 315 mothers and 311 neonates included in the Finnish HPV Family Study. METHODS: HPV testing by nested PCR and sequencing. Tyramide amplified in situ hybridization (ISH) for viral DNA localization in placenta. Correlation to mother's and neonate's oral and genital HPV status and maternal demographic data. MAIN OUTCOME MEASURES: Detection and cellular localization of HPV DNA. RESULTS: HPV DNA was detected in 4.2 and 3.5% of placenta and cord blood samples, respectively, including HPV types 16, 6, 83 and 39. In placenta, HPV6 and 16 DNA was localized in syncytiotrophoblasts. Abnormal cytology increased the risk of HPV+ placenta and cord blood. History of genital warts was the only independent predictor of cord blood HPV in multivariate analysis (adjusted OR=4.0, 95% CI: 1.09-14.54, p=0.036). HPV DNA in cord blood increased the risk of genital (OR=4.0, 95% CI: 1.08-14.83, p=0.048) and oral (OR=4.4, 95% CI: 1.17-16.14, p=0.039) HPV DNA carriage of the neonate. HPV+ placenta increased the risk of oral HPV of the neonate (OR=8.6, 95% CI: 2.73-27.13, p=0.0001). Delivery mode did not predict HPV status of the neonate. CONCLUSIONS: HPV DNA is detected in placental trophoblasts and umbilical cord blood. The presence of HPV DNA at these sites increases the risk of a neonate testing HPV-positive at birth.

Drug-Sensitivity Screening and Genomic Characterization of 45 HPV-Negative Head and Neck Carcinoma Cell Lines for Novel Biomarkers of Drug Efficacy.

There is an unmet need for effective targeted therapies for patients with advanced head and neck squamous cell carcinoma (HNSCC). We correlated gene expression, gene copy numbers, and point mutations in 45 human papillomavirus-negative HNSCC cell lines with the sensitivity to 220 anticancer drugs to discover predictive associations to genetic alterations. The drug response profiles revealed diverse efficacy of the tested drugs across the cell lines. Several genomic abnormalities and gene expression differences were associated with response to mTOR, MEK, and EGFR inhibitors. NOTCH1 and FAT1 were the most commonly mutated genes after TP53 and also showed some association with response to MEK and/or EGFR inhibitors. MYC amplification and FAM83H overexpression associated with sensitivity to EGFR inhibitors, and PTPRD deletion with poor sensitivity to MEK inhibitors. The connection between high FAM83H expression and responsiveness to the EGFR inhibitor erlotinib was validated by gene silencing and from the data set at the Cancer Cell Line Encyclopedia. The data provide several novel genomic alterations that associated to the efficacy of targeted drugs in HNSCC. These findings require further validation in experimental models and clinical series. Mol Cancer Ther; 17(9); 2060-71. ©2018 AACR.

Type-specific persistence of high-risk human papillomavirus infections in the New Independent States of the former Soviet Union Cohort Study.

BACKGROUND: Prospective follow-up studies have recently suggested that persistent high-risk human papillomavirus (HPV) infections play a key role in the progression of CIN lesions and in the development of cervical cancer. However, data on type-specific persistence, viral integration, and the role of multiple infections are scanty. MATERIALS AND METHODS: A cross-sectional/cohort study was conducted between 1998 and 2002 in three New Independent States of the former Soviet Union comprising a cohort of 3,187 women, of whom 854 women were followed up for a mean of 17 months (SD, 11.6). HPV genotyping was done with real-time PCR, detecting HPV types 16, 18/45, 31, 33/52/58, 35, and 39. The integration status of HPV16 was examined by using a novel Taqman-based PCR method. RESULTS: The mean clearance time for the individual high- risk-type infection was 16.5 months (range = 0.9-34.9 months). HPV16 and HPV31 were the most persistent infections (clearance times = 18.1 and 16.2 months, respectively), whereas HPV39 infections cleared most rapidly. The mean copies per cell in HPV18/45, HPV31, HPV33/52/58, and HPV39 infections were higher in persisting HPV infections than in HPV infections that cleared, but the difference was not significant. Integration of HPV16 was not found to correlate with HPV persistence. CONCLUSIONS: A large proportion of women remained high-risk HPV positive after 18 months. Coinfection with multiple HPV types, viral load, or integration status did not correlate with persistence of high-risk HPV infections.

