Human papilloma virus (HPV) integration signature in Cervical Cancer: identification of MACROD2 gene as HPV hot spot integration site

Abstract

Background Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality with infection by human papilloma virus (HPV) being the most important risk factor. We analysed the association between different viral integration signatures, clinical parameters and outcome in pre-treated CCs. Methods Different integration signatures were identified using HPV double capture followed by next-generation sequencing (NGS) in 272 CC patients from the BioRAIDs study [NCT02428842]. Correlations between HPV integration signatures and clinical, biological and molecular features were assessed. Results Episomal HPV was much less frequent in CC as compared to anal carcinoma (p < 0.0001). We identified >300 different HPV-chromosomal junctions (inter- or intra-genic). The most frequent integration site in CC was in MACROD2 gene followed by MIPOL1/TTC6 and TP63. HPV integration signatures were not associated with histological subtype, FIGO staging, treatment or PFS. HPVs were more frequently episomal in PIK3CA mutated tumours (p = 0.023). Viral integration type was dependent on HPV genotype (p < 0.0001); HPV18 and HPV45 being always integrated. High HPV copy number was associated with longer PFS (p = 0.011). Conclusions This is to our knowledge the first study assessing the prognostic value of HPV integration in a prospectively annotated CC cohort, which detects a hotspot of HPV integration at MACROD2; involved in impaired PARP1 activity and chromosome instability.

Circulating HPV DNA as a Marker for Early Detection of Relapse in Patients with Cervical Cancer

“…This is consistent with another retrospective study of 21 serum samples showing a poor detection rate (33%) of HPV integration site when analyzed by NGS before tumor resection (15). Hence, our results prioritize ctDNA detection by using HPV E7 sequences as a predictive biomarker of relapse when compared to HPV integration site or PIK3CA point mutations (16,27,30). However, it is well-known that HPV integration site is unique for each tumor and can be Research.…”

“…Hence, the release of multiple HPV copies from dying tumor cells into the bloodstream, contributes to an increased sensitivity of the detection method compared to that of a single point mutation (one copy/tumor cell). In addition, HPV E7 ctDNA detection rate is also superior to that of HPV integration site (Figure 2C) since it includes both the episomal and the integrated HPV (16,27). This is consistent with another retrospective study of 21 serum samples showing a poor detection rate (33%) of HPV integration site when analyzed by NGS before tumor resection (15).…”

“…In the present study from the European prospectively collected BioRAIDs (NCT02428842) cervical cancer dataset (27)(28)(29)(30)(31), the main objective was to investigate whether HPV ctDNA may be used for the early prediction of relapse after primary treatment in CC, similarly to other HPV-related cancers. Beyond HPV E7 detection in serum, we also assessed viral-cellular DNA junction sequences resulting from HPV integration into the tumor genome, together with PIK3CA mutations, a somatic marker of high prevalence in CC.…”

Prevalence and Genotype Distribution of Human Papillomavirus Infection among 12 076 Iranian Women

“…They can be classified into either oncogenic, also called high-risk HPV (HR-HPV), or non-oncogenic-low-risk HPV (LR-HPV)-groups based on their associations with malignant or benign proliferative lesions ( Al-Shabanah et al, 2013, Shafaghi et al, 2013. Although most HPV infections are transient and do not cause serious dis-ease, some persist for several years and may have great potential to cause tumor malignancy ( Jalilian et al, 2017, Kamal et al, 2021.…”

Recurrent Integration of Human Papillomavirus Genomes at Transcriptional Regulatory Hubs

“…Sites of recurrent HPV DNA integration in different tumor samples are termed integration hotspots. We defined integration hotspots (five or more sites located <5Mb apart) in our CESC dataset and compared them to previously defined hotspots from the literature 10,15,28,[36][37][38][39][40] . We identified a total of 37 hotspots in CESC tumors (Supplementary Table S4), which represented 313/584 (53.6%) integration loci from our CESC dataset (Figure 2b-c).…”