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Erin Anne Marshall
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MA 10 - Immunotherapy I (ID 664)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:S. Wang, Robert Pirker
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 303 + 304
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MA 10.09 - Increased T Follicular Helper Cell Infiltration in Lung Adenocarcinoma Tertiary Lymphoid Organs (ID 8487)
12:00 - 12:05 | Presenting Author(s): Erin Anne Marshall
- Abstract
- Presentation
Background:
T follicular helper cells (Tfh) are an antigen-experienced CD4+ T cell subset that have been found to play crucial roles in the development of humoral immunity. In particular, their presence in the B cell-rich germinal centre of secondary and tertiary lymphoid tissue aids in B cell maturation through selection of B cells producing high-affinity antibodies. Tfh cells have known roles in autoimmune disease and B cell malignancies; however, their role in many solid tumours, including those of the lung, remains unclear.
Method:
We analyzed 83 paired tumour-normal lung adenocarcinoma samples from the BC Cancer Agency (BCCA) as well as 576 unpaired samples from The Cancer Genome Atlas (TCGA). Relative immune cell content was obtained from gene expression data using a linear support vector regression deconvolution approach (CIBERSORT). Spatial positioning of B and T cells within selected tumour sections was examined through IHC. The impact of Tfh infiltration on patient survival was analyzed using a Cox Proportional Hazard model.
Result:
T follicular helper cells are increased in tumour tissue, accompanied by global upregulation of Tfh markers PDL1 and CXCR5 in both the BCCA and TCGA cohorts. Histological analysis revealed localization of Tfh cells within tertiary lymphoid organs, with direct contact with B cells in the follicular zone observed. Importantly, Tfh recruitment appears to be an early event in tumour development and a function of neoantigen exposure, indicative of an active anti-tumour response rather than a result of chronic inflammation of the tumour microenvironment.
Conclusion:
T follicular helper cells are required for B cell maturation and subsequent antibody responses. As such, it is not surprising that Tfh infiltration in tumour-resident ectopic lymphoid structures correlates with patient survival in various cancer types. Given the importance of tumour-specific antibody responses in natural and therapeutic immunity, further investigation of Tfhs may show prognostic utility and be a marker of early-stage lung tumours.
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MA 15 - Lung Cancer Biology II (ID 670)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 2
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MA 15.12 - Expanding the Lung Small RNA Transcriptome: Discovery of Unannotated microRNAs with Roles in Development and Tumourigenesis (ID 9100)
17:00 - 17:05 | Author(s): Erin Anne Marshall
- Abstract
- Presentation
Background:
MicroRNAs (miRNAs) are key regulators of gene expression. They participate in many biological and pathological processes, from organ development to malignant transformation. Their functions are widely conserved, involving post-transcriptional silencing of gene expression. Over 2500 mature miRNA sequences have been identified in humans; however, recent studies have showed that the number of annotated miRNAs represent only a fraction of the total pool of existing miRNAs, suggesting that there are still many potentially undiscovered biologically relevant miRNAs encoded by the human genome. Here, we perform a comprehensive study to identify novel miRNA sequences expressed in non-malignant lung tissues, as well as samples from developmental stages and pathological conditions.
Method:
A total of 422 samples were included in this analysis. First, 209 non-malignant samples from two cohorts (BCCA, n=118 and TCGA, n=91) were analyzed using our customized small RNA sequence analysis pipeline. Sequence reads were aligned to the hg38 build of the human genome (STAR algorithm) and novel miRNAs were predicted using mirDeep2. The results were compared to miRNA databases and further filtered by abundance and for miRNA-compatible structure. The same procedure was applied to matched tumours (n=209) and samples derived from fetal lungs (n=4). The biological relevance of the novel sequences was investigated by assessing their expression in tumours and fetal samples, together with gene target prediction and tissue-specific protein-protein interaction (PPI) network analyses using IID.