High-risk types of human papillomavirus (HPV) DNA in oral and genital mucosa of infants during their first 3 years of life: experience from the Finnish HPV Family Study.

BACKGROUND: This study is aimed to clarify data on the acquisition, persistence, and clearance of high-risk types of human papillomavirus (HPV) DNA from the mucosa and the determinants of persistent mucosal HPV infection in infants. METHODS: Oral and genital scrapings from 324 infants were collected at birth, 3 days after delivery, and 1, 2, 6, 12, 24, and 36 months after delivery and tested for the presence of HPV DNA by nested polymerase chain reaction and hybridization with 12 high-risk HPV oligoprobes. HPV status and demographic data for parents were analyzed. RESULTS: During the follow-up period (median duration, 26.2 months), HPV DNA was found to be present in 12%-21% of oral scrape samples and in 4%-15% of genital scrape samples obtained from the infants. Oral HPV infection was acquired by 42% of children, cleared by 11%, and persisted in 10% of the infants, whereas 37% were never infected. The corresponding figures for genital HPV infection were 36%, 14%, 1.5%, and 47%. Kaplan-Meier analysis revealed that both the cumulative incidence of infection and clearance of HPV were parallel in oral and genital sites. Persistent oral HPV infection in the child was significantly associated with persistent oral HPV infection in the mother at month 36 of follow-up, hand warts in the mother, young age at onset of sexual activity for the mother, and the mother's use of oral contraception, as well as with the father's oral HPV status at 24 months. Persistent genital HPV infection in the infant was predicted by if the mother had started smoking at 18-21 years of age and by a history of genital warts. CONCLUSIONS: Persistent carriage of high-risk HPV types was detected in oral and genital mucosa specimens obtained from 10% and 1.5% of the infants during their first 26 months of life. The rates of acquisition and clearance of HPV were similar in oral and genital mucosa.

Prevalence of the most common high-risk HPV genotypes among women in three new independent states of the former Soviet Union.

Type distribution of HPV has been studied in different geographic regions, but the data are scanty from the new independent states of the former Soviet Union. Here the HPV prevalence and distribution of the most frequent high-risk HPV types among 3,187 women at different risk for HPV and cervical intraepithelial neoplasia in Russia, Belarus, and Latvia is reported. HPV detection, type distribution and viral load analysis in DNA samples from cervical scrapes were done with real-time PCR-based assay detecting HPV types 16, 18, 31, 33, 35, 39, 45, 52, and 58. The overall HPV prevalence was 31.2%, HPV16 was the most prevalent type followed by HPV31 and HPV33 group. The overall HPV prevalences in Russia, Belarus and Latvia were 33.4%, 27.5%, and 26.2%. The type distributions were similar in these countries, except for Latvia where HPV39 was the third prevalent genotype. HPV prevalence was highest (40.8%) among women from sexually transmitted disease clinic, followed by 30.9% among gynecological outpatients and 27.2% in screening patients. HPV detection increased with cytological abnormality (P = 0.0001) and lesion grade in the biopsy (P = 0.0001), from 27% to 72% in normal samples to cancer, and from 64% to 77% in cervical intraepithelial neoplasia 1 to cancer. The normalized viral loads varied greatly between and among different HPV-types. The mean log HPV33 group copies/cell increased from negative for intraepithelial lesions to cancer (P = 0.049). Distribution of the most common high-risk HPV-types seems to be similar in these countries as reported in other major geographical regions.

Over-expression of topoisomerase IIalpha is related to the grade of cervical intraepithelial neoplasia (CIN) and high-risk human papillomavirus (HPV), but does not predict prognosis in cervical cancer or HPV clearance after cone treatment.

