Introduction

HPV6 and HPV11 cause Recurrent Respiratory Papillomatosis (RRP), a rare disease characterized by the growth of papillomas in the airway. The clinical course of RRP is highly variable, and the factors that drive an aggressive versus an indolent course are largely unknown.

Objective: To determine if HPV6 and HPV11 genome variation is related to the clinical course of RRP patients, and if specific HPV6/11 variants are associated with RRP compared to 351 anogenital infections, using a large multicenter international collection of 436 RRP patients.

Methods

We whole-genome sequenced HPV6 (N=267) and/or HPV11 (N=170) DNA from RRP patients from 35 international centers. 351 anogenital HPV6/11 genomes for comparison were from our NCI-SUCCEED study and also retrieved from GenBank. We evaluated if HPV6/11 sublineages and SNPs were associated with RRP compared to anogenital infections restricted to White individuals, and if they were associated with RRP clinical course (e.g., aggressive vs. indolent) or age at diagnosis.

Results

The RRP HPV6/11 sublineage distribution was significantly different than that in anogenital infections (P=0.004). Compared to anogenital infections, HPV11 A2 was disproportionally more frequent in RRP (OR=1.8, 95%CI=1.2-2.6, P=0.002). Importantly, there were significant differences in the lineages present in aggressive vs. indolent RRP (P=0.046), severe pulmonary vs. not pulmonary RRP (P=0.001), and by age at RRP diagnosis (P=3.7x10^-6). In particular, the HPV11 A2 sublineage was strongly associated with pulmonary RRP (OR=10.8, 95%CI=3.0-38.3, P= 2.3x10^-4). Three individual SNPs within HPV11, two in the E1 gene and one in the E2 gene, were associated with aggressive vs. indolent disease course (e.g., E1 SNP, OR=2.4, 95%CI=1-5.9, P=0.029).

Conclusions

HPV6 and HPV11 genetic variation influences the occurrence and clinical course of RRP. The HPV11 A2 sublineage was most associated with severe pulmonary RRP.

Introduction

HPV-driven oropharynx cancer (OPC) has increased over the past decades in developed countries and is predominantly related to HPV16 infection. Little is known about HPV16 genetic variation in OPC.

Objective: To relate HPV16 genetic variation and OPC for each sublineage and SNP observed in whole-genome sequencing of HPV16, compared to HPV16 in cervical infections, from a total of 4,668 individuals from the U.S. or European regions (primarily White).

Methods

We whole-genome sequenced viral DNA from 253 HPV16-positive OPC from the U.S. University of Pittsburgh or Vanderbilt University Medical Centers and compared viral genomes to 4,415 women with cervical precancer (CIN2/CIN3/AIS; n=2,515), cancer (n=113), or benign (<CIN2; n=1,455) infections from two U.S. NCI studies (KPNC PaP, SUCCEED) and cancers collected by IARC (n=332). We assessed HPV16 sublineages, SNPs and rare variant distributions in OPC compared to HPV16 at the cervix.

Results

The HPV16 sublineage distribution was significantly different in OPC compared to cervical benign infections (P=1.0x10^-8), precancers (P=5x10^-6) and cancers (P=0.016), particularly compared to cervical adenocarcinoma (P=6.3x10^-16). The OPC sublineage distribution was most similar to cervical squamous cell carcinomas (SCC;P=0.18); with a similar enrichment of sublineages A4 (P=5.6x10^-6) and D2/3 (P=0.002) compared to benign infections. Interestingly, A2 was uniquely more frequent in OPC compared to all cervical infections (P=3.1x10^-5). Several individual SNPs, independent of sublineage-defining sites, were enriched in OPC compared to cervical cancers (P<0.05). Comparing OPC to cervical cancer, the strongest difference observed was a SNP within the A2 sublineage (URR snp, OR=5.2, 95%CI=3.1-8.6, P=2.8x10^-10). Combined rare variant analyses determined that OPC had similar hypovariation in E7 to cervical cancers, with higher variation within E6.

Conclusions

OPC HPV16 genetic variation is most similar to cervical SCC. There are some unique differences in OPC that may influence oropharyngeal carcinogenicity; HPV16 variants may help explain its unique ability to cause cancer at multiple anatomic sites.