利用3200名女性的人乳头瘤病毒全基因组序列分析16型人乳头瘤病毒亚谱系与组织学特异性癌症风险的关联
HPV16 Sublineage Associations With Histology-Specific Cancer Risk Using HPV Whole-Genome Sequences in 3200 Women.
作者信息
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
机构信息
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)
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).
出版信息
J Natl Cancer Inst. 2016 Apr 29;108(9). doi: 10.1093/jnci/djw100. Print 2016 Sep.
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.
背景
人乳头瘤病毒16型（HPV16）是一种常见的性传播感染，尽管只有少数感染会导致宫颈癌前病变/癌症；我们无法区分也无法从机制上解释为什么只有某些感染会进展。HPV16可分为四个主要的进化衍生变异谱系（A、B、C、D），此前有人认为它们具有不同的疾病风险。
方法
我们使用高通量HPV16全基因组测序分析来研究3215名感染HPV16的女性中的变异谱系风险。以A1/A2亚谱系作为对照，我们评估了在三年或更长时间的随访中所有变异谱系与感染结果的关联：1107名对照受试者（<CIN2）、906名CIN2患者、1008名CIN3患者、69名鳞状细胞癌（SCC）患者、85名原位腺癌（AIS）患者和40名腺癌患者。使用逻辑回归模型来估计比值比（OR）和95%置信区间（CI）。所有统计检验均为双侧检验。
结果
A4亚谱系与癌症风险增加相关，特别是腺癌（OR = 9.81，95% CI = 2.02至47.69，P = 4.7×10⁻³）。B谱系患CIN3的风险较低（OR = 0.51，95% CI = 0.28至0.91，P = 0.02），而C谱系风险增加（OR = 2.06，95% CI = 1.09至3.89，P = 0.03）。D2/D3亚谱系与CIN3和癌症风险增加密切相关，尤其是D2（癌症的OR = 28.48，95% CI = 9.27至87.55，P = 5.0×10⁻⁹）。D2患腺性病变、原位腺癌（OR = 29.22，95% CI = 8.94至95.51，P = 2.3×10⁻⁸）和腺癌（OR = 137.34，95% CI = 37.21至506.88，P = 1.5×10⁻¹³）的风险增加最为显著。此外，特定变异谱系的癌前病变和癌症风险因女性的种族/族裔而异；那些种族/族裔与感染的HPV16变异相匹配的女性患CIN3+的风险增加（P < 0.001）。
结论
特定的HPV16变异亚谱系强烈影响癌前病变和癌症组织学类型的风险，病毒基因变异可能有助于解释其独特的致癌特性。
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