Krisztina Szarka

TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies.

BACKGROUND Cervical cancer is caused primarily by human papillomaviruses (HPV). The polymorphism rs1042522 at codon 72 of the TP53 tumour-suppressor gene has been investigated as a genetic cofactor. More than 80 studies were done between 1998 and 2006, after it was initially reported that women who are homozygous for the arginine allele had a risk for cervical cancer seven times higher than women who were heterozygous for the allele. However, results have been inconsistent. Here we analyse pooled data from 49 studies to determine whether there is an association between TP53 codon 72 polymorphism and cervical cancer. METHODS Individual data on 7946 cases and 7888 controls from 49 different studies worldwide were reanalysed. Odds ratios (OR) were estimated using logistic regression, stratifying by study and ethnic origin. Subgroup analyses were done for infection with HPV, ethnic origin, Hardy-Weinberg equilibrium, study quality, and the material used to determine TP53 genotype. FINDINGS The pooled estimates (OR) for invasive cervical cancer were 1.22 (95% CI 1.08-1.39) for arginine homozygotes compared with heterozygotes, and 1.13 (0.94-1.35) for arginine homozygotes versus proline homozygotes. Subgroup analyses showed significant excess risks only in studies where controls were not in Hardy-Weinberg equilibrium (1.71 [1.21-2.42] for arginine homozygotes compared with heterozygotes), in non-epidemiological studies (1.35 [1.15-1.58] for arginine homozygotes compared with heterozygotes), and in studies where TP53 genotype was determined from tumour tissue (1.39 [1.13-1.73] for arginine homozygotes compared with heterozygotes). Null results were noted in studies with sound epidemiological design and conduct (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes), and studies in which TP53 genotype was determined from white blood cells (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes). INTERPRETATION Subgroup analyses indicated that excess risks were most likely not due to clinical or biological factors, but to errors in study methods. No association was found between cervical cancer and TP53 codon 72 polymorphism when the analysis was restricted to methodologically sound studies. FUNDING German Research Foundation (DFG).

The characteristics of human papillomavirus DNA in head and neck cancers and papillomas.

Aim: To determine the prevalence, type, physical state, and viral load of human papillomavirus (HPV) DNA in cases of head and neck cancer and recurrent respiratory papillomatosis (RRP). Methods: The prevalence and type of HPV DNA was determined in 27 fresh frozen tissue specimens from patients with head and neck cancers and 16 specimens from 10 patients with RRP by MY09/MY11 and GP5+/GP6+ nested polymerase chain reaction (PCR) and subsequent restriction enzyme cleavage. The physical state of HPV DNA was analysed by E1, E2, and E1E2 specific PCRs and Southern blot hybridisation (SBH). Results: HPV DNA was detected in 13 of 27 cancers and 10 of 10 papillomas. Both low risk HPV-6 and HPV-11 and high risk HPV-16 were present in cancers in low copy numbers, whereas papillomas exclusively harboured low risk HPV-6 and HPV-11. E1E2 PCRs failed to determine the physical state of HPV in cancers except one case where HPV-6 DNA was integrated. In contrast to cancers, all papillomas showed the episomal state of HPV DNA and a relatively higher viral load. Conclusions: Based on the prevalence, type, physical state, and copy number of HPV DNA, cancers and papillomas tend to show a different HPV DNA profile. The 100% positivity rate of low risk HPV types confirms the role of HPV-6 and HPV-11 in the aetiology of RRP.

Progressive increase of human papillomavirus carriage rates in potentially malignant and malignant oral disorders with increasing malignant potential

INTRODUCTION We investigated the potential role of human papillomaviruses (HPVs) in potentially malignant oral disorders, oral leukoplakia (OL) and oral lichen planus (OLP), and in oral squamous cell cancer (OSCC) in an Eastern Hungarian population with a high incidence of OSCC. METHODS Excised tumor samples (65 OSCC patients) and exfoliated cells from potentially malignant lesions (from 44 and 119 patients with OL and OLP, respectively) as well as from healthy controls (72 individuals) were analysed. OLPs were classified based on clinical appearance, 61 patients had erosive-atrophic lesions (associated with higher malignancy risk, EA-OLP) and 58 had non-erosive non-atrophic lesions (with lower risk of becoming malignant, non-EA-OLP), respectively. Exfoliated cells collected from apparently healthy mucosa accompanied each lesion sample. HPV was detected by MY/GP polymerase chain reaction (PCR) and genotyped by restriction analysis of amplimers. Copy numbers in lesions were determined using real-time PCR. Prevalence rates, copy number distributions, and association with risk factors and diseases were analysed using chi-square test, t-test, and logistic regression, respectively. RESULTS We detected HPVs significantly more frequently in lesions than in controls (P < or = 0.001 in all comparisons). HPV prevalence increased gradually with increasing severity of lesions (32.8, 40.9, and 47.7% in OLP, OL, and OSCC, respectively). Copy number distribution patterns roughly corresponded to prevalence rates, but OLP and OL were comparable. HPV prevalence differed significantly between EA-OLP and non-EA-OLP groups (42.6 vs. 22.4%); EA-OLP group showed a prevalence similar to that found in OL. CONCLUSION HPVs may be involved in the development or progression of not only OSCC but also of potentially malignant oral lesions.

