Human Cancer Genetics Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA;
Genome Res. 2014 Feb;24(2):185-99. doi: 10.1101/gr.164806.113. Epub 2013 Nov 7.
Genomic instability is a hallmark of human cancers, including the 5% caused by human papillomavirus (HPV). Here we report a striking association between HPV integration and adjacent host genomic structural variation in human cancer cell lines and primary tumors. Whole-genome sequencing revealed HPV integrants flanking and bridging extensive host genomic amplifications and rearrangements, including deletions, inversions, and chromosomal translocations. We present a model of "looping" by which HPV integrant-mediated DNA replication and recombination may result in viral-host DNA concatemers, frequently disrupting genes involved in oncogenesis and amplifying HPV oncogenes E6 and E7. Our high-resolution results shed new light on a catastrophic process, distinct from chromothripsis and other mutational processes, by which HPV directly promotes genomic instability.
基因组不稳定性是人类癌症的一个标志，包括 5%由人乳头瘤病毒 (HPV) 引起的癌症。在这里，我们报告了 HPV 整合与人类癌细胞系和原发性肿瘤中相邻宿主基因组结构变异之间的惊人关联。全基因组测序显示，HPV 整合体侧翼和桥接广泛的宿主基因组扩增和重排，包括缺失、倒位和染色体易位。我们提出了一种“环化”模型，其中 HPV 整合体介导的 DNA 复制和重组可能导致病毒-宿主 DNA 连接物，经常破坏参与致癌的基因，并扩增 HPV 癌基因 E6 和 E7。我们的高分辨率结果为这一灾难性过程提供了新的认识，该过程不同于染色体重排和其他突变过程，HPV 通过该过程直接促进基因组不稳定性。
