While infection with high-risk human papillomavirus (HPV) types is necessary for cervical cancer (CC) development, it is not enough, and other risk factors are required. Several studies have reported the activation of HERV-K in different cancers; however, the investigation of HERV-K expression levels in CC is scarce. In this study, it was hypothesized that activation of HERV-K could play an essential role in CC development. In this order, the expression levels of HERV-K Env, Np9, and Rec transcripts were investigated on 147 normal to CC uterine cervical tissues using quantitative real-time PCR. The significantly higher levels of HERV-K Env and Np9 transcripts were found in patients with cervical intraepithelial neoplasia (CIN) II-III and CC groups compared to those in the normal/CIN I group. Expression of Rec transcript was also higher only in the CC group than normal/CIN I group. Among CC patients, meaningfully higher levels of HERV-K Env and Np9 transcripts were found in patients with squamous cell carcinoma rather than in adenocarcinoma. When only the HPV 16 positive samples were investigated, it was found that the mean difference in Env and Np9 mRNA levels was meaningfully higher among precancer lesions and the cancer group in comparison with the normal group. However, the Rec mRNA level showed no significant differences. The association between the expression of HERV-K genes was investigated, and a significant positive correlation of Env expression with Np9 transcript was found only in the group with precancer lesions (R = 0.6, p = 0.0037). Moreover, a significant positive correlation was found between Rec and Np9 transcripts in patients with normal cervix tissues (R = 0.26, p = 0.033). However, no correlations were observed between the expression of Env and Rec in the three groups. In conclusion, our results showed that HERV-K transcripts, especially Env and Np9, upregulated during cervical lesion progression. These findings highlight the potential use of HERV-K Env and Np9 as biomarkers for CC diagnosis and prognosis. Further investigation is needed to determine the clinical utility of these markers and whether targeting HERV-K oncogenes could be a viable therapeutic strategy for CC.

The expression analysis of human endogenous retrovirus-K Env, Np9, and Rec transcripts in cervical cancer.

Background: Endogenous retroviruses (ERV) are traces of ancestral retroviral germline infections that constitute a significant portion of mammalian genomes and function as LTR-retrotransposons. ERVs remain understudied in ruminants and usually focus on specific families, highlighting a need for comprehensive and thorough exploration of the ERV landscape in these species. Results: We characterized 23 de novo Class I and II ERV families across four reference assemblies of domestic and wild sheep and goats, and one assembly of cattle. Among these families, 15 were shared by the five ruminant species, while six were exclusive to small ruminants and two were exclusive to cattle. The presence of these families in other ruminant species revealed multiple endogenization events over 40 million years. We identified a total of 113,812 ERV insertions across the five genomes, representing between 0.5 and 1% of their genomes. Solo-LTRs account for 84.5% of the annotated copies demonstrating that most of the ERVs are relics of past events. Although Class I ERVs showed similar sequence divergence landscapes between species, Class II ERVs displayed contrasting evolutionary dynamics. Families II-3 and II-5 showed higher abundance and copy conservation in small ruminants. Family II-5 was closely related to circulating exogenous retroviruses and was identified with 22 copies sharing identical LTRs and 12 with complete coding capacities in the domestic goat. Conclusions: Our results indicate that two ERV families may have retain their transpositional activity within ruminants, particularly in domestic goats, illustrating distinct evolutionary dynamics among ruminant species. This work highlights the ongoing influence of ERVs on genomic landscapes and provides further insights into their evolutionary trajectories in ruminant genomes. 

pdf/a-genome-wide-study-of-ruminants-reveals-two-endogenous-5y3p34sk62.pdf

A genome-wide study of ruminants reveals two endogenous retrovirus families still active in goats

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections that are part the human genome and are normally silenced through epigenetic mechanisms. However, HERVs can be induced by various host and environmental factors, including viral infection, and transcriptionally active HERVs have been implicated in various physiological processes. In this review, we summarize mounting evidence of transactivation of HERVs by a wide range of DNA and RNA viruses. Though a mechanistic understanding of this phenomenon and the biological implications are still largely missing, the link between exogenous and endogenous viruses is intriguing. Considering the increasing recognition of the role of viral infections in disease, understanding these interactions provides novel insights into human health. 

