Virtual Library

Start Your Search

Erin A Marshall



Author of

  • +

    MA21 - Molecular Subtyping, CBL3, and Non Coding RNA (ID 924)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 205 BD
    • +

      MA21.10 - Large-Scale Discovery of Novel Human Oncofetal Transcripts in Lung (ID 13552)

      16:20 - 16:25  |  Author(s): Erin A Marshall

      • Abstract
      • Presentation
      • Slides

      Background

      Oncofetal genes are those expressed during both embryogenesis and tumourigenesis, but silenced in normal adult tissues. Although most described oncofetal genes have been shown to play important roles in tumour development and display potential as diagnostic and prognostic markers, this area of research remains largely unexplored. The advent of high-throughput technologies has not only allowed for large-scale discovery of biomarkers, but has also highlighted the role of non-coding RNAs from tissue development to malignant transformation. Small non-coding RNAs (sncRNAs, e.g., miRNA, snoRNA, piRNA, snRNA) are key players in gene-regulatory networks, and have shown promise as fluid-based biomarkers. In this study, we performed a comprehensive characterization of the sncRNA transcriptome of fetal, non-malignant and tumour lung tissues to identify development-associated (oncofetal) sncRNAs with roles in lung cancer, including the discovery of previously unannotated miRNAs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Here, 209 paired non-malignant/tumour lung samples from two cohorts (BCCA, n=118 and TCGA, n=91) and 25 fetal lung samples were analyzed through the platform miRMaster. This platform aligns sequence reads to the hg38 genomic build, quantifies known sncRNA species and predicts novel miRNA candidates using the mirDeep2 algorithm. The sncRNA species that had no significant alterations in expression between fetal and tumours samples, but displayed significant differential expression between fetal/non-malignant and tumour/non-malignant tissues were classified as oncofetal sncRNAs. The biological relevance of the oncofetal sncRNAs and the novel miRNA candidates was investigated by gene-target prediction and pathway enrichment analyses, using mirDIP, IID and pathDIP databases.

      4c3880bb027f159e801041b1021e88e8 Result

      Our study provides the first large-scale characterization of the lung sncRNA transcriptome in fetal, non-malignant and tumour tissues. In particular, we discovered the expression of 464 novel miRNA candidates and identified a large subset of oncofetal sncRNAs. Target prediction analysis showed that the novel miRNA candidates discovered in all lung tissues are involved in cellular processes associated with cell proliferation, migration and survival, including the Wnt, MAPK and Notch signaling pathways, which are known to be associated with the development and progression of lung cancer. Additionally, oncofetal sncRNAs were found to be associated with cell cycle control and differentiation, highlighting the functional relevance of these molecules.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We have not only expanded the lung sncRNA transcriptome, but also revealed the expression of a large number of sncRNAs relevant to lung tumourigenesis that are not expressed in normal adult tissues. Our results will aid in the development of more accurate fluid-based biomarkers for the early-detection of lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    MA24 - Genomic Evolution, KEAP 3 and More Non-Coding RNA (ID 928)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 205 BD
    • +

      MA24.06 - Long Non-Coding Rna Expression Patterns Delineate Infiltrating Immune Cells in the Lung Tumour Microenvironment (ID 13978)

      11:05 - 11:10  |  Author(s): Erin A Marshall

      • Abstract
      • Presentation
      • Slides

      Background

      The tumour microenvironment is characterized by complex interactions between different cell types, including immune cells that may exhibit pro- or anti-tumour effects. Sequencing and deconvolution techniques present opportunities to identify immune cell composition of bulk tumour data; similarly, these have renewed an interest in the non-coding transcriptome and its regulation of immune- and tumour-biology. Numerous long non-coding RNAs (lncRNAs; >200nt) have emerged as regulators of tumour initiation, progression, and metastasis. Additionally, several immune-related lncRNAs mediate fine-level regulation to balance pro- and anti-inflammatory phenotypes; yet, the landscape of lncRNA expression in human immune cells remains uncharacterized. Thus, delineating these multifaceted regulatory networks is critical to cancer immunology, particularly in immunogenic malignancies such as lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      RNA-sequencing data of purified immune-cell subsets (CD8+ T, CD4+ T, B, Monocytes, Neutrophils, and Natural Killer) obtained from flow-sorted healthy peripheral blood samples were probed for lncRNA expression. Sequencing reads were aligned to the hg38 reference genome and quantified to Ensembl v89, yielding 4919 expressed lncRNAs. These immune-associated lncRNAs were correlated with immune cell infiltrate in tumour and paired non-malignant lung adenocarcinoma samples (n=54, The Cancer Genome Atlas) as estimated by the proportion of consistent immune-associated methylation profiles, denoted by leukocytes unmethylation for purity (LUMP) scores.

