Diverse repetitive element RNA expression defines epigenetic and immunologic features of colon cancer

Desai, Niyati; Sajed, Dipti; Arora, Kshitij S.; Solovyov, Alexander; Rajurkar, Mihir; Bledsoe, Jacob R.; Sil, Srinjoy; Amri, Ramzi; Tai, Eric C.; MacKenzie, Olivia C.; Mino‐Kenudson, Mari; Aryee, Martin J.; Ferrone, Cristina R.; Berger, David L.; Rivera, Miguel N.; Greenbaum, Benjamin; Deshpande, Vikram; Ting, David T.

doi:10.1172/jci.insight.91078

Cited by 25 publications

(29 citation statements)

References 17 publications

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“…FISH (and other similar methods) for DNA and IHC for proteins have been performed for many years also at the clinical level, but today, we also have reproducible in situ methods for mRNAs and noncoding RNAs and developing tools to detect most genetic, genomic, and epigenetic types of alterations. ITH can be studied at the in situ level for gene amplification and CIN with FISH ( 113 , 114 ), for single nucleotide mutation ( 115 ), for fusion transcripts detection ( 116 ), for repetitive RNAs related to hypomethylation ( 117 ), and for in situ detection of histone modification ( 118 ). For proteins, more sophisticated methods, such as matrix-assisted laser desorption/ionization imaging can be used ( 119 ).…”

Section: Methods To Study Ithmentioning

confidence: 99%

Overview on Clinical Relevance of Intra-Tumor Heterogeneity

2018

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Today, clinical evaluation of tumor heterogeneity is an emergent issue to improve clinical oncology. In particular, intra-tumor heterogeneity (ITH) is closely related to cancer progression, resistance to therapy, and recurrences. It is interconnected with complex molecular mechanisms including spatial and temporal phenomena, which are often peculiar for every single patient. This review tries to describe all the types of ITH including morphohistological ITH, and at the molecular level clonal ITH derived from genomic instability and nonclonal ITH derived from microenvironment interaction. It is important to consider the different types of ITH as a whole for any patient to investigate on cancer progression, prognosis, and treatment opportunities. From a practical point of view, analytical methods that are widely accessible today, or will be in the near future, are evaluated to investigate the complex pattern of ITH in a reproducible way for a clinical application.

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Section: Methods To Study Ithmentioning

confidence: 99%

Overview on Clinical Relevance of Intra-Tumor Heterogeneity

2018

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“…As few total tumor RNA-seq data are publicly available, we examined the expression of LINE and ERV elements, which can be detected using poly (A) capture, increasing our sample size. We focused on LINE and ERV expression in colon and rectal adenocarcinoma cancers available in TCGA, given the well-established genetics of colon cancer progression, the established co-expression of LINE1 and HERV-K (Desai et al 2017), and the known presence of satellite repetitive element genome expansions (Bersani et al 2015). We examined 364 paired-end RNA-seq samples prepared with the poly(A) protocol.…”

Section: Global Repeat Depression Is Associated With An Immunosuppresmentioning

confidence: 99%

“…Moreover, many repeat RNAs include sequence and structure patterns typically found in pathogen genomes rather than human genomes (Chiappinelli et al 2015, Roulois et al 2015, Tanne et al 2015. Such pathogen "mimicry" can be detected by innate pattern recognition receptors (PRRs), initiating signaling in the tumor microenvironment relevant for immune and epigenetic therapies (Leonova et al 2013, Chiappinelli, et al 2015, Roulois et al 2015, Woo et al 2015Desai et al 2017, Greenbaum 2017). These direct immunomodulatory features of repetitive elements provide a novel functional signaling pathway not previously appreciated in human cancers.…”

Section: Introductionmentioning

confidence: 99%

Global Cancer Transcriptome Quantifies Repeat Element Polarization Between Immunotherapy Responsive and T cell Suppressive Classes

