HERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcome

Golkaram, Mahdi; Salmans, Michael L.; Kaplan, Shannon; Vijayaraghavan, Raakhee; Martins, Marta; Khan, Nafeesa; Garbutt, Cassandra; Wise, Aaron; Yao, Joyee; Casimiro, Sandra; Abreu, Catarina; Macedo, Daniela; Costa, Andreia; Alvim, Cecília; Mansinho, André; Filipe, P.; Costa, Pedro; Fernandes, Afonso; Borralho, Paula; Ferreira, Cristina; Aldeia, Fernando; Malaquias, João; Godsey, Jim; So, Alex; Pawlowski, Traci; Costa, Luís; Zhang, Shile; Liu, Li

doi:10.1038/s41525-021-00177-w

Cited by 20 publications

(26 citation statements)

References 54 publications

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“…Multivariate signatures composed of HERV and L1 elements, or simple repeats, stratified patients into distinct survival groups. Of note, HERV expression has been sporadically involved in various cancer types [62] and has recently been associated with poor prognosis in colorectal cancer [63].…”

Section: Discussionmentioning

confidence: 99%

The contribution of uncharted RNA sequences to tumor identity in lung adenocarcinoma

Wang

Xue

Aglave

et al. 2021

Preprint

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Background: Transcriptome analysis of cancer tissues has been instrumental in defining tumor subtypes, diagnostic signatures and cancer regulatory networks. Cancer transcriptomes are still predominantly analyzed at the level of gene expression. Few studies have addressed transcript-level variations, and most of these only looked at splice variants. Previously we introduced a k-mer based, reference-free method, DE-kupl, that performs differential analysis of RNA-seq data at the k-mer level, which enables distinguishing RNAs differing by a single nucleotide. Here we evaluate the significance of differential events discovered by this method in two independent lung adenocarcinoma RNA-seq datasets (N=583 and N=154). Results: Focusing on differential events in a tumor vs normal setting, we found events in endogenous repeats, alternative splicing and polyadenylation sites, long non-coding RNAs, retained introns and unmapped RNAs. Replicability was highly significant for most event classes (assessed by comparing to events shared between unrelated tumors). Overall about 160,000 differential k-mer contigs were shared between datasets, including a large set of sequences from hypervariable genes such as immunoglobulins, SFTP and mucin genes. Most interestingly, we identified a set of novel tumor-specific long non-coding RNAs in intergenic and intronic regions. We found that expressed endogenous transposons defined two major groups of patients (high/low repeat expression) with distinct clinical characteristic. A number of repeats, intronic RNAs and lincRNA achieved strong patient stratification in univariate or multivariate survival models. Finally, using antigen presentation prediction, we identified 55 contigs predicted to produce recurrent tumor-specific antigens. Conclusions: K-mer based RNA-seq analysis enables description of cancer transcriptomes at nucleotide precision, independently of prior transcript annotation. Application to lung cancer data uncovered events stemming from a wide variety of transcriptional and postranscriptional mechanisms. Among those events, a significant subset was replicable between cohorts, thus constituting novel RNA hallmarks of cancer. The code is available at: https://github.com/Transipedia/dekupl-lung-cancer-inter-cohort.

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Section: Discussionmentioning

confidence: 99%

The contribution of uncharted RNA sequences to tumor identity in lung adenocarcinoma

Wang

Xue

Aglave

et al. 2021

Preprint

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“…The LM22 immune cell signature which was validated and published along with CIBERSORT is used. We also used FRICTION [25] to deconvolute WTS into absolute CD8 and CD4 T cells as well as CD19 B cells.…”

Section: Methodsmentioning

confidence: 99%

“…We used WTS to quantify HERVs as described before [25]. Briefly, all WTS reads were aligned (using STAR aligner with optimized multi mapping options) to a custom genome built were human reference (hg19) and HERV specific reference are combined.…”

Section: Methodsmentioning

confidence: 99%

Spatiotemporal evolution of the ccRCC microenvironment links intra-tumoral heterogeneity to immune escape