Result:
Our study discovered the expression of 294 novel miRNA sequences in lung tissue, significantly expanding the current human lung miRNA transcriptome. These novel miRNAs showed similar nucleotide composition and genomic distribution compared to known miRNAs, providing additional evidence of their miRNA-compatible nature. Interestingly, a subset of these miRNAs were also found to be expressed in tumour and fetal samples, indicating that they might play important roles in organ development and tumourigenesis. Likewise, target prediction analysis revealed that these novel miRNAs are involved in key cellular processes including cell proliferation, migration and survival, as well as pathways known to be deregulated in cancer, as comprehensively analyzed using pathDIP.
Conclusion:
Our study has significantly expanded the lung small RNA transcriptome, and provided evidence that the novel miRNAs are involved in molecular networks relevant to lung biology and pathology. These results also highlight their specific roles in developmental regulation and malignant transformation, suggesting their role as biological regulators and implicating their potential as therapeutic targets.
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MA 15.14 - Long Non-Coding RNA Disruption in Lung Adenocarcinoma Reveals Novel Mechanisms of Metastasis (ID 8659)
17:10 - 17:15 | Author(s): Erin Anne Marshall
- Abstract
- Presentation
Background:
Identifying the drivers of metastasis will yield new molecular targets for prognostics and therapeutics. Long non-coding RNAs (lncRNAs) are known to regulate gene transcription through their influence on the expression of nearby (cis) and distant (trans) genes. Emerging evidence suggests that lncRNAs are involved in key cellular processes, presenting an opportunity for large-scale identification of lncRNA genes critical to lung cancer progression. Here we investigate the contribution of this class of non-coding RNA to lung adenocarcinoma (LUAD) metastasis.
Method:
Stage T1 and T2 tumours with (N≥1 and/or M≥1) and without (N=0 and M=0) metastasis were examined for expression comparisons. Sequencing data from 265 non-metastatic and 130 metastatic tumours obtained from The Cancer Genome Atlas were used as our discovery cohort. Results were validated in 20 non-metastatic and 10 metastatic tumour samples microdissected to 90% purity and sequenced using the Illumina Hi-Seq platform. Normalized sequence read count comparisons were performed (Mann Whitney U-Test, FDR-BH p<0.05) to identify lncRNAs significantly deregulated in metastatic samples. LncRNAs over- and under-expressed in metastatic LUAD were compared to nearby protein-coding-target genes to identify putative mechanisms of regulation in cis.
Result:
We discovered 150 lncRNAs to be significantly differentially expressed between metastatic and non-metastatic tumours, including lncRNAs with previously described oncogenic roles in lung cancer, such as Lung Cancer Associated Transcript 1 and H19. As individual lncRNAs can positively or negatively regulate target-gene expression, it is noteworthy that we identified potential protein-coding-target genes that display both concordant and discordant expression patterns with specific lncRNAs. For example, we discovered the upregulation of linc00942 in metastatic LUAD (FDR-BH p=0.001) and the concordant overexpression of its corresponding protein-coding-target gene, ELKS/RAB6-Interacting/CAST Family Member 1 (ERC1) (FDR-BH p=0.02). Further, metastatic LUAD samples stratified by linc00942 expression also display corresponding elevation of ERC1 (p=0.0002), which holds true in the validation cohort. ERC1 (an upstream member of the NF-κB signaling pathway) is implicated in cell migration and focal adhesion, and displays deregulated expression in a number of cancer types. Thus, overexpression of linc00942 may act as a novel positive cis-regulator of ERC1, promoting metastasis.
Conclusion:
This work has led to the discovery of a large number of lncRNA genes deregulated in metastatic LUAD, suggesting that altered lncRNA expression contributes functionally to malignant progression. Understanding cis- or trans-mediated mechanisms of gene deregulation enacted by metastasis-associated lncRNAs will present novel opportunities for diagnosis and treatment.
