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Elizaberth Starren



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    P1.03 - Biology (ID 161)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.03-06 - Integrative Omics Analysis Reveals Important Roles of Adenosine Diphosphate in Haemostasis and Platelet Activation in NSCLC (ID 1273)

      09:45 - 18:00  |  Author(s): Elizaberth Starren

      • Abstract

      Background

      Lung cancer is the leading cause of cancer-related deaths in the world. The most prevalent subtype, accounting for 85% of cases, is non-small cell lung cancer (NSCLC). Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are the most common subtypes. Despite recent advances in treatment, the low 5-year survival rate of NSCLC patients (approximately 13%) reflects the lack of early diagnostic biomarkers and incomplete understanding of the underlying disease mechanisms.

      Method

      We hypothesised that integration of metabolomic, transcriptomic and genetic profiles of tumours and matched normal tissues could help to identify important factors and potential therapeutic targets that contribute to tumorigenesis. We integrated omics profiles in tumours and matched adjacent normal tissues of patients with LUSC (N = 20) and LUAD (N = 17) using multiple system biology approaches.

      Result

      We confirmed the presence of previously described metabolic NSCLC pathways, particularly those mediating the Warburg effect. In addition, through our combined omics analyses we found that metabolites and genes that contribute to haemostasis, angiogenesis, platelet activation and cell proliferation were predominant in both subtypes of NSCLC.

      Conclusion

      The important roles of adenosine diphosphate (ADP) in promoting cancer metastasis through platelet activation and angiogenesis suggests this metabolite could be a potential therapeutic target.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-10 - Comprehensive Molecular Profiling and Comparison of Common and Rarer Subtypes of Lung Cancer (ID 1870)

      10:15 - 18:15  |  Author(s): Elizaberth Starren

      • Abstract
      • Slides

      Background

      Genomic profiling of tumours has become a crucial component of precision cancer medicine. In order to comprehensively characterize molecular alterations in different lung cancer subtypes, we analysed a total number of 327 samples by using Whole-Exome Sequencing (WES) and SNP genotyping arrays. Additionally, we used Targeted Capture Sequencing (TCS) for scanning a selected panel of genes (n=52) at high sequencing depth.

      Method

      We WES (McGill University Innovation Centre in Montreal) 153 paired tumour-normal samples, with a further 174 paired tumour-normal samples undergoing TCS. Sequencing data were processed and mutations identified using BWA (v.0.7.15), Picard (v.2.17.11), GATK (v.3.7), VarScan (v.2.4.2) and VEP (v. 92) softwares. Illumina OmniExpressExome (v1.6) arrays were used for genotyping all samples and copy number alterations (CNAs) were identified using ASCAT (v.2.5.2), DNACopy (v.1.56.0) and GISTIC (v.2.0) softwares.

      Result

      The analysed samples had a tumour content varying from 20 to 90%. The age range of patients was between 28 to 89 years. Out of 159 lung cancer patients, 89 patients had lung adenocarcinoma (LUAD), 36 squamous cell carcinoma (LUSC) and 34 lung neuroendocrine (NET), of which 22 were subclassified as lung carcinoid (LC), 6 small cell carcinoma (LSCLC), 5 large cell carcinoma (LCNEC) and 1 combined NET subtype.

      TP53 appeared as the most mutated gene in LUSCs (82%), non-carcinoid NETs (58%) and LUADs (47%), but not in the LC subtype, while the chromatin remodelling gene ARID1A was altered across all subtypes (9%). Other mutated genes in LUAD were KRAS (31%), STK11 (22%), RBM10 (15%), EGFR (14%) and KEAP1 (14%); in LUSC were PTEN (26%), CDKN2A (21%), KEAP1 (21%) and NF1 (15%); in NET, non-carcinoid top mutated genes included RB1 (42%), ENPP2 (33%), ERBB4 and STK11 (17% for each), while ARID1A and ACKR3 were each present in 9.5 % of LC.

      In LUADs, mutations in EGFR and KRAS appeared as mutually-exclusive (P=0.007), while gene pairs NFE2L2 - AKT1 (P=0.012) and STK11- ALK (P=0.029) were co-mutated in LUAD and LUSC, respectively. Deletions in exons 19 and 20 of EGFR correlated with longer survival time compared to patients with wild-type EGFR (P=0.058). In NET, patients with mutated RB1 showed lower survival time compared to patients with wild-type RB1 (P=0.022).

      Examination of CNAs showed TERT amplifications (5p15.33 cytoband) were commonly found at high frequencies across all subtypes, especially in non-carcinoid NET (71.4%). Other recurrent CNAs included amplifications in MYC in 37% of LUAD and 40% of LUSC, and in EGFR in 33% of LUAD and 14% of LUSC. Deletions in the CDKN2A locus were seen at frequencies of 31% and 28% in LUAD and LUSC, respectively.

      LC patients showed longer survival time compared to other tumours (P=0.015). COSMIC mutational signatures 18 (of unknown aetiology) and 24 (associated with exposure to aflatoxin) were exclusively found in LC.

      Conclusion

      The results confirm that lung cancer is a group of heterogenous diseases. In addition to the known effects of EFGR mutations, possible therapeutic avenues could be suggested for TERT amplifications, for which nucleoside analogues have shown to promote cancer cell death or EZH2 inhibitors for ARID1A-mutated cancers.

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