HPV alternative splicing in cervical cancer radiation response

项目总结/摘要 人乳头瘤病毒（HPV）感染是宫颈癌的主要病因。局部晚期宫颈 癌症（LACC）是不可治愈的，在标准护理放化疗（CRT）后具有高复发率。 高危型HPV基因型已经进化出复杂的调控策略来严格控制病毒基因表达 和选择性剪接。最近的研究表明，一些选择性剪接的HPV基因具有不同的 在宫颈肿瘤复制和肿瘤发生中的功能比它们的全长癌基因对应物更强。之比 全长和选择性剪接的HPV转录物的表达在具有不同高风险的宫颈肿瘤中可能不同。 HPV基因型。我们手动检查了全转录组测序（RNA-seq）数据， 含有选择性剪接HPV转录物和长基因间非 蛋白质编码的人类RNA（lncRNA）。HPV选择性剪接在宫颈癌生物学中很重要; 然而，目前尚不清楚选择性剪接的HPV转录物是否影响化疗和放疗反应。 宫颈癌患者。这项拟议中的研究将确定选择性剪接的HPV转录本是否 对宫颈癌患者的预后和机制具有重要意义。具体来说，我们将 使用HPV转化的DNA片段来确定选择性剪接的HPV转录物是否调节辐射反应。 宫颈癌细胞和端粒酶逆转录酶（hTERT）转化的宫颈上皮细胞。我们 还将评估选择性剪接的HPV转录物是否可以作为不同HPV的生物标志物 使用cDNA捕获测序数据和来自已建立的LACC患者队列的临床数据分析基因型 用治疗性CRT均匀治疗。最后，我们将开发新的算法来识别病毒宿主基因 融合并使用RNA-seq数据和临床结果数据检查其功能后果。成功 这项转化研究的完成将确定选择性剪接的HPV转录本是准确的， LACC的预后分子生物标志物和合适的新靶点。建立机制功能， HPV选择性剪接在宫颈癌放射反应中的作用将最终促进 优化治疗并改善患者预后。

PROJECT SUMMARY/ABSTRACT Human papillomavirus (HPV) infection is the primary cause of cervical carcinoma. Locally advanced cervical cancer (LACC) is incurable with a high recurrence rate after standard-of-care chemoradiation therapy (CRT). High-risk HPV genotypes have evolved complex regulatory strategies to tightly control viral gene expression and alternative splicing. Recent studies indicate that some alternatively spliced HPV genes have different functions in cervical tumor replication and oncogenesis than their full-length oncogene counterparts. The ratio of full-length and alternatively spliced HPV transcripts can vary in cervical tumors harboring different high-risk HPV genotypes. We manually inspected whole transcriptome sequencing (RNA-seq) data and discovered recurrent HPV-human gene fusions containing alternatively spliced HPV transcripts and long intergenic non- protein-coding human RNAs (lncRNA). HPV alternative splicing is important in cervical cancer biology; however, it is still unclear whether alternatively spliced HPV transcripts affect the chemoradiation response in cervical cancer patients. The proposed research will determine whether alternatively spliced HPV transcripts have prognostic and mechanistic significance for patient outcomes in cervical cancer. Specifically, we will determine whether alternatively spliced HPV transcripts modulate radiation response using HPV-transformed cervical cancer cells and telomerase-reverse-transcriptase (hTERT) transformed cervical epithelial cells. We will also evaluate whether alternatively spliced HPV transcripts can serve as biomarkers for different HPV genotypes using cDNA capture sequencing data and clinical data from an established cohort of LACC patients uniformly treated with curative-intent CRT. Finally, we will develop novel algorithms to identify viral-host gene fusions and examine their functional consequences using RNA-seq data and clinical outcome data. Successful completion of this translational research will identify alternatively spliced HPV transcripts as accurate prognostic molecular biomarkers and suitable novel targets in LACC. Establishing the mechanistic function of HPV alternative splicing in cervical cancer radiation response will ultimately facilitate the development of optimized therapies and improve patient outcomes.