Transactivation of Human Endogenous Retroviruses by Viruses

内源逆转录病毒在肿瘤和人类其他疾病中的研究进展

Avoidance of an immune response is critical to completion of the human papillomavirus (HPV) life cycle, which occurs in the stratified epithelium and is linked to epithelial differentiation. We previously demonstrated that high-risk HPVs use apoptotic caspases to suppress an antiviral innate immune response during the productive phase of the life cycle. We found that caspase-8 and caspase-3 suppress a type I IFN-β and type III IFN-λ response by disabling the MDA5/MAVS double-stranded RNA (dsRNA) sensing pathway, indicating that immunogenic RNAs increase upon differentiation in HPV+ cells. In this study, we demonstrate that caspase inhibition results in aberrant transcription of a subset of endogenous retroviruses (ERVs) that have been shown to activate an IFN response through dsRNA-sensing pathways. We show that the increase in ERV transcription is accompanied by an enrichment in dsRNA formation. Additionally, we demonstrate that the robust increase in ERV expression requires activation of the JAK/STAT-signaling pathway, indicating that this subset of ERVs is IFN-inducible. Overall, these results suggest a model by which caspase activity blocks the reactivation of ERVs through the JAK/STAT pathway, protecting HPV+ cells from an increase in immunogenic dsRNAs that otherwise would trigger an IFN response that inhibits productive viral replication. 

Apoptotic Caspases Suppress Expression of Endogenous Retroviruses in HPV31+ Cells That Are Associated with Activation of an Innate Immune Response

Endogenous human retroviruses (ERVs) are remnants of exogenous retroviruses that have integrated into the human genome. Using publicly available RNA-seq data from 63 cervical cancer patients, we investigated the expression of ERVs in cervical cancers. Four aspects of cervical cancer were investigated: patient ancestral background, tumor HPV type, tumor stage and patient survival. Between the racial subgroups, 74 ERVs were significantly differentially expressed, with Black Americans having 30 upregulated and 44 downregulated (including MER21C, HERV9-int, and HERVH-int) ERVs when compared to White Americans. We found that 3313 ERVs were differentially expressed between HPV subgroups, including MER41A, HERVH-int and HERVK9. There were 28 downregulated (including MLT1D and HERVH-int) and 61 upregulated (including MER41A) ERVs in locally advanced-stage compared to early-stage samples. Tissue microarrays of cervical cancer patients were used to investigate the protein expression of ERVs with protein coding potential (i.e., HERVK and ERV3). Significant differences in protein expression of ERV3 (p = 0.000905) were observed between early-stage and locally advanced-stage tumors. No significant differential expression at the protein level was found for HERVK7 (p = 0.243). We also investigated a prognostic model, supplementing a baseline prediction model using FIGO stage, age and HPV positivity with ERVs data. The expression levels of all ERVs in the HERVd were input into a Lasso-Cox proportional hazards model, developing a predictive 67-ERV panel. When ERVs expression levels were supplemented with the clinical data, a significant increase in prognostic power (p = 9.433 × 10−15) relative to that obtained with the clinical parameters alone (p = 0.06027) was observed. In summary, ERV RNA expression in cervical cancer tumors is significantly different among racial cohorts, HPV subgroups and disease stages. The combination of the expression of certain ERVs in cervical cancers with clinical factors significantly improved prognostication compared to clinical factors alone; therefore, ERVs may serve as future prognostic biomarkers and therapeutic targets. Novelty and Impact: When endogenous retroviral (ERV) expression signatures were combined with currently employed clinical prognosticators of relapse of cervical cancer, the combination outperformed prediction models based on clinical prognosticators alone. ERV expression signatures in tumor biopsies may therefore be useful to help identify patients at greater risk of recurrence. The novel ERV expression signatures or adjacent genes possibly impacted by ERV expression described here may also be targets for the development of future therapeutic interventions.

/pdf/endogenous-retrovirus-rna-expression-differences-between-14u9t1no.pdf

Endogenous Retrovirus RNA Expression Differences between Race, Stage and HPV Status Offer Improved Prognostication among Women with Cervical Cancer


