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Abstract Background Vulvar squamous cell carcinoma (VSCC) is a rare malignancy of the female genital tract. We aimed to determine the mucosal high-risk human papillomavirus (HPV)-attributable fraction of VSCCs from Italian women using multiple markers of viral infections. Methods VSCCs and 8 metastatic lymph node samples from 107 Italian women were analyzed by a highly type-specific multiplex genotyping assay for the presence of DNA from 119 different HPVs. Tissues were further analyzed for HPV RNA and for upregulation of the cellular protein p16INK4a. Results The rate of mucosal HPV-related tumors defined by viral DNA and RNA positivity was low (7.8%). HPV16 was the most prevalent, followed by 53, 56, and 58. Only five (4.9%) p16INK4a-positive tumors were also positive for both viral DNA and RNA. One (14.3%) metastatic lymph node sample was positive for all three markers. DNA of cutaneous HPVs was detected in only two VSCCs, i.e. genus beta types 5 and 110. Conclusion A small proportion of Italian VSCCs is putatively HPV-related, i.e. positive for both viral DNA and RNA of the same type, thus reinforcing the importance of HPV vaccination. Moreover, this study suggests that a direct role of HPV from genus beta and gamma in vulvar carcinogenesis is unlikely.

Background: Recurrent mutations in the promoter of the telomerase reverse transcriptase (TERT) gene (C228T and C250T) detected in tumours and cells shed into urine of urothelial cancer (UC) patients are putative biomarkers for UC detection and monitoring. However, the possibility of detecting these mutations in cell-free circulating DNA (cfDNA) in blood and urine, or DNA from urinary exfoliated cells (cellDNA) with a single-gene sensitive assay has never been tested in a case-control setting. Methods: We developed a single-plex assay (UroMuTERT) for the detection of low-abundance TERT promoter mutations. We tested 93 primary and recurrent UC cases and 94 controls recruited in France (blood, urine samples and tumours for the cases), and 50 primary UC cases and 50 controls recruited in Portugal (urinary exfoliated cell samples). We compared our assay with urine cytology. Findings: In the French series, C228T or C250T were detected in urinary cfDNA or cellDNA in 81 cases (87·1%; 95% CI 78·6–93·2), and five controls (Specificity 94·7%; 95%CI 88·0–98·3), with 98·6% (95% CI 92·5–99·96) concordance in matched tumours. Detection rate in plasma cfDNA among cases was 7·1%. The UroMuTERT sensitivity was (i) highest for urinary cfDNA and cellDNA combined, (ii) consistent across primary and recurrent cases, tumour stages and grades, (iii) higher for low-risk non-muscle invasive UC (86·1%) than urine cytology (23·0%) (P

Human papillomavirus type 16 (HPV16) and other oncoviruses have been shown to block innate immune responses and to persist in the host. However, to avoid viral persistence, the immune response attempts to clear the infection. IL-1β is a powerful cytokine produced when viral motifs are sensed by innate receptors that are members of the inflammasome family. Whether oncoviruses such as HPV16 can activate the inflammasome pathway remains unknown. Here, we show that infection of human keratinocytes with HPV16 induced the secretion of IL-1β. Yet, upon expression of the viral early genes, IL-1β transcription was blocked. We went on to show that expression of the viral oncoprotein E6 in human keratinocytes inhibited IRF6 transcription which we revealed regulated IL-1β promoter activity. Preventing E6 expression using siRNA, or using E6 mutants that prevented degradation of p53, showed that p53 regulated IRF6 transcription. HPV16 abrogation of p53 binding to the IRF6 promoter was shown by ChIP in tissues from patients with cervical cancer. Thus E6 inhibition of IRF6 is an escape strategy used by HPV16 to block the production IL-1β. Our findings reveal a struggle between oncoviral persistence and host immunity; which is centered on IL-1β regulation.

BACKGROUND:Limited information is available about the involvement of human papillomavirus (HPV) in head and neck squamous cell carcinomas (HNSCCs) in Romanian patients. OBJECTIVE:To evaluate the HPV-attributable fraction in HNSCCs collected in Northeastern Romania. MATERIALS AND METHODS:In total, 189 formalin-fixed paraffin-embedded tissue samples (99 oral cavity tumors, 28 oropharynx, 48 pharynx, and 14 larynx/hypopharynx) were analyzed for HPV DNA and RNA using Luminex-based assays, and for overexpression of p16INK4a (p16) by immunohistochemistry. RESULTS:Of the 189 cases, 23 (12.2%) were HPV DNA-positive, comprising half of the oropharyngeal cases (14/28, 50.0%) and 9/161 (5.6%) of the non-oropharyngeal cases. HPV16 was the most prevalent HPV type (20/23, 86.9%), followed by HPV18 (5/23, 21.7%) and HPV39 (1/23, 4.3%). Only two (2/189, 1.1%) HNSCC cases were HPV-driven, i.e. positive for both HPV DNA and RNA. CONCLUSION:A very small subset of HNSCC cases within this cohort from Northeastern Romania appeared to be HPV-driven.

The possible role of viruses in breast cancer etiology remains an unresolved question. We hypothesized that if some viruses are involved, it may be in a subgroup of breast cancers only. Epidemiological arguments drove our interest in breast cancer subgroups that are more frequent in Africa, namely inflammatory breast cancer (IBC) and triple-negative breast cancer. We tested whether viral prevalence was significantly higher in these subgroups.One hundred fifty-five paraffin-embedded malignant breast tumors were randomly selected at the pathology laboratory of the University Hospital of Annaba (Algeria) to include one third of IBC and two thirds of non-IBC. They were tested for the presence of DNA from 61 viral agents (46 human papillomaviruses, 10 polyomaviruses, and 5 herpesviruses) using type-specific multiplex genotyping assays, which combine multiplex PCR and bead-based Luminex technology.Viral DNA was found in 22 (17.9%) of 123 tumors. The most prevalent viruses were EBV1 and HPV16. IBC tumors carried significantly more viruses (any type) than non-IBC tumors (30% vs. 13%, p

Gene expression microarray and next generation sequencing efforts on conventional, clear cell renal cell carcinoma (ccRCC) have been mostly performed in North American and Western European populations, while the highest incidence rates are found in Central/Eastern Europe. We conducted whole-genome expression profiling on 101 pairs of ccRCC tumours and adjacent non-tumour renal tissue from Czech patients recruited within the "K2 Study", using the Illumina HumanHT-12 v4 Expression BeadChips to explore the molecular variations underlying the biological and clinical heterogeneity of this cancer. Differential expression analysis identified 1650 significant probes (fold change ≥2 and false discovery rate