危地马拉的宫颈癌:罕见HPV类型致癌的分子机制

Introduction: Cervical cancer (CC), the fourth most common cancer among women worldwide, continues to impose a disproportionate burden on low- and middle-income countries. In Guatemala, limited access to preventive services and screening contributes to a persistently high incidence of CC. Of more than 200 HPV types identified, 13 are classified as high-risk (hrHPV), with HPV16, 18, and 45 accounting for approximately 75% of CC cases globally. Although, these common hrHPV types are well characterized, far less is known about the oncogenic potential of rare hrHPV types, including HPV31, 33, 35, 39, 51, 52, 56, 58, 59, and 68. Their contribution to CC, particularly in high-incidence regions like Guatemala, remains insufficiently understood. To address this knowledge gap, we investigated the genetic variation of rare hrHPV types in cervical tumors from Guatemala by examining viral genome structure and associated host genomic alterations linked to carcinogenesis. Methods: In total 700 cervical tumor tissues were collected from Guatemalan patients aged 18 years and older between 2011 and 2013. A subset of 58 tumors with rare HPV types were selected for sequencing using Oxford Nanopore long-read whole-genome sequencing (WGS), with each sample achieving a minimum coverage of 30X. Raw reads were aligned to the human reference genome (hg38) and to HPV reference genomes using EPI2ME Labs. Tumor sequences were further analyzed with bioinformatic tools including IGV, BLAT, BLAST, RStudio, and MEGA to characterize HPV type, subtype, and integration or episomal patterns. Results: Of the 58 cervical tumors analyzed, 52 (90%) were confirmed to have one of ten rare hrHPV types or a probable hrHPV type (HPV26, HPV30) infection. Among these, HPV52 (19%) and HPV58 (17%) were the most frequent, followed by HPV39 (12%), HPV31 (10%), and HPV35 (10%). Across all 52 tumors, we observed a slightly higher proportion of integrated HPV forms (54%) compared with episomal forms (46%). When tumors were grouped by HPV alpha-genera, we detected alpha-5, 6, 7, 9 types with alpha-9 (65%) being the most prevalent followed by alpha-7 (19%). Episomal HPV tumors were significantly more common in alpha-9 infections (59%) compared to the combined alpha-5, 6, and 7 group (22%) (p=0.019). Conclusion: In this study, we identified rare hrHPV types in cervical tumor tissues conducted the first investigation of their molecular mechanisms using Oxford Nanopore long-read WGS. Our findings advance the understanding of how rare HPV types contribute to cervical cancer in patients from Guatemala. Ongoing analyses include bioinformatic assessment of viral and host mutations, as well as phylogenetic and statistical approaches to characterize HPV sublineages and their roles in carcinogenesis.