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HPV16 Sublineage Associations With Histology-Specific Cancer Risk Using HPV Whole-Genome Sequences in 3200 Women
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Abstract
Background: HPV16 is a common sexually transmitted infection although few infections lead to cervical precancer/cancer; we cannot distinguish nor mechanistically explain why only certain infections progress. HPV16 can be classified into four main evolutionary-derived variant lineages (A, B, C, D) that have been previously suggested to have varying disease risks.
Methods: We used a high-throughput HPV16 whole-genome sequencing assay to investigate variant lineage risk among 3215 HPV16-infected women. Using sublineages A1/A2 as the reference, we assessed all variant lineage associations with infection outcome over three or more years of follow-up: 1107 control subjects (<CIN2), 906 CIN2, 1008 CIN3, 69 squamous cell carcinomas (SCC), 85 adenocarcinomas in situ (AIS), and 40 adenocarcinomas. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two-sided.
Results: A4 sublineage was associated with an increased risk of cancer, specifically adenocarcinoma (OR = 9.81, 95% CI = 2.02 to 47.69, P = 4.7x10 −03 ). Lineage B had a lower risk of CIN3 (OR = 0.51, 95% CI = 0. 28 to 0.91, P = .02) while lineage C showed increased risk (OR = 2.06, 95% CI = 1.09 to 3.89, P = .03). D2/D3 sublineages were strongly associated with an increased risk of CIN3 and cancer, particularly D2 (OR for cancer = 28.48, 95% CI = 9.27 to 87.55, P = 5.0x10 −09 ). D2 had the strongest increased risk of glandular lesions, AIS (OR = 29.22, 95% CI = 8.94 to 95.51, P = 2.3x10 −08 ), and adenocarcinomas (OR = 137.34, 95% CI = 37.21 to 506.88, P = 1.5x10 −13 ). Moreover, the risk of precancer and cancer for specific variant lineages varied by a women’s race/ethnicity; those women whose race/ethnicity matched that of the infecting HPV16 variant had an increased risk of CIN3 + ( P < .001).
Conclusions: Specific HPV16 variant sublineages strongly influence risk of histologic types of precancer and cancer, and viral genetic variation may help explain its unique carcinogenic properties.