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Comprehensive multiomic characterization of human papillomavirus-driven recurrent respiratory papillomatosis reveals distinct molecular subtypes.

ABSTRACT: Recurrent respiratory papillomatosis (RRP) is a debilitating neoplastic disorder of the upper aerodigestive tract caused by chronic infection with low-risk human papillomavirus types 6 or 11. Patients with severe RRP can require hundreds of lifetime surgeries to control their disease and pulmonary papillomatosis can be fatal. Here we report the comprehensive genomic and transcriptomic characterization of respiratory papillomas. We discovered and characterized distinct subtypes with transcriptional resemblance to either a basal or differentiated cell state that associate with disease aggressiveness and differ in key molecular, immune and APOBEC mutagenesis profiles. Through integrated comparison with high-risk HPV-associated head and neck squamous cell carcinoma, our analysis revealed divergent molecular and immune papilloma subtypes that form independent of underlying genomic alterations. Cumulatively our results support the development of dysregulated cellular proliferation and suppressed anti-viral immunity through distinct programs of squamous cell differentiation and associated expression of low-risk HPV genes. These analyses provide insight into the pathogenesis of respiratory papillomas and provide a foundation for the development of therapeutic strategies.

SUBMITTER: Sievers C

PROVIDER: S-EPMC8688513 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceRecurrent respiratory papillomatosis (RRP) is a rare benign chronic disease of the larynx etiologically linked with the infection of low-risk human papillomavirus (HPV). Combination of surgical and immunomodulatory therapy has limited success. Possible use of prophylactic HPV vaccine that includes HPV-6 and HPV-11 antigens has been studied.ObjectiveTo evaluate if the HPV vaccination is associated with a lower number of recurrences requiring surgical intervention in patients with new and recurrent RRP.Design, setting, and participantsThis was a non-placebo-controlled intervention study. Enrollment data were collected from October 2011 to August 2013. The patients were followed up at 1 month, 12 months, and 5 years after the third dose of the vaccine and clinically monitored until December 31, 2018. Data were analyzed from 2019 to 2021. Altogether, 50 adults with active RRP were enrolled and followed up in referral centers. For the final outcome, follow-up data for 42 patients were available. Eight patients who did not fulfill the protocol were excluded.InterventionsAll patients received HPV vaccine as an adjuvant treatment and were clinically followed up. When RRP progression or a significant recurrent lesion was detected, surgical removal via direct laryngoscopy was indicated. No adjuvant therapy with antiviral or biological agents was used.Main outcomes and measuresThis study compared the prevaccination and postvaccination positivity for HPV-specific antibodies. The main outcome was the difference in the frequency of RRP recurrences in the prevaccination and postvaccination period.ResultsA total of 50 patients with RRP were enrolled (median [SD] age, 41.5 [12.3] years [range, 21-73 years]; 39 [78%] men and 11 [22%] women). After HPV vaccination, patients with previously no HPV-specific antibodies showed seroconversion, and all patients developed 100-fold higher levels of HPV vaccine type-specific antibodies compared with the prevaccination period. In patients with recurrent RRP, decreased frequency of recurrences requiring surgical treatment was present after vaccination (from 0.85 to 0.36 recurrences/y). No difference in postvaccination recurrences was found between patients with newly diagnosed and recurrent RRP.Conclusions and relevanceIn this nonrandomized clinical trial, the frequency of RRP recurrences was significantly lower after HPV vaccination, and patients with RRP thus had a reduced burden of disease. Because no difference was detected in the frequency of recurrent postvaccination lesions in patients with new and recurrent disease, it appears that both groups showed equal benefit following HPV vaccination. These findings suggest that the earlier that patients with RRP receive HPV vaccine, the sooner they may show reduced burden of disease.Trial registrationEudraCT Identifier: 2011-002667-14; ClinicalTrials.gov Identifier: NCT01375868.

Project description:In this cohort study we examined whether gender, age at onset, observation time or human papillomavirus (HPV) genotype are risk factors for an aggressive clinical course in Recurrent Respiratory Papillomatosis (RRP). Clinical data from patient records comprised gender, age at onset, date of first endolaryngeal procedure with biopsy, date of last follow-up, total number of endolaryngeal procedures, and complications during the observation period. Disease was defined as juvenile (JoRRP) or adult onset (AoRRP) according to whether the disease was acquired before or after the age of 18. Aggressive disease was defined as distal spread, tracheostomy, four surgical operations annually or >10 surgeries in total. DNA was extracted from formalin-fixed paraffin-embedded tissue. HPV genotyping was performed by quantitative PCR assay identifying 15 HPV genotypes. The study included 224 patients. The majority were males (141/174 in AoRRPs and 31/50 in JoRRPs; p = 0.005). The median follow-up from initial diagnosis was 12.0 years (IQR 3.7-32.9) for JoRRPs and 4.0 years (IQR 0.8-11.7) for AoRRPs. The disease was more aggressive in juveniles than adults (p<0.001), a difference that disappeared after 10 years' observation. JoRRPs with aggressive disease were younger at onset (mean difference 4.6 years, 95%CI [2.4, 6.8], p = 0.009). HPV6 or -11 was present in all HPV-positive papillomas. HPV11 was more prevalent in aggressive disease, and HPV6 in non-aggressive disease (p<0.001). Multiple logistic regression revealed that only age at onset (OR = 0.69, 95% CI [0.53, 0.88], p = 0.003) was associated with aggressive disease in juveniles, while HPV11 (OR = 3.74, 95% CI [1.40, 9.97], p = 0.008) and observation time >10 years (OR = 13.41, 95% CI [5.46, 32.99[, p<001) were risk factors in adults. In conclusion, the only significant risk factor for developing aggressive disease in JoRRPs was age at onset, but both HPV11 and observation time >10 years were risk factors for an aggressive disease course in AoRRPs.

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Comprehensive multiomic characterization of human papillomavirus-driven recurrent respiratory papillomatosis reveals distinct molecular subtypes.

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