TY - JOUR
T1 - HPV16 Sublineage Associations with Histology-Specific Cancer Risk Using HPV Whole-Genome Sequences in 3200 Women
AU - Mirabello, Lisa
AU - Yeager, Meredith
AU - Cullen, Michael
AU - Boland, Joseph F.
AU - Chen, Zigui
AU - Wentzensen, Nicolas
AU - Zhang, Xijun
AU - Yu, Kai
AU - Yang, Qi
AU - Mitchell, Jason
AU - Roberson, David
AU - Bass, Sara
AU - Xiao, Yanzi
AU - Burdett, Laurie
AU - Raine-Bennett, Tina
AU - Lorey, Thomas
AU - Castle, Philip E.
AU - Burk, Robert D.
AU - Schiffman, Mark
N1 - Publisher Copyright:
© 2016 Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the United States.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
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U2 - 10.1093/jnci/djw100
DO - 10.1093/jnci/djw100
M3 - Article
C2 - 27130930
AN - SCOPUS:84989184550
SN - 0027-8874
VL - 108
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 9
M1 - djw100
ER -