Survivin promoter polymorphism and cervical carcinogenesis.

Background: Survivin, a novel member of the inhibitor of apoptosis family, plays an important role in cell cycle regulation. A common polymorphism at the survivin gene promoter (G/C at position 31) was shown to be correlated with survivin gene expression in cancer cell lines. Aim: To investigate whether this polymorphism could be involved in the development of human papillomavirus (HPV)-associated cervical carcinoma. Methods: Survivin promoter polymorphism was detected in patients with cervical cancer, in patients with equivocal cytological atypia and in a control population using polymerase chain reaction (PCR-restriction fragment length polymorphism (RFLP) and PCR-single strand conformation polymorphism analysis. HPV was typed in patients with cervical cancer and cytological atypia using PCR-RFLP. Results: No statistically significant differences were found in the genotype distributions of the survivin promoter variants among our study groups. Conclusions: The survivin promoter polymorphism at position 31 may not represent an increased risk for the development of cervical cancer, at least in the population studied here.

Epstein-Barr virus prevalence in oral squamous cell cancer and in potentially malignant oral disorders in an eastern Hungarian population

We tested 65, 44, and 116 patients with oral squamous cell cancer (OSCC), oral leukoplakia (OL), and oral lichen planus (OLP) against 68 age-matched controls for the presence of Epstein-Barr virus (EBV). Apparently healthy mucosa was simultaneously sampled and examined in all patients. Paraffin-embedded tissue sections of all EBV-positive patients with OSCC were examined for latent membrane protein-1 (LMP-1) expression (demonstrable in most EBV-associated malignancies) using immunohistochemistry. The prevalence of EBV in the controls and in OSCC, OL, and OLP lesions was 19.1%, 73.8%, 29.5%, and 46.6%, respectively, and 66.2%, 22.7%, and 31.9% in the healthy mucosa of patients, respectively. The prevalence of EBV in OSCC patients was significantly higher than in controls or in respective samples of the other two patient groups both in the lesion and in the healthy mucosa. Comparisons including only patients with EBV-negative lesions yielded similar results. Lesions of patients with OLP, but not of patients with OL, differed significantly from controls in EBV prevalence. In OSCC, LMP-1 expression was not detected, and EBV carriage was not significantly associated with any risk factors and did not influence the outcome. Although a high prevalence of EBV was found in OSCC, comparable carriage rates on healthy mucosa of patients indicated that an aetiological role of EBV is unlikely.

High co-prevalence of genogroup 1 TT virus and human papillomavirus is associated with poor clinical outcome of laryngeal carcinoma

Background: The aetiology and factors leading to the progression of laryngeal cancer are still unclear. Although human papillomavirus (HPV) has been suggested to play a role, reports concerning the effect of HPV infection on tumour development are controversial. Recently, transfusion transmitted virus (TTV) was suggested to play a role in certain infections as a causative or coinfecting agent. Aims: To investigate whether the development and progression of laryngeal squamous cell carcinoma is associated with coinfection with TTV and HPV. Methods: The prevalence of TTV and HPV was investigated using the polymerase chain reaction in tissue samples from 40 healthy individuals, 10 patients with recurrent papillomatosis, five patients with papillomatosis with malignant transformation, and 25 patients with laryngeal carcinoma. The obtained prevalence data were compared and analysed statistically. Results: In the 11 patients with carcinoma who had metastasis or relapse there was a high rate of coinfection with genogroup 1 TTV and HPV (eight of 11), whereas in the 14 without tumour progression no coinfection was found. Coinfection was associated with significantly lower tumour free survival in patients with carcinoma (p < 0.001). Furthermore, four of five patients who had papillomatosis with malignant transformation were coinfected with genogroup 1 TTV and HPV. Conclusions: Although the nature of cooperation between HPV and TTV needs to be investigated further, coinfection with genogroup 1 TTV and HPV appears to be associated with poor clinical outcome in laryngeal cancer.

The prognostic significance of HPV‐16 genome status of the lymph nodes, the integration status and p53 genotype in HPV‐16 positive cervical cancer: a long term follow up

Objective Prognostic evaluation of HPV‐16 genome status of the pelvic lymph nodes, the integration status of HPV‐16 and p53 codon 72 polymorphism in cervical cancer.

