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Elizabeth Starren



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    MA 06 - Lung Cancer Biology I (ID 660)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Biology/Pathology
    • Presentations: 1
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      MA 06.13 - Direct Metabolomic Profiling of Lung Cancers (ID 10319)

      15:45 - 17:30  |  Presenting Author(s): Elizabeth Starren

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancers rely on metabolites to fuel growth and to signal to surrounding tissues. Systematic study of these molecules may identify biomarkers for early diagnosis and novel pathways tractable to therapy. Previous studies of the metabolome in lung cancer have been confined to the serum and to sputum. We have therefore interrogated biochemical profiles in human lung cancers and matched adjacent normal tissues with the aim of identifying metabolites and metabolic signatures associated with lung cancer.

      Method:
      Global biochemical profiles were determined in human lung tumour and adjacent normal tissue. 12 tumours and 12 matched normal samples were tested from adenocarcinoma (ADC) patients, and 12 tumour/normal pairs were similarly tested from squamous cell carcinoma (SCC) patients. Samples were analysed on the Metabolon GC/MS and LC/MS/MS platforms, with the inclusion of technical replicates.

      Result:
      Application of PCA as a function of the tissue metabolome demonstrated that the normal, ADC and SCC groups were clearly distinguishable. We observed general metabolic changes associated with tumour tissue (q<0.10 throughout), with reductions in glucose and concomitant elevations in sorbitol and lactate indicative of Warburg metabolism in both ADC and SCC. Levels of reduced glutathione (GSH) were higher in SCC compared to ADC and normal tissue, indicating elevated antioxidant capacity in SCC. Conversely, alternative antioxidants including taurine, biliverdin, ascorbate, alpha- and gamma-tocopherol, and ergothioneine were higher in ADC than SCC. The neurotransmitters serine, NAA, GABA, and NAAG were also significantly elevated in ADC but not SCC. Finally, elevations in prostaglandin D2 and 6-keto prostaglandin F1alpha were confined to SCC and prostaglandin E2 was elevated to a much greater extent (8-fold versus 3-fold) in SCC vs. ADC, as compared respectively to normal lung tissue.

      Conclusion:
      Results from this pilot global profiling study confirm greater glucose utilization and lactate production, increased fatty acid synthesis, and changes in membrane biology in ADC and SCC. However, changes in glutathione metabolism, antioxidant capacity, neuroactive metabolites, and inflammation appear to vary according to tumour type. A larger scale study may identify differential therapeutic avenues and response to therapy. Profiling of matched serum/plasma from lung cancer patients may allow for identification of disease-specific biomarkers to supplement histological-based diagnostic techniques.

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    P1.02 - Biology/Pathology (ID 614)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-054 - The Molecular Characterisation of Lung Adenocarcinoma Subgroups (ID 9412)

      09:30 - 16:00  |  Presenting Author(s): Elizabeth Starren

      • Abstract

      Background:
      Lung adenocarcinoma is a heterogeneous disease which can be challenging to classify accurately, yet precise histological subtyping is becoming increasingly important. Subgroup patterns have been shown to confer important prognostic information. In this study, we sort to identify gene expression profiles for the six predominant subtypes within adenocarcinoma, in a sequential cohort of resected tumours, to explore whether molecular markers could enhance standard histological diagnosis.

      Method:
      89 paired (fresh frozen tumour and normal tissue) lung adenocarcinomas were profiled both histologically and by global gene expression and correlated with multiple clinical parameters including stage, age, gender and smoking status. The tumour samples were reviewed by a thoracic pathologist to determine the predominant subtype and assigned into lepidic, acinar, papillary, micropapillary, solid or cribriform predominant groups. Gene expression was generated using Affymetrix Human gene 1.1ST arrays and the Genetitan platform. All RINs > 6. The data was rma treated using Affymetrix Power Tools and poor quality arrays were detected and excluded using Array Quality Metrics. Low expressed probes and control probes were removed. Differential gene expression of the adenocarcinoma predominant subtypes was evaluated using Limma.

      Result:
      Survival analysis confirms that age and stage are the most significant predictors of outcome. Application of a highly stringent threshold (adj. P value 0.0001) identified 4805 gene transcripts that were significantly differentially expressed among the six predominant adenocarcinoma subtypes. We determined that 3887 of these transcripts are unique to one of the adenocarcinoma subgroups and therefore have the potential to contribute to a predominant subtype defining transcriptional signature. These unique transcripts include functionally interesting genes such as transcriptional factors SOX2/4/7/13/18 involved in determination of cell fate and ROR1 a receptor tyrosine kinase-like orphan receptor among others. A pairwise comparison of the individual subgroups identified that the most significant gene variation is seen between lepidic predominant and solid predominant, indicating that these subgroups are transcriptionally the most disparate to one another.

      Conclusion:
      In this study multiple highly significant gene transcripts that allow differentiation between the adenocarcinoma subgroups have been identified. These adenocarcinoma subtype gene signatures have the potential to augment current histological diagnosis of lung adenocarcinoma and provide valuable insights into the different biological processes underpinning the six adenocarcinoma subtypes.