      4c3880bb027f159e801041b1021e88e8 Result

      We observed that lncRNA expression patterns display a greater degree of cell-type specificity than protein-coding genes in immune cells. In fact, 676 lncRNAs had detectable expression in exclusively one cell type. We uncovered previously-uncharacterized lncRNAs that have expression patterns suggestive of immune-regulatory roles. Compared with lung tumour samples, 19 immune-associated lncRNAs were significantly negatively correlated with LUMP scores (r<-0.400, BH-p<0.0100), 17 of which were also strongly positively correlated with CD45 gene expression (r>0.400, BH-p<0.0100) suggesting expression from immune rather than tumour cells. For instance, the lncRNA USP30-AS1 is significantly downregulated in tumours (average fold-change=2.96, BH-p=6.88*10-13), suggesting its relevance to tumour biology; however, higher transcript expression is correlated with decreased LUMP score (r=-0.685, BH-p=1.02*10-4), illustrating its specificity to immune cells.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Here, we present an atlas of cell-type specific lncRNAs in human immune cells. Our data suggest a functional relevance of lncRNAs to the biology of the tumour microenvironment, and the necessary consideration of tumour purity when examining non-coding RNA expression in order to avoid conclusions confounded by immune cells in bulk tumour data. Thus, we provide a resource for further elucidation of genomic links between immune and malignant cells, which may aid the development of future prognostic and therapeutic strategies.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      MA24.07 - A Novel cis-Acting lncRNA Controls HMGA1 Expression in Lung Adenocarcinoma (ID 13979)

      11:10 - 11:15  |  Author(s): Erin A Marshall

      • Abstract
      • Presentation
      • Slides

      Background

      High mobility group A1 (HMGA1) chromatin remodeling protein is enriched in several aggressive cancer types, including NSCLC, where mRNA and protein expression are markedly increased. Additionally, high HMGA1 expression has been associated with poor overall survival and chemotherapy resistance. While HMGA1 is deregulated in lung cancer, the mechanisms that mediate its expression are only beginning to emerge. Long non-coding RNAs (lncRNAs), are a class of transcripts have been implicated in the onset of cancer-associated phenotypes in tumourigenesis and metastasis. Recently, an emerging class of lncRNAs - cis-acting - has been shown to regulate the expression of neighbouring protein-coding genes, including oncogenes and tumour suppressor genes. Thus, lncRNAs may represent novel actionable therapeutic intervention points in known cancer driving pathways. Here we investigate the role of a cis-acting lncRNA, RP11.513I15.6, its deregulation in NSCLC, and its relationship with HMGA1.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      LncRNA transcriptomes were deduced from RNA-sequences of 36 microdissected tumour and matched non-malignant tissues. Normalized sequence read counts were used to identify transcripts with significantly deregulated expression (Wilcoxon Signed-Rank Test, BH-p<0.05). Sequencing data obtained from The Cancer Genome Atlas were analyzed to validate these results. SiRNA-mediated knockdown of lncRNA candidates identified in these analyses were performed in a non-malignant lung epithelial cell line (BEAS-2B). Quantitative real-time PCR quantified the effects of lncRNA knockdown on the expression of neighbouring cancer-associated protein-coding genes.

      4c3880bb027f159e801041b1021e88e8 Result

      Our analyses identified RP11.513I15.6, an undescribed lncRNA neighbouring HMGA1, to be significantly downregulated in adenocarcinoma (>2-fold downregulation in 81.5% of cases). This observation was confirmed in our validation cohort. HMGA1 expression was found to be anticorrelated with RP11.513I15.6, as tumours with downregulated RP11.513I15.6 displayed significant overexpression of HMGA1. This suggested that this lncRNA may be a key negative regulator of HMGA1. In vitro experiments demonstrated siRNA-mediated inhibition of RP11.513I15.6 in immortalized lung epithelial cells resulted in a significant increase in the expression of HMGA1 mRNA and protein. Taken together, our results suggest that RP11.513I15.6 is a novel cis-acting lncRNA that negatively regulates HMGA1, and may contribute mechanistically to the maintenance of cancer phenotypes.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We have discovered a novel, 18-fold downregulated transcript that is anti-correlated with expression of HMGA1, a well established oncogene. In vitro studies support the hypothesis that this transcript, RP11.513I15.6, is a cis-acting lncRNA as siRNA-mediated inhibition led to upregulation of neighbouring HMGA1. Characterizing this oncogene regulatory mechanism will not only further our understanding of cancer biology, but could uncover a novel therapeutic intervention point.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    OA08 - Mesothelioma: Immunotherapy and microRNA for Diagnosis and Treatment (ID 907)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 201 BD
    • +

      OA08.07 - In Silico Discovery of Unannotated miRNAs in Malignant Pleural Mesothelioma Reveals Novel Tissue-of-Origin Markers (ID 14155)

