Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Discov. 2023 Apr 3;13(4):910-927. doi: 10.1158/2159-8290.CD-22-0900.
The human papillomavirus (HPV) genome is integrated into host DNA in most HPV-positive cancers, but the consequences for chromosomal integrity are unknown. Continuous long-read sequencing of oropharyngeal cancers and cancer cell lines identified a previously undescribed form of structural variation, "heterocateny," characterized by diverse, interrelated, and repetitive patterns of concatemerized virus and host DNA segments within a cancer. Unique breakpoints shared across structural variants facilitated stepwise reconstruction of their evolution from a common molecular ancestor. This analysis revealed that virus and virus-host concatemers are unstable and, upon insertion into and excision from chromosomes, facilitate capture, amplification, and recombination of host DNA and chromosomal rearrangements. Evidence of heterocateny was detected in extrachromosomal and intrachromosomal DNA. These findings indicate that heterocateny is driven by the dynamic, aberrant replication and recombination of an oncogenic DNA virus, thereby extending known consequences of HPV integration to include promotion of intratumoral heterogeneity and clonal evolution.
Long-read sequencing of HPV-positive cancers revealed "heterocateny," a previously unreported form of genomic structural variation characterized by heterogeneous, interrelated, and repetitive genomic rearrangements within a tumor. Heterocateny is driven by unstable concatemerized HPV genomes, which facilitate capture, rearrangement, and amplification of host DNA, and promotes intratumoral heterogeneity and clonal evolution. See related commentary by McBride and White, p. 814. This article is highlighted in the In This Issue feature, p. 799.
人乳头瘤病毒 (HPV) 基因组在大多数 HPV 阳性癌症中整合到宿主 DNA 中，但对染色体完整性的影响尚不清楚。对口咽癌和癌细胞系的连续长读测序确定了一种以前未描述的结构变异形式，“异源连环”，其特征是在癌症中存在多样化、相互关联和重复的串联病毒和宿主 DNA 片段模式。独特的断点在结构变体之间共享，有助于逐步重建它们从共同分子祖先进化而来的过程。该分析表明，病毒和病毒-宿主串联物不稳定，并且在插入和从染色体中切除后，促进宿主 DNA 和染色体重排的捕获、扩增和重组。在染色体外和染色体内 DNA 中检测到异源连环。这些发现表明异源连环是由致癌 DNA 病毒的动态、异常复制和重组驱动的，从而将 HPV 整合的已知后果扩展到包括促进肿瘤内异质性和克隆进化。
对 HPV 阳性癌症的长读测序揭示了“异源连环”，这是一种以前未报道的基因组结构变异形式，其特征是肿瘤内存在异质、相互关联和重复的基因组重排。异源连环是由不稳定的串联 HPV 基因组驱动的，这些基因组促进了宿主 DNA 的捕获、重排和扩增，并促进了肿瘤内异质性和克隆进化。请参阅第 814 页 McBride 和 White 的相关评论。本文在本期特色文章中重点介绍，第 799 页。
