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

Lisa Mirabello, Meredith Yeager, Michael Cullen, Joseph F. Boland, Zigui Chen, Nicolas Wentzensen, Xijun Zhang, Kai Yu, Qi Yang, Jason Mitchell, David Roberson, Sara Bass, Yanzi Xiao, Laurie Burdett, Tina Raine-Bennett, Thomas Lorey, Philip E. Castle, Robert D. Burk, Mark Schiffman

Research output: Contribution to journalArticlepeer-review

117 Scopus citations


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.

Original languageEnglish (US)
Article numberdjw100
JournalJournal of the National Cancer Institute
Issue number9
StatePublished - Sep 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'HPV16 Sublineage Associations with Histology-Specific Cancer Risk Using HPV Whole-Genome Sequences in 3200 Women'. Together they form a unique fingerprint.

Cite this