Characterization of Novel Cutaneous Human Papillomavirus Genotypes HPV-150 and HPV-151

DNA from two novel HPV genotypes, HPV-150 and HPV-151, isolated from hair follicles of immuno-competent individuals, was fully cloned, sequenced and characterized. The complete genomes of HPV-150 and HPV-151 are 7,436-bp and 7,386-bp in length, respectively. Both contain genes for at least six proteins, namely E6, E7, E1, E2, L2, L1, as well as a non-coding upstream regulatory region located between the L1 and E6 genes: spanning 416-bp in HPV-150 (genomic positions 7,371 to 350) and 322-bp in HPV-151 (genomic positions 7,213 to 148). HPV-150 and HPV-151 are phylogenetically placed within the Betapapillomavirus genus and are most closely related to HPV-96 and HPV-22, respectively. As in other members of this genus, the intergenic E2-L2 region is very short and does not encode for an E5 gene. Both genotypes contain typical zinc binding domains in their E6 and E7 proteins, but HPV-151 lacks the regular pRb-binding core sequence within its E7 protein. In order to assess the tissue predilection and clinical significance of the novel genotypes, quantitative type-specific real-time PCR assays were developed. The 95% detection limits of the HPV-150 and HPV-151 assays were 7.3 copies/reaction (range 5.6 to 11.4) and 3.4 copies/reaction (range 2.5 to 6.0), respectively. Testing of a representative collection of HPV-associated mucosal and cutaneous benign and malignant neoplasms and hair follicles (total of 540 samples) revealed that HPV-150 and HPV-151 are relatively rare genotypes with a cutaneous tropism. Both genotypes were found in sporadic cases of common warts and SCC and BCC of the skin as single or multiple infections usually with low viral loads. HPV-150 can establish persistent infection of hair follicles in immuno-competent individuals. A partial L1 sequence of a putative novel HPV genotype, related to HPV-150, was identified in a squamous cell carcinoma of the skin obtained from a 64-year old immuno-compromised male patient

Differential Regulation of Cutaneous Oncoprotein HPVE6 by wtp53, Mutant p53R248W and ΔNp63α is HPV Type Dependent

UV exposure and p53 mutations are major factors in non-melanoma skin cancer, whereas a role for HPV infections has not been defined. Previous data demonstrated the wtp53-mediated degradation of cutaneous HPV20E6 by caspase-3. ΔNp63α and hot-spot mutant p53R248W conveyed a protective effect on HPV20E6 under these conditions. We demonstrate a differential regulation by wtp53 of the E6 genes of cutaneous types HPV4, HPV5, HPV7, HPV27, HPV38, HPV48, HPV60 and HPV77. Caspase- or proteasome-mediated down-regulation was HPV type dependent. Mutant p53R248W up-regulated expression of all these E6 proteins as did ΔNp63α except for HPV38E6 which was down-regulated by the latter. None of these cellular proteins affected HPV41E6 expression. Ectopic expression of both mutp53R248W and ΔNp63α in the normal NIKS keratinocyte cell line harbouring endogenous p53 and p63however led to a down-regulation of HPV20E6. We demonstrate that HPV20E6 expression in these cells is modulated by additional, yet unidentified, cellular protein(s), which are not necessarily involved in apoptosis or autophagy. We further demonstrate proliferation of HPV20E6-expressing keratinocytes. Levels of proteins involved in cell cycle control, cyclin-D1, cdk6 and p16INK4a, phosphorylated pRB, as well as c-Jun and p-c-Jun, were all increased in these cells. HPV20E6 did not compete for the interaction between p16INK4a with cyclin-D1 or cdk6. Phosphorylation of pRB in the HPV20E6 expressing cells seems to be sufficient to override the cytokenetic block induced by the p16INK4a/pRB pathway. The present study demonstrates the diverse influence of p53 family members on individual cutaneous HPVE6 proteins. HPV20E6 expression also resulted in varying protein levels of factors involved in proliferation and differentiation

Defining the Validity of Skin Self-Examination as a Screening Test for the Detection of Suspicious Pigmented Lesions: A Meta-Analysis of Diagnostic Test Accuracy.

BACKGROUND: Skin self-examination (SSE) is widely promoted for the detection of suspicious pigmented lesions. However, determining screening accuracy is essential to appraising the usefulness of SSE. OBJECTIVES: The aim of this work was to pool estimates from studies of SSE diagnostic accuracy in the detection of suspicious pigmented lesions. METHODS: This study was registered with PROSPERO (CRD42021246356) and conducted in accordance with PRISMA-DTA guidelines. A systematic search of Medline (PubMed) EMBASE, CINAHL, and The Cochrane Library was conducted to identify relevant studies. We included studies that examined the accuracy of SSE, either whole-body or site-specific, for detecting change in individual pigmented lesions or detecting an atypical naevus. A univariate random-effects model, based on logit-transformed data, was used to calculate a summary diagnostic odds ratio (DOR) as well as pooled sensitivity and specificity. Cochran's Q test and the I2 statistic were calculated to assess heterogeneity. A proportional hazards model was used to calculate the area under the curve (AUC) and plot the summary receiver operator characteristic curve. We used the Quality Assessment of Diagnostic Accuracy Studies-2 tool to grade study quality. RESULTS: We identified 757 studies, of which 3 met inclusion criteria for quantitative synthesis. The pooled sensitivity and specificity based on 553 included participants was 59 and 82%, respectively. The summary DOR was 5.88 and the AUC was 0.71. There were some concerns regarding risk of bias in all 3 studies. CONCLUSIONS: SSE can detect suspicious pigmented lesions with reasonable sensitivity and relatively high specificity, with the AUC suggesting acceptable discriminatory ability