Investigation of the occurrence of torque tenovirus in malignant and potentially malignant disorders associated with human papillomavirus

In a previous pilot study, a significantly poorer outcome of laryngeal cancer was found in patients co‐infected with human papillomavirus (HPV) and genogroup 1 torque tenovirus (TTV). The present study aimed to collect data on the overall prevalence of TTVs on the prevalence of genogroup 1 TTV in two other malignancies associated with HPV, oral squamous cell cancer and cervical cancer, and in oral and cervical premalignant lesions (oral lichen planus, oral leukoplakia, cervical atypia). Oral samples from all patients were accompanied with a sample from the healthy mucosa. The overall prevalence of TTV was significantly higher both in oral squamous cell cancer and cervical cancer compared with other patient groups or with the respective controls. The prevalence of genogroup 1 TTV was significantly higher in lesions of oral squamous cell cancer and oral lichen planus, but not in lesions of oral leukoplakia (24.6%, 10.1%, and 4.5%, respectively), compared with the prevalence in the oral cavity of controls (1.4%). Co‐infection rates with genogroup 1 TTV and HPV were significantly higher in oral squamous cell cancer than in controls, oral lichen planus or oral leukoplakia patients (12.3%, 0.0%, 6.7%, and 4.5%, respectively). The prevalence of genogroup 1 TTV in all cervical samples were comparable. These data suggest that genogroup 1 TTV may be associated specifically with some head and neck mucosal disorders, but disproves a (co)carcinogenic role in oral cancer or cervical cancer as well as an association with HPV or with malignancies associated with HPV. J. Med. Virol. 81:1975–1981, 2009.

Virological failure of intralesional cidofovir therapy in recurrent respiratory papillomatosis is not associated with genetic or epigenetic changes of HPV11: complete genome comparison of sequential isolates.

Five sequential human papillomavirus type 11 (HPV11) positive samples collected from an aggressive juvenile onset recurrent respiratory papillomatosis before, during and after intralesional cidofovir therapy leading to virological failure after initial response were analyzed. Sequencing of the complete genome as well as methylation analysis by bisulfate modification and sequencing of the long control region (LCR) were performed to seek for genetic and epigenetic changes as a possible background for therapy failure. Single-strand conformation polymorphism of E1, E2, E6, E7 and LCR was used to exclude the presence of multiple HPV11 infection. All five complete genomes were identical and all four E2 binding sites in the LCR were uniformly unmethylated in all five genomes. Thus the virological failure was not due to virological factors suggesting that cidofovir action may depend more heavily on the host.

Prevalence of HPV infection in racial-ethnic subgroups of head and neck cancer patients

The landscape of HPV infection in racial/ethnic subgroups of head and neck cancer (HNC) patients has not been evaluated carefully. In this study, a meta-analysis examined the prevalence of HPV in HNC patients of African ancestry. Additionally, a pooled analysis of subject-level data was also performed to investigate HPV prevalence and patterns of p16 (CDNK2A) expression amongst different racial groups. Eighteen publications (N = 798 Black HNC patients) were examined in the meta-analysis, and the pooled analysis included 29 datasets comprised of 3,129 HNC patients of diverse racial/ethnic background. The meta-analysis revealed that the prevalence of HPV16 was higher among Blacks with oropharyngeal cancer than Blacks with non-oropharyngeal cancer. However, there was great heterogeneity observed among studies (Q test P<0.0001). In the pooled analysis, after adjusting for each study, year of diagnosis, age, gender and smoking status, the prevalence of HPV16/18 in oropharyngeal cancer patients was highest in Whites (61.1%), followed by 58.0% in Blacks and 25.2% in Asians (P<0.0001). There was no statistically significant difference in HPV16/18 prevalence in non-oropharyngeal cancer by race (P=0.682). With regard to the pattern of HPV16/18 status and p16 expression, White patients had the highest proportion of HPV16/18+/p16+ oropharyngeal cancer (52.3%), while Asians and Blacks had significantly lower proportions (23.0% and 22.6%, respectively) [P <0.0001]. Our findings suggest that the pattern of HPV16/18 status and p16 expression in oropharyngeal cancer appears to differ by race and this may contribute to survival disparities. at Freie U nivrsitaet B erlin on D ecem er 8, 2016 http://carcfordjournals.org/ D ow nladed fromThe landscape of HPV infection in racial/ethnic subgroups of head and neck cancer (HNC) patients has not been evaluated carefully. In this study, a meta-analysis examined the prevalence of HPV in HNC patients of African ancestry. Additionally, a pooled analysis of subject-level data was also performed to investigate HPV prevalence and patterns of p16 (CDNK2A) expression amongst different racial groups. Eighteen publications (N = 798 Black HNC patients) were examined in the meta-analysis, and the pooled analysis included 29 datasets comprised of 3,129 HNC patients of diverse racial/ethnic background. The meta-analysis revealed that the prevalence of HPV16 was higher among Blacks with oropharyngeal cancer than Blacks with non-oropharyngeal cancer. However, there was great heterogeneity observed among studies (Q test P<0.0001). In the pooled analysis, after adjusting for each study, year of diagnosis, age, gender and smoking status, the prevalence of HPV16/18 in oropharyngeal cancer patients was highest in Whites (61.1%), followed by 58.0% in Blacks and 25.2% in Asians (P<0.0001). There was no statistically significant difference in HPV16/18 prevalence in non-oropharyngeal cancer by race (P=0.682). With regard to the pattern of HPV16/18 status and p16 expression, White patients had the highest proportion of HPV16/18+/p16+ oropharyngeal cancer (52.3%), while Asians and Blacks had significantly lower proportions (23.0% and 22.6%, respectively) [P <0.0001]. Our findings suggest that the pattern of HPV16/18 status and p16 expression in oropharyngeal cancer appears to differ by race and this may contribute to survival disparities.