Abstract
Human papillomavirus (HPV) integration is the major contributor to cervical cancer (CC) development by inducing structural variations (SVs) in the human genome. SVs are directly associated with the three-dimensional (3D) genome structure leading to cancer development. The detection of SVs is not a trivial task, and several genome-wide techniques have greatly helped in the identification of SVs in the cancerous genome. However, in cervical cancer, precise prediction of SVs mainly translocations and their effects on 3D-genome and gene expression still need to be explored. Here, we have used high-throughput chromosome conformation capture (Hi-C) data of cervical cancer to detect the SVs, especially the translocations, and validated it through whole-genome sequencing (WGS) data. We found that the cervical cancer 3D-genome architecture rearranges itself as compared to that in the normal tissue, and 24% of the total genome switches their A/B compartments. Moreover, translocation detection from Hi-C data showed the presence of high-resolution t(4;7) (q13.1; q31.32) and t(1;16) (q21.2; q22.1) translocations, which disrupted the expression of the genes located at and nearby positions. Enrichment analysis suggested that the disrupted genes were mainly involved in controlling cervical cancer-related pathways. In summary, we detect the novel SVs through Hi-C data and unfold the association among genome-reorganization, translocations, and gene expression regulation. The results help understand the underlying pathogenicity mechanism of SVs in cervical cancer development and identify the targeted therapeutics against cervical cancer.
Highlights
Cervical cancer (CC) is the fourth most common cancer affecting women worldwide
DLO HiC tool first filtered out the same (AA, BB) as well as the different (AB, BA) linkers, ∼285 million for normal tissues ∼146, ∼142, ∼156, and ∼162 million reads were obtained from four cervical cancer tissue replicates (Supplementary Table 2)
high-throughput chromosome conformation capture (Hi-C) results showed the numbers of valid reads of normal sample CRX040578, cervical cancer tissue CRX040576, and cervical cancer tissue CRX040577 as 60,929,741, 28,518,853, and 36,389,304, respectively (Supplementary Table 3)
Summary
Cervical cancer (CC) is the fourth most common cancer affecting women worldwide. Cervical Cancer Development Mechanism Identification due to several genomic changes such as gene mutations, insertion/deletions, and chromosomal rearrangements (Engreitz et al, 2012). Several studies have suggested that human papillomavirus (HPV) is the leading cause of cervical cancer and HPV genome integration is the key mechanism. Reported studies had suggested that the HPV integration hotspots, molecular pathogenesis, the role of episomal HPV E6/E7 expression, and HPV integration in human genome 3D structure (Fudenberg et al, 2011; Koneva et al, 2018; Cao et al, 2020) play a vital role in cervical cancer development (Garraway and Lander, 2013)
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