Dataset Information

HPV transcription in skin tumors.

ABSTRACT:

Background

Although more than 95% of viral sequences found in skin tumors typically belong to human papillomaviruses (HPVs), HPV transcription has so far not been detected. As current technology allows very deep transcriptome sequencing, we examined skin tumors and precursor lesions for HPV transcription.

Method

Fresh frozen biopsies from 12 skin specimens (11/12 were positive for HPV DNA) were subjected to total RNA sequencing. The cervical cancer cell line CaSki was included as a positive control for HPV transcription.

Results

HPV RNA was detected and confirmed in 1/12 skin lesions at a median depth of 66 million reads per sample. One specimen was positive for HPV 110 transcripts mapping to E6, E7, E2/E4 and L2 open reading frames, as well as to a spliced E1^E4 transcript.

Conclusion

In conclusion, the study revealed that a minority of skin lesions contains HPV transcripts and that HPV DNA detection does not predict HPV transcriptional activity.

SUBMITTER: Hultin E

PROVIDER: S-EPMC6544312 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

HPV transcription in skin tumors.

Hultin Emilie E Arroyo Mühr Laila Sara LS Lagheden Camilla C Dillner Joakim J

PloS one 20190531 5

<h4>Background</h4>Although more than 95% of viral sequences found in skin tumors typically belong to human papillomaviruses (HPVs), HPV transcription has so far not been detected. As current technology allows very deep transcriptome sequencing, we examined skin tumors and precursor lesions for HPV transcription.<h4>Method</h4>Fresh frozen biopsies from 12 skin specimens (11/12 were positive for HPV DNA) were subjected to total RNA sequencing. The cervical cancer cell line CaSki was included as ...[more]

PMID: 31150522

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Project description:Many malignancies that occur in high excess in kidney transplant recipients (KTRs) are due to viruses that thrive in the setting of immunosuppression. Keratinocyte carcinoma (KC), the most frequently occurring cancer type in KTR, has been associated with skin infection by human papillomavirus (HPV) from the beta genus. In this report, we extend our previous investigation aimed at identifying the presence of active β-HPV infection in skin tumors from KTRs through detection of viral protein expression. Using a combination of antibodies raised against the E4 and L1 proteins of the β-genotypes, we were able to visualize infection in five tumors [one keratoacanthoma (KA), three actinic keratoses (AKs), and one seborrheic keratoses (SKs)] that were all removed from two patients who had been both transplanted twice, had developed multiple KCs, and presented with a long history of immunosuppression (>30 years). These infected tissues displayed intraepidermal hyperplasia and increased expression of the ΔNp63 protein, which extended into the upper epithelial layers. In addition, using a xenograft model system in nude mice displaying a humanized stromal bed in the site of grafting, we successfully engrafted three AKs, two of which were derived from the aforementioned KTRs and displayed β-HPV infection in the original tumor. Of note, one AK-derived xenograft, along with its ensuing lymph node metastasis, was diagnosed as squamous cell carcinoma (SCC). In the latter, both β-HPV infection and ΔNp63 expression were no longer detectable. Although the overall success rate of engrafting was very low, the results of this study show for the first time that β-HPV+ and ΔNp63+ intraepidermal hyperplasia can indeed progress to an aggressive SCC able to metastasize. Consistent with a series of reports attributing a causative role of β-HPV at early stages of skin carcinogenesis through ΔNp63 induction and increased keratinocytes stemness, here we provide in vivo evidence that these events are also occurring in the affected skin of KTRs. Due to these β-HPV-driven molecular pathways, the nascent tumor cell is able to acquire a high enough number of carcinogenic insults that its proliferation and survival will eventually become independent of viral gene expression.

Project description:We analyzed transcriptional data from 104 HPV+ (Human papillomavirus) HNSCC (head and neck squamous cell carcinoma) tumors together with two publicly available sources to identify highly robust transcriptional programs (modules) which could be detected consistently despite heterogeneous sequencing and quantification methodologies. Among 22 modules identified, we found a single module that naturally subclassifies HPV+ HNSCC tumors based on a bimodal pattern of gene expression, clusters all atypical features of HPV+ HNSCC biology into a single subclass, and predicts patient outcome in four independent cohorts. The subclass-defining gene set was strongly correlated with Nuclear factor kappa B (NF-κB) target expression. Tumors with high expression of this NF-κB module were rarely associated with activating PIK3CA alterations or viral integration, and also expressed higher levels of HPHPV E2 and had decreased APOBEC mutagenesis. Alternatively, they harbored inactivating alterations of key regulators of NF-κB, TNF receptor associated factor 3 (TRAF3), and cylindromatosis (CYLD), as well as retinoblastoma protein (RB1). HPV+ HNSCC cells in culture with experimental depletion of TRAF3 or CYLD displayed increased expression of the subclass-defining genes, as well as robust radio-sensitization, thus recapitulating both the tumor transcriptional state and improved treatment response observed in patient data. Across all gene sets investigated, methylation to expression correlations were the strongest for the subclass-defining, NF-κB-related genes. Increased tumor-infiltrating CD4+ T cells and increased Estrogen receptors alpha (ERα) expression were identified in NF-κB active tumors. Based on the relatively high rates of cure in HPV+ HNSCC, deintensification of therapy to reduce treatment-related morbidity is being studied at many institutions. Tumor subclassification based on oncogenic subtypes may help guide the selection of therapeutic intensity or modality for patients with HPV+ HNSCC.

Dataset Information

HPV transcription in skin tumors.

Background

Method

Results

Conclusion

Publications

HPV transcription in skin tumors.

Similar Datasets

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