Genomic instability and genetic mutations can lead to exhibition of several cancer hallmarks in affected cells such as sustained proliferative signaling, evasion of growth suppression, activated invasion, deregulation of cellular energetics, and avoidance of immune destruction. Similar biological changes have been observed to be a result of pathogenic viruses and, in some cases, have been linked to virus-induced cancers. Human endogenous retroviruses (HERVs), once external pathogens, now occupy more than 8% of the human genome, representing the merge of genomic and external factors. In this review, we outline all reported effects of HERVs on cancer development and discuss the HERV targets most suitable for cancer treatments as well as ongoing clinical trials for HERV-targeting drugs. We reviewed all currently available reports of the effects of HERVs on human cancers including solid tumors, lymphomas, and leukemias. Our review highlights the central roles of HERV genes, such as gag, env, pol, np9, and rec in immune regulation, checkpoint blockade, cell differentiation, cell fusion, proliferation, metastasis, and cell transformation. In addition, we summarize the involvement of HERV long terminal repeat (LTR) regions in transcriptional regulation, creation of fusion proteins, expression of long non-coding RNAs (lncRNAs), and promotion of genome instability through recombination.

Hispanic children with acute lymphoblastic leukemia (ALL) experience poorer overall survival (OS) than non-Hispanic White children; however, few studies have investigated the social determinants of this disparity. In Texas, many Hispanic individuals reside in ethnic enclaves—areas with high concentrations of immigrants, ethnic-specific businesses, and language isolation, which are often socioeconomically deprived. We determined whether enclave residence was associated with ALL survival, overall and among Hispanic children. We computed Hispanic enclave index scores for Texas census tracts, and classified children (N = 4083) as residing in enclaves if their residential tracts scored in the highest statewide quintile. We used Cox regression to evaluate the association between enclave residence and OS. Five-year OS was 78.6% for children in enclaves, and 77.8% for Hispanic children in enclaves, both significantly lower (p < 0.05) than the 85.8% observed among children not in enclaves. Children in enclaves had increased risk of death (hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.01–1.49) after adjustment for sex, age at diagnosis, year of diagnosis, metropolitan residence and neighborhood socioeconomic deprivation and after further adjustment for child race/ethnicity (HR 1.19, 95% CI 0.97–1.45). We observed increased risk of death when analyses were restricted to Hispanic children specifically (HR 1.30, 95% CI 1.03–1.65). Observations suggest that children with ALL residing in Hispanic enclaves experience inferior OS.

BACKGROUND: Kaposi sarcoma (KS) is among the most common childhood cancers in Eastern and Central Africa. Pediatric KS has a distinctive clinical presentation compared with adult KS, which includes a tendency for primary lymph node involvement, a considerable proportion of patients lacking cutaneous lesions, and a potential for fulminant disease. The molecular mechanisms or correlates for these disease features are unknown. METHODS: This was a cross-sectional study. All cases were confirmed by IHC for KS-associated herpesvirus (KSHV) LANA protein. Baseline blood samples were profiled for HIV and KSHV genome copy numbers by qPCR and secreted cytokines by ELISA. Biopsies were characterized for viral and human transcription, and KSHV genomes were determined when possible. RESULTS: Seventy participants with pediatric KS were enrolled between June 2013 and August 2019 in Malawi and compared with adult patients with KS. They exhibited high KSHV genome copy numbers and IL-6/IL-10 levels. Four biopsies (16%) had a viral transcription pattern consistent with lytic viral replication. CONCLUSION: The unique features of pediatric KS may contribute to the specific clinical manifestations and may direct future treatment options. FUNDING: US National Institutes of Health U54-CA-254569, PO1-CA019014, U54-CA254564, RO1-CA23958.

Papillary thyroid cancer (PTC) is one of the fastest-growing cancers worldwide, lacking established causal factors or validated early diagnostics. Human endogenous retroviruses (HERVs), comprising 8% of human genomes, have potential as PTC biomarkers due to their comparably high baseline expression in healthy thyroid tissues, indicating homeostatic roles. However, HERV regions are often overlooked in genome-wide association studies because of their highly repetitive nature, low sequence coverage, and decreased sequencing quality. Using targeted whole-genome sequence analysis in conjunction with high sequencing depth to overcome methodological limitations, we identified associations of specific HERV variants with PTC. Analyzing WGS data from 138 patients with PTC generated through The Cancer Genome Atlas project and 2015 control samples from the 1000 Genomes Project, we examined the mutational variation in HERVs within a 20 kb radius of known cancer predisposition genes (CPGs) differentially expressed in PTC. We discovered 15 common and 13 rare germline HERV variants near or within 20 CPGs that distinguish patients with PTC from healthy controls. We identified intragenic–intronic HERV variants within RYR2, LRP1B, FN1, MET, TCRVB, UNC5D, TRPM3, CNTN5, CD70, RYR1, RUNX1, CRLF2, and PCDH1X, and three variants downstream of SERPINA1 and RUNX1T1. Sanger sequencing analyses of 20 thyroid and 5 non-thyroid cancer cell lines confirmed associations with PTC, particularly for MSTA HERV-L variant rs200077102 within the FN1 gene and HERV-L MLT1A LTR variant rs78588384 within the CNTN5 gene. Variant rs78588384, in particular, was shown in our analyses to be located within a POL2 binding site regulating an alternative transcript of CNTN5. In addition, we identified 16 variants that modified the poly(A) region in Alu elements, potentially altering the potential to retrotranspose. In conclusion, this study serves as a proof-of-concept for targeted variant analysis of HERV regions and establishes a basis for further exploration of HERVs in thyroid cancer development.