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R. Mallick



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    ORAL 39 - Potential Biomarkers for CT Screening (ID 149)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Screening and Early Detection
    • Presentations: 1
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      ORAL39.06 - Whole Blood microRNA Expression May Not Be Useful for Screening Non-Small Cell Lung Cancer (ID 2547)

      16:45 - 18:15  |  Author(s): R. Mallick

      • Abstract
      • Presentation
      • Slides

      Background:
      Five studies have shown that microRNA levels in whole blood can be used to diagnose lung cancer. We conducted a large bi-institutional study to validate this finding.

      Methods:
      PAXgene[TM] Blood miRNA System (Qiagen®) was used for peripheral venous blood collection and total RNA isolation for 85 pathologic stage IA-IIIB non-small cell lung cancer cases and 76 clinically-relevant controls who either had a high risk of developing lung cancer because of smoking and age >50 y, or had a benign pulmonary nodule. Cases and controls were accrued at two institutions in the United States, Roswell Park Cancer Institute, Buffalo and University of Pennsylvania, Philadelphia. MiRCURY™ microarrays (Exiqon®) with locked nucleic acid hybridization probes were used to quantify microRNAs in RNA isolates. Quantification was also performed using Taqman™ microRNA reverse transcription (RT)-PCR assays (ABI®) for five microRNAs whose lung cancer-diagnostic biomarker utility had been suggested by the five published studies.

      Results:
      Cases (n=85) and controls (n=76) were similar for age, gender, race, and blood hemoglobin and leukocyte but not platelet levels (Table 1). Of the 1936 human mature microRNAs detectable with the microarray platform, 586 (30%) were identified as expressed and reliably quantified among the study's subjects. However, none of the microRNAs was differentially expressed between cases and controls (P >0.05 in test using empirical Bayes-moderated t statistics and false discovery rate <5%). In classification analysis using the whole blood microRNA profiles with leave-one-out internal cross-validation, accuracy was 48% and 50% with the support vector machines and top-scoring pair methods, respectively. With RT-PCR assays, cases and controls did not differ for any of the five microRNAs whose biomarker potential had been suggested by previous studies.

      Table 1. Characteristics of study groups; *Fisher's exact test for categorical variables, and t test for others; #blood values for 84 cases and 30 controls.
      Cases Controls P*
      85 76
      Mean age, y (range, SD) 64 (41-83, 8) 61 (45-83, 9) 0.07
      %male 49 51 0.87
      %white 90 93 0.57
      RPCI 42 32 0.43
      U. Pennsylvania 43 44
      Adenocarcinoma 43
      Squamous cell 33
      Other non-small cell 9
      High-risk control 58
      Nodule control 18
      Leukocytes (x1000/µl; mean, SD)# 8.2 (2.6) 7.8 (2.1) 0.37
      Platelets (x1000/µl; mean, SD)# 291.8 (114.3) 238.2 (50.2) 0.01
      Hemoglobin (g/dl; mean, SD)# 13.4 (1.8) 13.9 (1.4) 0.15


      Conclusion:
      This study suggests that whole blood microRNA expression profiles may not be useful for developing biomarkers for use in non-invasive blood-based assays for generic screening of non-small lung cancer. Further studies are required to examine if whole blood microRNA diagnostic biomarkers may exist for use with specific types of lung cancer or non-cancer control conditions.

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    P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P3.04-107 - MicroRNA Expression in Epithelial and Stromal Components of Early-Stage Non-Small Cell Lung Tumors (ID 3220)

      09:30 - 17:00  |  Author(s): R. Mallick

      • Abstract

      Background:
      MicroRNAs are ultra-short, non-coding RNAs that play important roles in the biology of lung cancer. In addition, biomarker utility of lung cancer tumor microRNAs for diagnosis, histological sub-typing, prognosis and prediction of response to therapy has been demonstrated in a large number of studies. Like all tumors, those of non-small cell lung cancer contain both cancerous epithelial and non-cancerous stromal cells. To facilitate our understanding of the role of microRNAs in lung cancer biology as well as their application as biomarkers, we examined microRNA expression in epithelial and stromal components of early-stage non-small cell lung tumors.

      Methods:
      Laser capture microdissection of 8 µm-thick, hematoxylin-eosin-stained sections of formalin-fixed specimens was used to separately collect epithelial and stromal components of 77 resected pathologic stage I non-small cell lung cancer tumors. Total RNA was extracted from the dissectates with the Norgen Biotek® FFPE Tissue RNA Isolation kit and quantified with Ribogreen™ assay (Invitrogen®). MiRCURY™ microarrays (Exiqon®) with locked nucleic acid hybridization probes were used to quantify microRNAs in 350 ng of each RNA isolate. For validating the microarray data, 10 microRNAs in the RNA isolates were also quantified using Taqman™ microRNA reverse transcription (RT)-PCR assays (ABI®).

      Results:
      Microdissection was performed for 35 adenocarcinoma, 16 bronchioloalveolar carcinoma and 26 squamous cell carcinoma tumors. Of the 1936 human mature microRNAs detectable with the microarray platform, 595 (31%) were identified as expressed and reliably quantified among the RNA samples. Microarray-based quantification of 10 microRNAs in the samples was validated by RT-PCR. Significant differences for microRNA expression between tumor epithelia and stroma, and between cancer of different histologies was noted.

      Conclusion:
      Our study provides information on microRNA expression in epithelial and stromal components of early-stage non-small cell lung tumors.