HPV16 Sublineage Associations With Histology-Specific Cancer Risk Using HPV Whole-Genome Sequences in 3200 Women

• Published in: JNCI : Journal of the National Cancer Institute Vol. 108; no. 9; p. djw100
• Main Authors: Mirabello, Lisa, Yeager, Meredith, Cullen, Michael, Boland, Joseph F., Chen, Zigui, Wentzensen, Nicolas, Zhang, Xijun, Yu, Kai, Yang, Qi, Mitchell, Jason, Roberson, David, Bass, Sara, Xiao, Yanzi, Burdett, Laurie, Raine-Bennett, Tina, Lorey, Thomas, Castle, Philip E., Burk, Robert D., Schiffman, Mark
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.09.2016
• Subjects: Adenocarcinoma - ethnology; Adenocarcinoma - virology; Adenocarcinoma in Situ - ethnology; Adenocarcinoma in Situ - virology; Adult; Aftercare; California - epidemiology; Carcinoma - ethnology; Carcinoma - virology; Carcinoma, Squamous Cell - ethnology; Carcinoma, Squamous Cell - virology; Female; Genome; High-Throughput Nucleotide Sequencing; Human papillomavirus 16 - classification; Human papillomavirus 16 - genetics; Human papillomavirus 16 - pathogenicity; Humans; Middle Aged; Papillomavirus Infections - ethnology; Papillomavirus Infections - virology; Phylogeny; Precancerous Conditions - ethnology; Precancerous Conditions - virology; Risk Factors; Uterine Cervical Dysplasia - ethnology; Uterine Cervical Dysplasia - virology; Uterine Cervical Neoplasms - ethnology; Uterine Cervical Neoplasms - virology; Young Adult
• ISSN: 0027-8874; 1460-2105; 1460-2105
• DOI: 10.1093/jnci/djw100

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. 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. 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). 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.