title: HPV16 Sublineage Associations With Histology-Specific Cancer Risk Using HPV Whole-Genome Sequences in 3200 Women.
abstract: 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.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB) mirabellol@mail.nih.gov.
authors.forename: Lisa
authors.initials: L
authors.lastname: Mirabello
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB).
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB).
authors.forename: Michael
authors.initials: M
authors.lastname: Cullen
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB).
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Boland
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB).
authors.forename: Zigui
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB).
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wentzensen
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB).
authors.forename: Xijun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB).
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB).
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB).
authors.forename: Jason
authors.initials: J
authors.lastname: Mitchell
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB).
authors.forename: David
authors.initials: D
authors.lastname: Roberson
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB).
authors.forename: Sara
authors.initials: S
authors.lastname: Bass
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB).
authors.forename: Yanzi
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB).
authors.forename: Laurie
authors.initials: L
authors.lastname: Burdett
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB).
authors.forename: Tina
authors.initials: T
authors.lastname: Raine-Bennett
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB).
authors.forename: Thomas
authors.initials: T
authors.lastname: Lorey
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB).
authors.forename: Philip E
authors.initials: PE
authors.lastname: Castle
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB).
authors.forename: Robert D
authors.initials: RD
authors.lastname: Burk
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (LM, MY, MC, JFB, NW, XZ, KY, QY, JM, DR, SB, LB, YX, MS); Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD (MY, MC, JFB, XZ, QY, JM, DR, SB, LB); Department of Microbiology, The Chinese University of Hong Kong, Hong Kong (ZC); Women's Health Research Institute, Division of Research, Kaiser Permanente Northern California, Oakland CA (TRB); Regional Laboratory, Kaiser Permanente Northern California, Oakland, CA (TL); Department of Epidemiology and Population Health, at Albert Einstein College of Medicine, Bronx, NY (PEC, RDB); Departments of Pediatrics; Microbiology & Immunology; and, Obstetrics, Gynecology and Women's Health, at Albert Einstein College of Medicine, Bronx, NY (RDB).
authors.forename: Mark
authors.initials: M
authors.lastname: Schiffman
mesh_terms: D000230:Adenocarcinoma / Q000208:ethnology / Q000821:virology; D065311:Adenocarcinoma in Situ / Q000208:ethnology / Q000821:virology; D000328:Adult; D000359:Aftercare; D002140:California / Q000453:epidemiology; D002277:Carcinoma / Q000208:ethnology / Q000821:virology*; D002294:Carcinoma, Squamous Cell / Q000208:ethnology / Q000821:virology; D005260:Female; D016678:Genome; D059014:High-Throughput Nucleotide Sequencing; D052162:Human papillomavirus 16 / Q000145:classification* / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000208:ethnology / Q000821:virology*; D010802:Phylogeny; D011230:Precancerous Conditions / Q000208:ethnology / Q000821:virology*; D012307:Risk Factors; D002583:Uterine Cervical Neoplasms / Q000208:ethnology / Q000821:virology*; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000208:ethnology / Q000821:virology