OBJECTIVE: One of the pathways leading to cervical cancer is a loss of normal cell cycle control. Topoisomerase IIalpha and IIbeta are important nuclear proteins controlling the G2/M checkpoint, and shown to be over-expressed in many human cancers. Their links to oncogenic human papillomavirus (HPV) types and their prognostic value in cervical cancer are practically unexplored. MATERIAL AND METHODS: As part of our HPV-PathogenISS study, a series of 150 squamous cell carcinomas (SCC) and 152 CIN lesions were examined using immunohistochemical (IHC) staining for topoisomerase IIalpha (topo IIalpha), and tested for HPV using PCR with three primer sets (MY09/11, GP5/GP6, SPF). Follow-up data were available from all SCC patients, and 67 CIN lesions had been monitored with serial PCR for HPV clearance/persistence after cone treatment. RESULTS: Topo IIalpha expression increased with increasing grade of CIN (p = 0.0001), with the most dramatic up-regulation upon progression from CIN2 to CIN3 and peaking in SCC (OR 16.23; 95%CI 7.89-33.38). Topo IIalpha up-regulation was also significantly associated with HR-HPV detection in univariate analysis (OR = 3.07; 95%CI 1.70-5.52), but was confounded by the histological grade (Mantel-Haenszel common OR = 1.622; 95%CI 0.782-3.365), and by entering both p16(INK4a) (9) and Survivin (33) in the multivariate regression model. Topo IIalpha did not predict clearance/persistence of HR-HPV after treatment of CIN, and it was not a prognostic factor in cervical cancer in either univariate or multivariate analysis. CONCLUSIONS: Over-expression of topo IIalpha is significantly associated with progression from CIN2 to CIN3, being a late marker of cell proliferation. Its close association with HR-HPV is plausibly explained by the fact that E7 oncoproteins of these HR-HPV (but not LR-HPV) block the normal pRb-mediated inhibition of topo IIalpha by degrading the wild-type Rb.

Transmission of high-risk human papillomavirus (HPV) between parents and infant: a prospective study of HPV in families in Finland.

The Finnish HPV Family Study is a prospective cohort study assessing the dynamics of human papillomavirus (HPV) transmission between parents and infant. Serial genital and oral scrapings from 76 families, including mother, father, and infant, and semen samples were collected over 2 years of follow-up, analyzed by nested PCR, and confirmed by hybridization with 12 high-risk (HR) HPV types. The most common HPV profile was HR HPV in all family members (29%), followed by HPV-positive mother-infant pairs (26%). HPV-positive father-infant pairs were less frequent (11%), and in six (8%) families, only the infant was HR HPV positive. The prevalence of genital HR HPV in the parents ranged from 13 to 25%, and that of oral HPV ranged from 8 to 34%. In the infants, HPV DNA was detected in 15% of the genital and 10% of the oral samples at birth, reaching peaks of 18 and 21%, respectively, at 6 months, and declining to 10% at 24 months. Persistent HPV in the mother was a risk factor for oral HPV in the infant (odds ratio [OR], 5.69; 95% confidence interval [95% CI], 1.5 to 21.3), while oral HPV in the mother at 6 months was a risk factor for genital HR HPV (OR, 6.38; 95% CI, 1.15 to 35.32). No such independent risk could be attributed to subclinical HPV in the father. Persistent maternal cervical HPV and subclinical oral HPV affect the risk of infant HPV. The age of 6 months is a critical point for the infant to acquire or be free of HR HPV DNA.

Human papillomavirus DNA is found in the vas deferens.

The role of the male reproductive tract as a reservoir for human papillomavirus (HPV) infection is poorly understood. To analyze the presence of HPV DNA, 27 samples, comprising postvasectomy semen samples and pre- and postejaculation urine samples, were obtained from 18 men recalled for follow-up. HPV DNA was analyzed by nested polymerase chain reaction, confirmed with Southern blot hybridization, cloned, and sequenced. Multiple HPV types were found in different DNA samples of the same men. Five (18.5%) of 27 vas deferens samples contained HPV type 6, 11, or 16. Five (27.8%) of 18 seminal plasma samples (secretions without semen cells) were HPV DNA positive. None of the men had both vas deferens and semen plasma samples HPV positive. Several HPV types can be detected in the male reproductive tract at the same time. This is the first report to show HPV DNA in the vas deferens.