 Objectives: Endogenous human retroviruses (ERVs) are remnants of exogenous retroviruses that gained access to germline cells allowing integration into the human genome. Emerging data suggest that some ERVs may become activated allowing epigenetic alterations through DNA methylation or histone modification, which can further alter gene regulation. This may serve as a targeted therapeutic opportunity in modulating oncogenesis, through aberrant oncogene activation or tumor suppressor gene inactivation. This is an emerging area of exploration in ovarian cancer.
 Methods: We applied our ERV mapping tools (1) to RNA-seq data from 24 female patients with ovarian, fallopian tube, or primary peritoneal cancers to investigate expression of ~550,000 ERV elements from the Human Endogenous Retrovirus database (HERVd) (2, 3). Univariate Cox regression models were constructed with normalized ERV expression data and the most significantly differentially expressed ERVs were then filtered using a penalized Lasso-Cox proportional-hazards model. ERV expression, alongside the available clinical data (including age, histotypes, and tumor stage) were provided as inputs and linear predictors generated by the model separated samples into either high or low risk categories. We identified a panel of 15 predictive ERVs and these risk evaluations allowed for Kaplan-Meier analyses of survival by clinical parameters alone versus combined with ERV signature. We also performed a secondary analysis of platinum resistant ovarian cancers using RNA-seq data (GSE102118) to investigate the effect of demethylating agent guadecitabine on ERV expression (n=9) (4).
 Results: Exploratory analyses of ERVs demonstrated significantly different expression between histologies (clear cell, mucinous, endometrioid, high grade serous) and FIGO disease stage. In our prognostic model, Kaplan-Meier survival analysis using only clinical parameters resulted in a significance level of 0.0013, however the supplemented model combining the 15-ERV panel and the clinical data discriminated the two risk groups for time to recurrence at a much higher significance level of p = 7.076 × 10−8. Included in the 15 ERV panel are HERVK, HERV3, and several putative ERV promoters including LTR12, LTR7, LTR3 and LTR4 (5). In our secondary analysis of platinum-resistant patients, the ERV transcripts were compared for each patient pre- and post-guadecitabine treatment and there were several ERVs with risk-predictive values induced in patients receiving guadecitabine including LTR7, LTR12 and HERVK.
 Conclusions: In summary, ERV RNA expression in ovarian cancer is significantly different between histologies and disease stages. The ability to successfully classify patients as either high-risk or low-risk for disease progression is of considerable value for patient management and ERVs may improve prognostication and guide future therapeutic targeting.
 Citation Format: Jill Alldredge, Vinay Kumar, Brook Sanders, Farahnaz Rahmatpanah. Endogenous human retroviruses in epithelial ovarian cancers: An exploratory analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6219.

Abstract 6219: Endogenous human retroviruses in epithelial ovarian cancers: An exploratory analysis


 Background: Non-Hispanic Black American patients (BA) with prostate cancer (PCa) tend to fare worse than their Non-Hispanic White American counterparts (WA), even with consideration of socioeconomic disparities. Clinically, BA face diagnosis at younger age with worse clinical outcomes. Stromal cells adjacent to the tumor, including carcinoma-associated fibroblasts (CAFs), play a critical role in tumorigenesis of PCa. Dysfunction in the tumor microenvironment play a crucial role in mediating prostate cancer tumorigenesis and is emerging as a key target for cancer therapy in solid tumors.
 Methods: To investigate whether DNA methylation varies in tumor adjacent stroma (TAS) among PCa patients with different geographical ancestries, areas immediate adjacent to tumor (i.e., less than 1mm) removed for methylation analysis. A complete genome-wide DNA methylation of PCa stroma using 17 BA and 15 WA patients who had radical prostatectomy was carried out. Methyl-Captured (mCap) sequencing data was generated for TAS of prostate cancer FFPE tissues. Methylated sites were identified with the MACS2 callpeak function using a band width of 300 bp and a false discovery rate of q < 0.05. A consensus peak set was derived from the aligned reads of BA and WA prostate cancer stroma samples that were sequenced. Pathway analysis was performed using Ingenuity Pathway Analysis (IPA) tools. CAFs from primary tumors of BA and WA was prepared by tissue culture and treated with demethylating agent (i.e., 5-Azacytidine) for 24 hours followed by maintenance of the cells in drug-free medium for 7-10 days and subjected to mCap sequencing.
 Results: We found racial disparities in genome-wide DNA methylation in TAS between the two populations in which BA PCa patients had significantly increased in global DNA methylation as compared to their WA counterpart (p value < 0.001). Hypomethylation occurred in CAFs from BA patients treated with 5-Azacytidine. We identified 1041 methylated sites corresponding to 409 unique genes that were differentially methylated in BA vs WA (p value < 0.05). Pathway analysis identified significant association between methylated genes in BA TAS and immune response pathways including IL-13, JACK/STAT, T cell receptors, NF-KB, and PD-1, PDL1 cancer immunotherapy. Evaluation of the methylome profile between patients based on the post-prostatectomy resection margins, negative (R0) vs positive (R1), showed that R0 resections had significantly greater (p value < 0.001) methylation than R1 resections. Further analysis identified 984 sites corresponding to 373 differentially methylated, unique genes (p value < 0.05).
 Conclusion: Tumor-adjacent stroma of BA prostate cancer patients has a distinct methylome as compared to WA patients. Differences in immune response pathways suggests a distinct immune response in TAS in men of different races.
 Citation Format: Santosh Sankaran, James Nguyen, Tara Jennings, Vinay Kumar, Michael B. Lilly, Michael M. Ittmann, Patricia Castro, Liankun Song, Thomas Keane, Weiping Chu, Xiaolin Zi, Omid Yazdanpanah, Arash Rezazadeh Kalebasty, Farah Rahmatpanah. Tumor-microenvironment from African-American prostate cancer exhibit methylation of multiple immune modulators [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2148.