Solovyov

Vabret

Arora

et al. 2017

Preprint

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SummaryGrowing evidence indicates that innate immune pathway activation is critical for responses to immunotherapy and overall cancer prognosis. It has been posited that innate immunity in the tumor microenvironment can be driven by derepression of endogenous repetitive element RNA. The ability to characterize these species can potentially provide novel predictive biomarkers for tumor immune responses and a mechanistic basis for elements of innate activation by tumors. We first compared total RNA and poly(A)-capture protocols applied to tumor RNA-sequencing to detect non-RNA coding transcriptomes in the TCGA. While the poly(A) protocol efficiently detects coding, most non-coding genes, and much of the LINE/SINE/ERV repeat repertoire, we found that it fails to capture overall repeat expression and co-expression. The probing of total RNA expression reveals distinct repetitive co-expression subgroups. Secondly, we found that total repeat element expression delivers the most dynamic changes in samples, which may serve as more robust biomarkers of clinical outcomes. Finally, we show that while expression of ERVs, but not other immunostimulatory repeats such as HSATII, is associated with response to immunotherapy in a cohort of patients with urothelial cancer treated with anti-PD-L1 therapy, global repeat derepression strongly correlates with an immunosuppressive phenotype in the microenvironment of colorectal and pancreatic tumors. We validate in situ in human primary tumors, associating the immunosuppressive phenotype with HSATII expression. In conclusion, we demonstrate the importance of analyzing repetitive element RNAs as potential biomarkers of response to immunotherapy and the need to better characterize these features in next generation sequencing protocols.

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“…Moreover, many repeat RNAs include specific sequence motifs ( Tanne et al, 2015 ) and general RNA structures ( Chiappinelli et al, 2015 ; Roulois et al, 2015 ) typically found in pathogen rather than human transcripts. Such pathogen “mimicry” can be detected by innate pattern recognition receptors (PRRs) and initiate signaling in the tumor microenvironment relevant for immune and epigenetic therapies ( Leonova et al, 2013 ; Chiappinelli et al, 2015 ; Roulois et al, 2015 ; Woo et al, 2015 ; Desai et al, 2017 ; Greenbaum, 2017 ). These direct immunomodulatory features of repetitive elements provide a functional signaling pathway not previously appreciated in human cancers.…”

Section: Introductionmentioning

confidence: 99%

Global Cancer Transcriptome Quantifies Repeat Element Polarization between Immunotherapy Responsive and T Cell Suppressive Classes

et al. 2018

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SUMMARY It has been posited that anti-tumoral innate activation is driven by derepression of endogenous repeats. We compared RNA sequencing protocols to assess repeat transcriptomes in The Cancer Genome Atlas (TCGA). Although poly(A) selection efficiently detects coding genes, most non-coding genes, and limited subsets of repeats, it fails to capture overall repeat expression and co-expression. Alternatively, total RNA expression reveals distinct repeat co-expression subgroups and delivers greater dynamic changes, implying they may serve as better biomarkers of clinical outcomes. We show that endogenous retrovirus expression predicts immunotherapy response better than conventional immune signatures in one cohort yet is not predictive in another. Moreover, we find that global repeat derepression, including the HSATII satellite repeat, correlates with an immunosuppressive phenotype in colorectal and pancreatic tumors and validate in situ. In conclusion, we stress the importance of analyzing the full spectrum of repeat transcription to decode their role in tumor immunity.

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Diverse repetitive element RNA expression defines epigenetic and immunologic features of colon cancer

Cited by 25 publications

References 17 publications

Overview on Clinical Relevance of Intra-Tumor Heterogeneity

Overview on Clinical Relevance of Intra-Tumor Heterogeneity

Global Cancer Transcriptome Quantifies Repeat Element Polarization Between Immunotherapy Responsive and T cell Suppressive Classes

Global Cancer Transcriptome Quantifies Repeat Element Polarization between Immunotherapy Responsive and T Cell Suppressive Classes

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