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OA 07 - Biomarker for Lung Cancer (ID 659)
- Event: WCLC 2017
- Type: Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:Philip Christopher Mack, Shinichi Toyooka
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 503
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OA 07.07 - Inhibition of the Novel Oncogene ELF3 Abolishes Lung Adenocarcinoma Growth (ID 8408)
17:00 - 17:10 | Author(s): Erin Anne Marshall
- Abstract
- Presentation
Background:
Oncogenic reactivation of transcription factors involved in fetal lung development is integral to lung adenocarcinoma (LUAD) biology, as observed with TITF1/NKX2-1 and the ETS transcription factors ETV4 and ETV5. ELF3 is an uncharacterized ETS family member implicated in fetal lung development encoded at 1q32.1. Interestingly, chromosome 1q is a region of frequent gain in LUAD that lacks a bona fide oncogene. We hypothesize that ELF3 is a novel oncogene and putative therapeutic target in LUAD.
Method:
Multiple independent datasets encompassing 1,685 clinical samples of LUAD, lung squamous cell carcinoma (LUSC), small cell lung cancer, and non-malignant lung tissues were analyzed to establish the frequency of ELF3 overexpression and underlying genetic mechanisms of selection. Protein-protein interaction (PPI) networks were constructed around ELF3, and integrated pathway analysis was performed to decipher the signaling network disruptions resulting from ELF3 overexpression. Isogenic cell lines were established to assess the ability of ELF3 to regulate oncogenic phenotypes. The effect of ELF3 loss on tumour growth was assessed in xenograft mouse models.
Result:
Strong ELF3 overexpression was frequently observed in LUAD (>2-fold: TCGA 40% p=1.5E-07; BCCA 73% p=1.6E-21), but was not observed in other lung cancer subtypes. Similarly, high ELF3 expression was significantly associated with poor overall survival of LUAD patients (all Stages p<0.0001, Stage I p<0.0001), but not LUSC patients (p>0.05). These clinical associations prompted further examination of ELF3 in the LUAD subtype of lung cancer. While mutations in ELF3 were rare, up to 80% of LUAD patients harboured focal amplification, DNA gain, and/or promoter hypomethylation at the ELF3 locus, which resulted in transcript overexpression. ELF3 overexpression induces remodeling of 23 direct PPI networks, resulting in loss of interaction with proteins such as MYC and GLI2, while forming new interactions with NKX2-1, HOXA5 and CDK8, among others. This reprogramming of PPI networks affects multiple oncogenic pathways including MAPK, TGF-beta and WNT. ELF3 knockdown in LUAD cell lines resulted in significantly reduced proliferation, viability, and anchorage-independent growth, demonstrating ELF3 has oncogenic properties. Loss of ELF3 abolished the ability of LUAD cells to establish tumours in xenograft mouse models, demonstrating the requirement of ELF3 expression for tumour growth.
Conclusion:
ELF3 is a novel LUAD oncogene encoded on chromosome 1q, activated in up to 73% of patients, and strongly associated with poor overall survival. As ELF3 inhibition abolished tumour growth, therapeutic targeting of ELF3 could benefit LUAD patient outcome.
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P1.02 - Biology/Pathology (ID 614)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.02-006 - Arsenic Promotes Persistent Alterations in the Lung PiRNA Transcriptome to Target Epigenetic Pathways (ID 9567)
09:30 - 09:30 | Author(s): Erin Anne Marshall
- Abstract
Background:
Chronic exposure to arsenic leads to the onset of different diseases, including lung cancer. Arsenic-induced lung tumors have been associated with a high-frequency of lung squamous-cell carcinomas among never smokers (a rare epidemiological pattern), suggesting a unique underlying biology. Epigenetic alterations are known to play a role in this process; however, detailed mechanisms are not yet fully elucidated. Piwi-interacting RNAs (piRNAs), a novel class of small non-coding RNAs (sncRNAs), play a key role in epigenetic regulation and maintenance of genome integrity. Here, we examine the impact of different arsenic species in the human piRNA transcriptome, using lung cell models mirroring chronic, low dose exposure. We also investigate the interaction network of deregulated piRNAs and identified biological pathways potentially affected.