Abstract 2148: Tumor-microenvironment from African-American prostate cancer exhibit methylation of multiple immune modulators


 Introduction. Prostate cancer (PCa) of American men of African ancestry (AA) is diagnosed at an earlier median age and more advanced stage with a poorer prognosis and significantly higher mortality than in Americans of primarily Northern European ancestry (EA). The mechanism of how ancestry contributes to aggressive PCa in AA patients is not well understood. Given the inherent heterogeneity and multifocality of prostate cancer, Spatial transcriptomics is of particular interest because it allows distinct cell populations within the tumor microenvironment to be characterized, and their possible effects on local tumors to be identified. Here we compare transcription between four AA and four EA patients in regions of peritumoral stroma, inflammation, Benign Prostatic Hyperplasia (BPH), and Gleason score patterns 3 (G3) and 4 (G4).
 Methods: Formalin fixed, paraffin embedded (FFPE) prostatectomy tissue blocks were obtained from 8 patients (4 AA and 4 EA) prior to treatment of the patients and matched for clinical variables (i.e., biochemical relapse, age, Gleason score, and tumor stage). 10um tissue sections were mounted onto Visium Spatial Gene Expression Slides and processed following 10x Genomics protocol. Sample counts were processed through Space Ranger. 18000 unique genes, spatial barcodes, and clinician guided annotations were imported to the R program Seurat. Data was processed using SCTransform. Significance of each transcript differences between each tissue were calculated.
 Results: Digital histologic slides of prostate cancer specimens from AA (n=4) and EA (n=4) patients were annotated by a urologic pathologist to identify regions of peritumoral stroma, inflammation, BPH, G3, and G4. Each spot was interrogated for the expression of 18000 transcripts, with an average of 17796 being detected per spot. Among the largest differences observed between AA and EA, G3 and G4 had distinct transcriptome profiles in the four AA as compared to G3 and G4 in four EA. Also, when differential expression (padj < 0.05) in peritumoral stroma was compared to G4 in AA, we identified 290 differentially expressed genes, whereas the same comparison in EA cohorts identified 600 differentially expressed genes.
 Conclusion: Spatial transcriptomic analysis revealed differences in gene expression across multiple tissue types in prostate cancer patients of different ancestries.
 Citation Format: Vinay Kumar, Dominic Castaneda, James A. Nguyen, Giovanna A. Giannico, Michael M. Ittmann, Patricia Castro, Omid Yazdanpanah, Arash Rezazadeh, Tara S. Jennings, Michael Mcclelland, Farah Rahmatpanah. Spatial transcriptomic analysis of histologically matched regions adjacent to and within prostate cancer reveals RNA expression differences between African Americans and European Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2150.

Abstract 2150: Spatial transcriptomic analysis of histologically matched regions adjacent to and within prostate cancer reveals RNA expression differences between African Americans and European Americans

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Endogenous Retrovirus RNA Expression Differences between Race, Stage and HPV Status Offer Improved Prognostication among Women with Cervical Cancer

Abstract 6219: Endogenous human retroviruses in epithelial ovarian cancers: An exploratory analysis

Abstract 2148: Tumor-microenvironment from African-American prostate cancer exhibit methylation of multiple immune modulators

Abstract 2150: Spatial transcriptomic analysis of histologically matched regions adjacent to and within prostate cancer reveals RNA expression differences between African Americans and European Americans