Research Article: HPV transcription in skin tumors

Date Published: May 31, 2019

Publisher: Public Library of Science

Author(s): Emilie Hultin, Laila Sara Arroyo Mühr, Camilla Lagheden, Joakim Dillner, Maria Lina Tornesello.


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.

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.

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.

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.

Partial Text

Human papillomaviruses (HPVs) infect keratinocytes in both mucosa and skin and can cause several diseases from benign lesions to malignant tumors [1, 2]. Cutaneous HPV types are often found both in healthy skin as well as in skin lesions such as benign skin warts [3], non-melanoma skin cancers (NMSCs) including squamous cell carcinoma (SCC) and basal cell carcinoma [4], actinic keratosis (precancerous skin lesions), keratoacanthomas (benign skin tumors) and Bowen’s disease (SCC in situ). The increased incidence of NMSCs among immunosuppressed patients has suggested that infectious agent(s) may be involved [5–9]. Metagenomic sequencing has revealed that more than 95% of the viral sequences present in skin tumor samples belong to the family Papillomaviridae [10], mostly to the cutaneous types belonging to beta and gamma genera [11, 12]. Patients with the skin disorder epidermodysplasia verruciformis, where beta-human papillomavirus infection is a phenotypic condition, develop NMSCs and are suspected to have a defect of immunity to beta-HPV [13]. This suggests that HPV may be involved in NMSC development.

Cutaneous HPVs are commonly detected both on healthy skin [34, 35] and in skin diseases [4, 19]. However, the cutaneous HPVs are only rarely present at more than 1 viral copy per cell [15, 22–24] and HPV transcription has not been detected in skin [26, 27]. We detected and confirmed HPV RNA in 1/12 skin lesions, with HPV 110 being found in one actinic keratosis lesion. The HPV 110 reads mapped to the E1^E4 spliced transcript, which is the most abundant transcript during an HPV infection, in both low grade and high grade lesions [36–38].