Method:
One normal lung (HBEC) and two lung cancer cell lines: A459 (adenocarcinoma) and H520 (squamous-cell carcinoma) were grown in 10 ppm of sodium arsenite (AsIII) or arsenate (AsV) for six passages. Total RNA was extracted at different time points and sequenced. piRNA expression was deduced using our custom sncRNA analysis pipeline, which interrogates >23K piRNA-encoding human loci. piRNA/DNA binding prediction was performed using two different algorithms (miRanda/ThermoBLAST). Network analysis was performed using Partek Pathways.
Result:
Overall, 691 piRNAs were expressed. Persistent changes in piRNA expression over time were identified, with specific patterns associated with the different arsenic species. In HBECs (non-malignant lung tissue), 14 piRNAs were persistently upregulated and 16 downregulated in response to AsIII. Similarly, 6 were up- and 11 downregulated when the same cells were exposed to AsV. Only 1 piRNA, DQ598008, was commonly upregulated in response to both arsenic species, while 4 piRNAs were commonly downregulated. Lung cancer cell lines follow the same arsenic species-specific trends, with a high subtype-specificity indicating these species maintain a role during lung tumor development. Remarkably, we found an enrichment of genes associated with methyltransferase activities predicted to be targeted by piRNAs altered by AsIII (a biologically-relevant form of arsenic), evidencing their role in arsenic-related carcinogenic mechanisms.
Conclusion:
Arsenic induces persistent alterations in the lung sncRNA transcriptome, particularly piRNAs, impacting pathways linked to epigenetic regulation. Together, these results provide insights into sncRNA-related mechanisms in arsenic-induced lung carcinogenesis. Moreover, different arsenic species induce distinct alteration patterns, highlighting the relevance of the source of exposure. piRNAs, as with other sncRNAs, are stable in biofluids, circulating tumour cells, and archival clinical materials. Therefore, piRNAs hold great promise as potential exposure and monitoring biomarkers for arsenic-related health effects.
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-017 - Aberrant Expression of Long Non-Coding RNAs from Pseudogene Loci Highlights Alternative Mechanisms of Cancer Gene Regulation (ID 10231)
09:30 - 09:30 | Author(s): Erin Anne Marshall
- Abstract
Background:
Less than half of lung adenocarcinoma (LUAD) patients harbour clinically actionable driver genes, emphasizing the need to explore alternative mechanisms of cancer gene deregulation. Long non-coding RNAs (lncRNAs) have emerged as important players in cell biology, and can be exploited by tumours to drive the hallmarks of cancer. Pseudogenes are DNA sequences that are defunct relatives of their functional protein-coding parent genes but retain high sequence homology. Interestingly, several lncRNAs expressed from pseudogene loci have been shown to regulate the protein-coding parent genes of these pseudogenes in trans due to sequence complementarity. We hypothesize that this phenomenon occurs more broadly than previously realized, and that these events provide an alternative mechanism of cancer gene deregulation in LUAD tumourigenesis that has clinical implications.
Method:
Illumina HiSeq reads were processed and aligned to the ENSEMBL annotation file in order to derive the most complete set of both protein-coding and non-coding genes. Two datasets were selected due to their paired nature, complete with both LUAD and non-malignant lung profiles (TCGA n=108, BCCA n=72). LncRNAs were filtered based on positional overlap within pseudogene loci, and a Wilcoxon sign-rank test was run to identify lncRNAs with significantly altered expression between paired tumour and normal tissues (FDR p<0.05). To identify lncRNAs that likely regulate protein-coding parent gene expression in trans, tumours were ranked by lncRNA expression, and protein-coding parent gene expression of top and bottom ranked tertiles was compared by Mann Whitney U-test (p<0.05). Survival analysis was performed using a Cox proportional hazard model.