      16:20 - 16:30  |  Author(s): Erin A Marshall

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant pleural mesothelioma (MPM) is an aggressive disease. One of the major clinical challenges associated with MPM is the lack of biomarkers capable of distinguishing primary MPM from cancers that have metastasized to the pleura. The current gold standard consists of a panel of positive and negative protein markers to confirm tissue-of-origin; however, many cases remain undistinguishable from other thoracic cancers. Recent studies have suggested that the human genome encodes more microRNAs (miRNAs) than currently annotated. These undescribed sequences have been shown to display enhanced tissue and lineage specificity. Therefore, we hypothesize that MPM tumors express a specific set of previously unannotated miRNA sequences with tissue-specific expression capable of distinguishing MPM from other thoracic diseases.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Novel miRNA candidates were detected from small RNA-sequencing data generated by The Cancer Genome Atlas (TCGA) (n=87 MPM) using the miRDeep2 algorithm, a well-established novel-miRNA prediction algorithm. The possible biological roles of these miRNA candidates were investigated by performing a genome-wide 3’UTR target prediction analysis. Additionally, their tissue-specificity was assessed using expression profiles of 1,093 lung tumors from four independent cohorts of adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). Finally, we developed a miRNA-based classifier model using the weighted voting class prediction method to distinguish MPM from other thoracic cancers.

      4c3880bb027f159e801041b1021e88e8 Result

      Our initial analysis revealed 424 miRNA candidates, which were subsequently filtered by RNA structure, abundance of sequencing reads, and genomic location, resulting in 154 previously unannotated miRNA sequences. Interestingly, the novel miRNAs were predicted to target protein-coding genes involved in MPM biology, including the Ataxia Telangiectasia Mutated (ATM) gene, a tumour-supressor gene frequently mutated in MPM. Likewise BRCA1 Associated Protein 1 (BAP1), involved in the DNA damage response pathway, was also a predicted target. Principal component analyses revealed that novel-miRNA expression was able to distinguish MPM from LUAD and LUSC. Furthermore, our miRNA-based classifier model revealed 10 novel miRNAs capable of successfully identifying 86 out of the 87 MPM cases (98.80%) and 100% of LUAD cases (true positive rate = 98.85%, false positive rate = 1.150%).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Here, we provide evidence for the presence of 154 previously unannotated miRNA species relevant to MPM. These miRNAs not only significantly expand the miRNA repertoire but also unveil specific roles in MPM biology. Most importantly, the strikingly high sensitivity and specificity of the novel miRNA-based classifier in distinguishing MPM from LUAD illustrates the potential of using these novel miRNAs to supplement current clinical markers to define MPM.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P2.03 - Biology (Not CME Accredited Session) (ID 952)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
    • +

      P2.03-18 - X-Inactivation Specific Transcript (XIST)-Mediated miRNA Sequestration In NSCLC (ID 12307)

      16:45 - 18:00  |  Presenting Author(s): Erin A Marshall

      • Abstract
      • Slides

      Background

      Long non-coding RNA (lncRNA; >200nt) transcripts have been recently recognized as crucial regulators of gene expression. XIST is a prototypical lncRNA involved in cis-silencing of an X chromosome in females; however, there are conflicting reports of lncRNA-mediated regulation in cancer biology and therapeutics through “sponging” of single miRNAs that cause upregulation of canonical miRNA-target genes. XIST-associated sex-specific differences afford the opportunity to study lncRNA sponging systems within a cancer type. Existing studies considering one miRNA in singular cancer types do not account for important biological considerations, including sex and localization of miRNA and XIST transcripts. Here, we detail an in-depth and unbiased pipeline for the discovery of candidate miRNA and gene targets in lncRNA sponging, and validate the miRNA that may be mediating these interactions in XIST.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed a comprehensive analysis of the role of XIST in the positive regulation of protein-coding genes using male and female lung adenocarcinoma (LUAD) samples as a model. To find genes regulated by XIST-mediated miRNA sponging, we correlated all Ensembl-annotated genes with XIST expression in female LUAD (n=307; rho>0.4, p<0.05). Using a specialized algorithm based on binding energies and sequence homology, we assessed the potential binding of all miRNAs against target genes and XIST. We then determine the best candidates for sponging by XIST using XIST-high (female and male) and XIST-low (male) systems, and validate the presence of these candidate miRNAs in the nucleus.

      4c3880bb027f159e801041b1021e88e8 Result

      Our analysis yielded 543 genes that may be defended from miRNAs by XIST (DMX), with a predicted 804 miRNAs targeting both DMX genes and XIST. We compared the changes in miRNA-DMX relationships in XIST-high and XIST-low systems and discovera high-confidence set of 13 miRNA-DMX gene pairs. Interestingly, 5 of these miRNA-DMX gene pairs involve miRNA with validated nuclear localization.

      8eea62084ca7e541d918e823422bd82e Conclusion

      A massive number of lncRNA sponging studies exist, but most only consider one miRNA in a singular type of cancer, are biased in their selection of this target, and limited in biological context. By analyzing the transcriptome of female and male LUAD, we show that the XIST-miRNA-DMX sponging axis is affected by expression of sex-specific genes and number of shared miRNA binding sites on DMX genes. Importantly, we identify that the miRNAs that mediate the XIST-DMX gene axis are enriched in the nucleus, co-localizing with XIST. In summary, our analysis provides both a comprehensive methodology for studying cancer-related miRNA sponge lncRNAs, and suggests the relevance of XIST in lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.