Genomic diversity of HPV6 and HPV11 in recurrent respiratory papillomatosis: Association with malignant transformation in the lungs and clinical outcomes

Abstract

Recurrent respiratory papillomatosis (RRP) is a rare, proliferative disease caused by human papillomavirus 6 (HPV6) and HPV11. RRP can occasionally spread and undergo malignant transformation. We analysed samples across time for five RRP patients with malignant transformation and four with highly recurrent, non-malignant RRP by applying high-throughput sequencing. Patients with malignant transformation were infected by HPV11_A1/A2, while most non-malignant cases were associated with HPV6. Transient multiple infections with HPV6 and HPV11 were found in two patients, and resolved later to single infections. Viral genome loads were homogeneous across groups (median = 78 viral genomes per human genome). Within-patient, we did not observe differences between the viral sequences in the papillomatous lesions and in the malignant tissue. Genetic analysis of the NLRP1 gene revealed no known mutations linked to idiopathic RRP, though some novel variants merit to be explored in larger cohorts. HPV11 infections appear associated with RRP malignant transformation in young patients. Multiple infections can occur in RRP, but within-patient viral diversity is minimal for a given genotype. Our results confirm the importance of viral genotype in disease prognosis and are consistent with growing evidence of HPV11 infections to be differentially associated with RRP malignant transformation in young patients.

Keywords: HPV11; HPV6; Human papillomavirus; Lineage; Malignant transformation; NLRP1; Recurrent respiratory papillomatosis; Squamous cell carcinoma; Variant; Viral diversity; Within-patient diversity.

Fig. 1

Histology of RRP from laryngeal papilloma to squamous cell carcinoma in patient T1 (A) Laryngeal papilloma of T1 in 2008 (sample T1_B). Left: conjonctivo-vascular axis (∗) lined by hyperplastic squamous epithelium (∗). Right: Higher magnification of the squamous epithelium: koïlocytes (ß) and basal cell hyperplasia with mitosis (∗). (B) Lung papilloma of T1 in 2011 (sample T1_C). Left and higher magnification at right: Squamous papillomatous proliferation (∗) extension inside alveolar spaces. (C) Lung squamous cell carcinoma of T1 in 2018 (sample T1_D). Left and higher magnification at right: lung parenchyma destruction by squamous cell carcinoma, presence of fibrous stroma (∗).