Result:
Our analysis has identified 129 lncRNAs expressed from pseudogene loci that were significantly deregulated in LUAD in both datasets. Remarkably, many of these deregulated lncRNAs (i) were expressed from the loci of pseudogenes related to known cancer genes, (ii) had expression that significantly correlated with protein-coding parent gene expression, and (iii) protein-coding parent gene expression was significantly associated with survival. For example, RP11-182J1.1 is a lncRNA expressed from a pseudogene to EGLN1, a previously described cancer gene involved in regulation of tumour hypoxia. RP11-182J1.1 was underexpressed in LUAD and significantly positively correlated with EGLN1 expression. In addition, EGLN1 was significantly associated with patient survival (p=1.2e-08) emphasizing the clinical potential of these lncRNAs.
Conclusion:
This work uncovers evidence to suggest the lncRNA-pseudogene-protein-coding gene axis is a prominent mechanism of cancer gene regulation. Further characterization of this understudied gene regulatory mechanism could lead to novel therapies that silence oncogenes or reactivate tumour suppressor genes.
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P2.02-022 - Alternative Regulation of Cancer-Associated Genes through Modulation of Long Non-Coding RNAs (ID 8658)
09:30 - 09:30 | Author(s): Erin Anne Marshall
- Abstract
Background:
Uncovering novel mechanisms of cancer-gene regulation may reveal new actionable targets to direct the treatment of patients who do not harbour targetable molecular drivers of lung cancer. Long non-coding RNAs (lncRNAs), are a class of transcripts that hold an emerging role in cell biology, particularly in gene regulation. These genes have since been implicated in cancer-associated phenotypes, and may represent attractive therapeutic intervention points; however, prediction of downstream regulatory targets of lncRNAs has been impeded due to their complex tertiary structure. Recently, a subset of lncRNAs has been shown to regulate the expression of neighbouring protein-coding genes in cis. Here we take a novel approach to identify lncRNAs deregulated in lung adenocarcinoma (LUAD) and examine their roles in the expression modulation of their cancer-associated protein-coding cis-partner genes.
Method:
RNA-sequencing was performed on 36 LUAD tumour samples with matched adjacent non-malignant tissue obtained via microdissection to 90% purity. Significantly deregulated lncRNAs and neighbouring protein-coding genes were identified by comparison of matched tumour and non-malignant normalized read counts (Wilcoxon Signed-Rank Test, FDR-BH<0.05). Fifty LUAD tumours with paired normal tissue from The Cancer Genome Atlas (TCGA) were used to validate these findings. Cox-Proportional Hazard analysis was performed on both datasets to assess survival associations of significantly deregulated lncRNAs.
Result:
Our approach revealed greater than 500 lncRNAs that were significantly deregulated between LUAD and matched normal tissues. Many of these lncRNAs have neighbouring protein-coding genes that also display deregulated expression patterns. Of particular interest are the protein-coding-target genes that have been previously implicated in cancer, including OIP5, which is involved in chromatin segregation, as well as HMGA1, which contributes to cell transformation and metastasis. In both of these cases, the neighbouring lncRNA is significantly underexpressed while the protein-coding gene is significantly overexpressed, suggesting a negative regulatory function of the lncRNA. Moreover, survival analyses revealed that patients with high expression of either OIP5 or HMGA1 had significantly shorter overall survival. Strikingly, patients with low expression of the lncRNA near OIP5 also displayed poorer overall survival, illustrating the clinical opportunity that these genes present.
