Koestler Aimee J, Nelson Chase W, Yeager Meredith, Chen Zigui, Mishra Sambit K, Burdett Laurie, Dean Michael, Suh-Burgmann Elizabeth, Lorey Thomas, Clifford Gary M, Wentzensen Nicolas, Castle Philip E, Schiffman Mark, Burk Robert D, Mirabello Lisa
Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), NIH, Rockville, Maryland, USA.
Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
Int J Cancer. 2025 Sep 15;157(6):1130-1141. doi: 10.1002/ijc.35464. Epub 2025 May 5.
Human papillomavirus type 45 (HPV45) causes ~6% of all cervical cancers and an even greater proportion of adenocarcinomas, the latter of which are challenging to detect using current cervical cancer screening. Little is known about how HPV45 genetic variation is related to the risk of cervical precancer/cancer. To investigate this, we whole-genome sequenced a total of 1,083 HPV45-positive samples from two large studies. We evaluated associations of HPV45 genetic variation (sublineages, subclades, and SNPs) with histology-specific precancer/cancer risk using logistic regression and evaluated risk modification by self-reported race/ethnicity. Compared to the common A1 sublineage, A2 and B1 were associated with increased precancer/cancer (A2, OR = 3.9, 95% CI = 1.9-8.5; B1, OR = 2.7, 95% CI = 1.3-5.8; B2, OR = 3.3, 95% CI = 1.6-7.3), and most strongly with the glandular precancers/cancers (AIS/ADC; A2, OR = 6.9, 95% CI = 1.0-184; B1, OR = 6.2, 95% CI = 1.1-159). The A2 sublineage was most prevalent in women in East Asia and women who self-reported as Asian/Pacific Islander (PI) in the U.S.; East Asian and Asian/PI women had the greatest precancer/cancer risk associated with A2 infections (OR = 5.8, 95% CI = 1.3-37.4) compared to all other sublineages among these women. We further evaluated precancer/cancer risk associations for 262 individual HPV45 SNPs and identified four SNPs significantly associated with only glandular precancers/cancers after correction for multiple tests (ORs ranged 7.8-20.7). One of these SNPs was a nonsynonymous variant in both overlapping viral E2/E4 ORFs. In summary, we show that HPV45 genetic variation influences the risk of precancer/cancer, specifically glandular precancer/cancer. Further studies of these genetic variants may improve our understanding of glandular lesions.
人乳头瘤病毒45型（HPV45）导致约6%的宫颈癌，腺癌中的占比更高，而腺癌使用当前的宫颈癌筛查方法难以检测。关于HPV45基因变异如何与宫颈癌前病变/癌症风险相关，人们知之甚少。为了对此进行研究，我们对两项大型研究中总共1083份HPV45阳性样本进行了全基因组测序。我们使用逻辑回归评估了HPV45基因变异（亚谱系、亚分支和单核苷酸多态性）与组织学特异性癌前病变/癌症风险的关联，并评估了自我报告的种族/族裔对风险的修正作用。与常见的A1亚谱系相比，A2和B1与癌前病变/癌症风险增加相关（A2，比值比[OR]=3.9，95%置信区间[CI]=1.9 - 8.5；B1，OR = 2.7，95% CI = 1.3 - 5.8；B2，OR = 3.3，95% CI = 1.6 - 7.3），与腺性癌前病变/癌症关联最为强烈（原位腺癌/腺癌；A2，OR = 6.9，95% CI = 1.0 - 184；B1，OR = 6.2，95% CI = 1.1 - 159）。A2亚谱系在东亚女性以及美国自我报告为亚裔/太平洋岛民（PI）的女性中最为常见；与这些女性中的所有其他亚谱系相比，东亚和亚裔/PI女性感染A2后患癌前病变/癌症的风险最高（OR = 5.8，95% CI = 1.3 - 37.4）。我们进一步评估了262个个体HPV45单核苷酸多态性的癌前病变/癌症风险关联，并在多重检验校正后确定了4个仅与腺性癌前病变/癌症显著相关的单核苷酸多态性（OR范围为7.8 - 20.7）。其中一个单核苷酸多态性是在重叠的病毒E2/E4开放阅读框中的非同义变异。总之，我们表明HPV45基因变异会影响癌前病变/癌症的风险，特别是腺性癌前病变/癌症。对这些基因变异的进一步研究可能会增进我们对腺性病变的理解。
