Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA.
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA.
Int J Cancer. 2019 May 1;144(9):2206-2214. doi: 10.1002/ijc.32038. Epub 2019 Jan 4.
Cervical cancer is driven by persistent infection of human papillomavirus (HPV), which is influenced by HPV type and intratypic variants, yet the impact of HPV type and intratypic variants on patient outcomes is far less understood. Here, we examined the association of cervical cancer stage and survival with HPV type, clade, lineage, and intratypic variants within the HPV E6 locus. Of 1,028 HPV-positive cases recruited through the CerGE study, 301 were in-situ and 727 were invasive cervical cancer (ICC), with an average post-diagnosis follow-up of 4.8 years. HPV sequencing was performed using tumor-isolated DNA to assign HPV type, HPV 16 lineage, clade, and intratypic variants within the HPV 16 E6 locus, of which nonsynonomous variants were functionally annotated by molecular modeling. HPV 18-related types were more prevalent in ICC compared to in-situ disease and associated with significantly worse recurrence-free survival (RFS) compared to HPV 16-related types. The HPV 16 Asian American lineage D3 and Asian lineage A4 associated more frequently with ICC than with in situ disease and women with an intratypic HPV 16 lineage B exhibited a trend toward worse RFS than those with A, C, or D lineages. Participants with intratypic E6 variants predicted to stabilize the E6-E6AP-p53 complex had worse RFS. Variants within the highly immunogenic HPV 16 E6 region (E14-I34) were enriched in ICC compared to in-situ lesions but were not associated with survival. Collectively, our results suggest that cervical cancer outcome is associated with HPV variants that affect virus-host interactions.
宫颈癌是由人乳头瘤病毒（HPV）持续感染引起的，HPV 类型和同型内变异会影响感染，但 HPV 类型和同型内变异对患者结局的影响还远未被充分了解。在这里，我们研究了宫颈癌分期和生存与 HPV 类型、进化枝、谱系和 HPV E6 基因座内同型内变异的关系。在 CerGE 研究中通过 HPV 阳性病例招募了 1028 例，其中 301 例为原位癌，727 例为浸润性宫颈癌（ICC），平均随访时间为 4.8 年。使用肿瘤分离的 DNA 进行 HPV 测序，以确定 HPV 类型、HPV16 谱系、进化枝和 HPV16E6 基因座内的同型内变异，其中非同义变异通过分子建模进行功能注释。与原位疾病相比，HPV18 相关类型在 ICC 中更为常见，与 HPV16 相关类型相比，复发无进展生存（RFS）显著更差。HPV16 亚洲裔美国谱系 D3 和亚洲谱系 A4 与 ICC 的相关性高于原位疾病，而 HPV16 同型内谱系 B 的女性 RFS 呈下降趋势，与 A、C 或 D 谱系相比。预测能稳定 E6-E6AP-p53 复合物的 E6 同型内变异的患者 RFS 更差。与原位病变相比，HPV16E6 区域（E14-I34）内的高度免疫原性变异在 ICC 中更为丰富，但与生存无关。总的来说，我们的结果表明，宫颈癌的结局与影响病毒-宿主相互作用的 HPV 变异有关。