Conclusion:
Our results highlight the landscape of lncRNA deregulation in LUAD and uncover a role of these non-coding transcripts in the cis-regulation of neighbouring protein-coding genes, many of which have been described in cancer and predict patient survival. Further characterization of this alternative lncRNA-mediated cancer-gene regulatory mechanism may reveal novel therapeutic targets that may improve treatment for LUAD patients without well defined molecular drivers.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 3
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-090 - Hypoxia-Induced Modifications of the Small Non-Coding RNA Transcriptome Delineates Risk of Recurrence in Early-Stage Lung Adenocarcinoma (ID 8400)
09:30 - 09:30 | Author(s): Erin Anne Marshall
- Abstract
Background:
Hypoxia is central to neoplastic diseases. It has been associated with reduced survival in several tumor types, including NSCLC. A spectrum of poor outcome suggests a multifactorial modulation of the hypoxic response. Piwi-interacting RNAs (piRNAs) are small non-coding RNAs (sncRNAs) with a pivotal role in genomic stability and epigenetic regulation of gene expression. Changes in piRNA expression have been recently found to be deregulated during tumor progression, and responsive to tumor microenvironment conditions. Here, we investigate if hypoxia alters the piRNA transcriptome in human lungs, and assessed whether these alterations are indicative of outcome in patients with hypoxic lung tumours.
Method:
Tumors from lung and other six organs (TCGA) were classified according to their oxygenation state using signatures derived from established hypoxia-associated gene expression changes. By investigating >3000 piRNA transcriptomes, we generated a baseline of hypoxia-related changes which were further validated in a panel of cell lines exposed to hypoxia in vitro (16h at 1% O~2~). In lung tumors (n=1,018), we identified the most robust hypoxia-related changes between hypoxic and non-hypoxic groups by including piRNAs that: 1) ≥ 10 RPKM median expression, 2) > 2-fold change in median expression, and 3) a significant p value following a Mann-Whitney U test. A piRNA-based score (piSco) was generated by grouping HR-piRNAs expression, weighted by coefficients from a Cox proportional hazard model.
Result:
Overall, piRNA expression is selectively deregulated by hypoxia. In vitro tumour models recapitulate HR-piRNAs expression patterns. Seventy-one HR-piRNAs were identified, showing statistically significant differences in expression between hypoxic and non-hypoxic tumours. Of these, 13 were exclusively deregulated in NSCLC tumors, showing a remarkable subtype specificity between adenocarcinomas and squamous cell carcinomas. We next investigated if the HR-piRNA based score (piSco) was associated with NSCLC patient outcome. We found that piSco classify patients with hypoxic lung LUAD and LUSC as low or high risk of RFS. Remarkably, piSco was also able to classify Stage I LUAD patients into the same categories above (p = 0.0051).
Conclusion:
This study reveals the influence of the tumour microenvironment on DNA-level regulatory mechanisms with important implications for predicting recurrence in patients with hypoxic lung tumours. Our data encourage further exploration of HR-piRNAs as clinical tools for evaluating the likelihood of tumour recurrence, and as a mean to identify patients that would most benefit from adjuvant therapies and/or therapies designed to target hypoxic tumour cells.
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P3.02-091 - Concurrent Aberrations in G2/M-Phase Transcriptional Programs and Genomic Gatekeepers Highlight Lung Cancer Predisposition in COPD Patients (ID 8485)
09:30 - 09:30 | Presenting Author(s): Erin Anne Marshall
- Abstract
Background:
Patients with chronic obstructive pulmonary disease (COPD) have a 7-fold increased risk of developing lung cancer. COPD is defined by clinical symptoms and reduced lung function measurements. It is characterized by chronic inflammation, small airway remodelling and loss as well as destruction of alveoli (emphysema). While this disease is an important lung cancer risk factor independent of smoking, the molecular progression from COPD to lung cancer tumourigenesis is relatively understudied.
Method:
In order to examine the molecular overlap between these two diseases, we first analyzed small airway epithelial gene expression profiles obtained from bronchial brushings from 127 COPD and 140 non-COPD ever-smoker patients. We performed weighted gene correlation network analysis (WGCNA) on these gene expression profiles to discover deregulated gene modules (‘metagenes’) associated with reduced lung function (Forced Expiratory Volume at 1 second, FEV~1~)—a clinical measure of COPD severity most robustly negatively correlated with lung cancer risk. We then assessed the preservation of these modules in two non-small cell lung cancer (NSCLC) tumour/normal data sets (lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), n= 887 tumors total). Airway and tumor patient cohorts were matched for age, gender, tumour stage, and smoking status.