Golkaram

Kuo

Gupta

et al. 2022

Preprint

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Background Intratumoral heterogeneity (ITH) is a hallmark of clear cell renal cell carcinoma (ccRCC) that reflects the trajectory of evolution and influences clinical prognosis. Here we seek to elucidate how ITH and tumor evolution during immune checkpoint inhibitor (ICI) treatment can lead to therapy resistance. Methods Here, we spatiotemporally profiled the genomic and immunophenotypic characteristics of 29 ccRCC patients, including pre- and post-therapy samples from 17 ICI treated patients. Deep multi-regional whole exome and transcriptome sequencing were performed on 29 patients at different time points before and after ICI therapy. T cell repertoire was also monitored from tissue and peripheral blood collected from a subset of patients to study T cell clonal expansion during ICI therapy. Results Angiogenesis, lymphocytic infiltration, and myeloid infiltration varied significantly across regions of the same patient, potentially confounding their utility as biomarkers of ICI response. Elevated ITH associated with a constellation of both genomic features (HLA LOH, CDKN2A/B loss) and microenvironmental features, including elevated myeloid expression, reduced peripheral T cell receptor (TCR) diversity, and putative neoantigen depletion. Hypothesizing that ITH may itself play a role in shaping ICI response, we derived a transcriptomic signature associated with neoantigen depletion that strongly associated with response to ICI and targeted therapy treatment in several independent clinical trial cohorts. Conclusions These results argue that genetic and immune heterogeneity jointly co-evolve and influence response to ICI in ccRCC. Trial registration We completed a single-arm pilot study at Memorial Sloan Kettering Cancer Center (MSKCC; ClinicalTrials.gov identifier NCT02595918) to examine the safety and feasibility of neoadjuvant nivolumab in patients with localized RCC.

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“…The expression of HERV oncoproteins has been associated with oncogenesis [ 284 , 285 , 286 ]. High expression of HERV ERV3‐1 has been reported in CRC samples [ 287 ], and transcriptome analysis in one paper suggested that an increase in HERV transcripts was associated with a poor prognosis in CRC patients [ 288 ]. Also, in our own series of colorectal cancer/metastasis samples [ 38 ], we frequently observed HERV‐K113 sequences in the genomes; however, due to the setting of the analysis (whole‐genome sequencing), we could not determine whether there were differences in retroviral expression between normal tissues, primary colorectal tumours and metastases, and therefore, future studies on this might lead to additionally interesting discoveries [ 39 ].…”

Section: Other Virusesmentioning

confidence: 99%

Viruses in colorectal cancer

Marongiu

Allgayer

2021

Molecular Oncology

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Increasing evidence suggests that microorganisms might represent at least highly interesting cofactors in colorectal cancer (CRC) oncogenesis and progression. Still, associated mechanisms, specifically in colonocytes and their microenvironmental interactions, are still poorly understood. Although, currently, at least seven viruses are being recognized as human carcinogens, only three of these – Epstein–Barr virus (EBV), human papillomavirus (HPV) and John Cunningham virus (JCV) – have been described, with varying levels of evidence, in CRC. In addition, cytomegalovirus (CMV) has been associated with CRC in some publications, albeit not being a fully acknowledged oncovirus. Moreover, recent microbiome studies set increasing grounds for new hypotheses on bacteriophages as interesting additional modulators in CRC carcinogenesis and progression. The present Review summarizes how particular groups of viruses, including bacteriophages, affect cells and the cellular and microbial microenvironment, thereby putatively contributing to foster CRC. This could be achieved, for example, by promoting several processes – such as DNA damage, chromosomal instability, or molecular aspects of cell proliferation, CRC progression and metastasis – not necessarily by direct infection of epithelial cells only, but also by interaction with the microenvironment of infected cells. In this context, there are striking common features of EBV, CMV, HPV and JCV that are able to promote oncogenesis, in terms of establishing latent infections and affecting p53‐/pRb‐driven, epithelial–mesenchymal transition (EMT)‐/EGFR‐associated and especially Wnt/β‐catenin‐driven pathways. We speculate that, at least in part, such viral impacts on particular pathways might be reflected in lasting (e.g. mutational or further genomic) fingerprints of viruses in cells. Also, the complex interplay between several species within the intestinal microbiome, involving a direct or indirect impact on colorectal and microenvironmental cells but also between, for example, phages and bacterial and viral pathogens, and further novel species certainly might, in part, explain ongoing difficulties to establish unequivocal monocausal links between specific viral infections and CRC.

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HERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcome

Cited by 20 publications

References 54 publications

The contribution of uncharted RNA sequences to tumor identity in lung adenocarcinoma

The contribution of uncharted RNA sequences to tumor identity in lung adenocarcinoma

Spatiotemporal evolution of the ccRCC microenvironment links intra-tumoral heterogeneity to immune escape

Viruses in colorectal cancer

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