Genomic characterization of viral integration sites in HPV‐related cancers

Abstract

Persistent infection with carcinogenic human papillomaviruses (HPV) causes the majority of anogenital cancers and a subset of head and neck cancers. The HPV genome is frequently found integrated into the host genome of invasive cancers. The mechanisms of how it may promote disease progression are not well understood. Thoroughly characterizing integration events can provide insights into HPV carcinogenesis. Individual studies have reported limited number of integration sites in cell lines and human samples. We performed a systematic review of published integration sites in HPV-related cancers and conducted a pooled analysis to formally test for integration hotspots and genomic features enriched in integration events using data from the Encyclopedia of DNA Elements (ENCODE). Over 1,500 integration sites were reported in the literature, of which 90.8% (N = 1,407) were in human tissues. We found 10 cytobands enriched for integration events, three previously reported ones (3q28, 8q24.21 and 13q22.1) and seven additional ones (2q22.3, 3p14.2, 8q24.22, 14q24.1, 17p11.1, 17q23.1 and 17q23.2). Cervical infections with HPV18 were more likely to have breakpoints in 8q24.21 (p = 7.68 × 10(-4) ) than those with HPV16. Overall, integration sites were more likely to be in gene regions than expected by chance (p = 6.93 × 10(-9) ). They were also significantly closer to CpG regions, fragile sites, transcriptionally active regions and enhancers. Few integration events occurred within 50 Kb of known cervical cancer driver genes. This suggests that HPV integrates in accessible regions of the genome, preferentially genes and enhancers, which may affect the expression of target genes.

HPV16 integration probably contributes to cervical oncogenesis through interrupting tumor suppressor genes and inducing chromosome instability

“…In a systematic screen on more than 1500 integration sites of HPV, Bodelon et al found few integration events happening in the neighborhood of cancer driver genes [10]. In our study, we discovered several integration sites located inside the introns of tumor suppressor genes (including the famous SCAI gene), implying a link between HPV integration and cervical oncogenesis, probably through manipulating the expression of cancer related genes.…”

“…Based on the observation that integration sites were closely linked to transcriptionally active regions, fragile sites, CpG regions, and enhancers, they proposed that HPV tend to integrate in open chromatin regions, which might affect the transcription of corresponding genes. Another interesting finding in their study was that HPV integration events rarely occurred in the vicinity of known cervical cancer driver genes (within 50 Kb) [10]. …”

The role of integration in oncogenic progression of HPV-associated cancers

“…Jeon and Lambert demonstrated that these fusion transcripts are very often more stable than their viral counterparts, yet again increasing HPV oncogene expression [18]. There are also cases in which an oncogenic HPV has integrated in the vicinity of a cellular oncogene or tumor suppressor gene [2, 19], but this is not thought to be a universal way in which HPV promotes oncogenesis.…”

“…These so-called genomic “hotspots” are highly correlated with common fragile sites [31] and transcriptionally active regions of the genome [19, 32]. Regions of microhomology (1–10 bp) between viral and human genomic sequences are sometimes found at integration breakpoints [2], as have AT-rich regions of the genome that have the potential to form stem—loop structures that promote the formation of stalled replication forks during replication stress [28].…”

Smoking and papillomavirus DNA in patients with p16‐positive N3 oropharyngeal squamous cell carcinoma

“…The adverse effect of smoking on tumor control in HPV‐related patients has been previously attributed to hypoxia as well as the immune suppressive effect of tobacco . However, a number of hypotheses remain to be explored today such as a questionable difference between smoking‐ and papillomavirus‐induced genetic alterations …”