Result:
We discovered 10 distinct small airway gene expression modules, two of which were significantly negatively correlated (p < 0.05) with patient FEV~1~. One of these FEV~1~ modules was the top overall module preserved in both NSCLC subtypes. This lung cancer-FEV~1~ module contained 31 genes solely enriched for two related mitotic functions— G2/M phase transition (BH-p = 0.02) and mitotic roles of polo-like kinase (BH-p = 0.001, n=31). Of these, 28 genes were significantly overexpressed in both LUAD and LUSC, and mapped to a highly-clustered sub-network of 23 proteins with 465 known and in silico-predicted protein-protein interactions. When tumours enriched for this lung-cancer-FEV~1 ~gene signature were further examined, we observed a significant co-occurrence of DNA-level alterations in DNA damage associated checkpoints, specifically mutated TP53.
Conclusion:
Coordinated gene expression changes associated with COPD severity measures in small airways and preserved in NSCLC tumors are enriched for G2/M phase transition genes. These genes are further disrupted in tumors, where co-occurring mutations to gatekeeper genes are present. Progression of mitosis during abnormal aneuploidy in lung tissues of COPD patients may confer increased risk of oncogenic transformation in this population, and may underlie the molecular progression from COPD to lung cancer.
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P3.02-094 - Identification of Oncofetal piRNAs in Lung (ID 9107)
09:30 - 09:30 | Author(s): Erin Anne Marshall
- Abstract
Background:
PIWI-interacting RNAs (piRNAs) are a class of small non-coding RNAs (distinct from microRNAs) that recognize complementary DNA sequences in the nucleus. Their primary functions involve epigenetic control of gene transcription and maintenance of genomic stability through repression of mobile elements. Recent observations of cancer type specific aberrant expression have raised the possibility of a role for piRNAs in lung cancer. Here we characterize piRNA transcriptomes of fetal, adult and tumour lung tissue to identify fetal piRNA genes that are silenced in normal adult lung and re-activated in cancer. Our goal is to identify oncofetal piRNAs, which might represent ideal cancer therapeutic targets, as they are absent in normal adult lung tissue.
Method:
We determined piRNA expression profiles from small-RNA sequencing libraries using an in-house pipeline. All sequence reads were aligned to the hg38 build of the human genome. The expression levels of fetal lung samples (n=25) and two tumour/non-malignant paired cohorts (BCCA, n=118 and TCGA, n=91; derived from non-small cell lung cancer cases) were compared. piRNAs not expressed in non-malignant samples but with comparable expression in both fetal and tumour tissues were classified as oncofetal piRNAs. In order to identify the biological functions of the identified oncofetal piRNAs, we performed piRNA/DNA binding prediction using the miRanda algorithm adjusted for piRNA-specific features.
Result:
Our results provide a comprehensive characterization of piRNA expression in both normal and tumour lung tissues, as well as an unique piRNA expression profile of fetal lung tissues. A subset of the piRNA pool expressed in lung tissues are similarly expressed between fetal lung and lung tumours, but are absent in non-malignant tissue, implying that tumour initiation might involve the reactivation of developmental pathways. More importantly, target prediction analysis revealed that the identified oncofetal piRNAs are involved in key cellular processes, such as cell proliferation, migration and survival.
Conclusion:
Our study provides an unique and comprehensive characterization of the piRNA pool of lung tissues, as well as the identification of specific similarities in piRNA expression during both organ and tumour development. These similarities between fetal and tumour tissues might represent a promising avenue for the identification of strong biomarkers or optimal therapeutic targets with little toxicity for the treatment of lung cancer. Therefore, our study provides new and promising insights for lung tumour biology and may aid in the development of novel therapeutic approaches.
