Expression Profiling-Based Subtyping Identifies Novel Non-small Cell Lung Cancer Subgroups and Implicates Putative Resistance to Pemetrexed Therapy Jun.

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Expression Profiling-Based Subtyping Identifies Novel Non-small Cell Lung Cancer Subgroups and Implicates Putative Resistance to Pemetrexed Therapy Jun Hou, PhD, Margaretha Lambers, MSc, Bianca den Hamer, MSc, Michael A. den Bakker, PhD, Henk C. Hoogsteden, PhD, Frank Grosveld, PhD, Joost Hegmans, PhD, Joachim Aerts, PhD, Sjaak Philipsen, PhD Journal of Thoracic Oncology Volume 7, Issue 1, Pages 105-114 (January 2012) DOI: 10.1097/JTO.0b013e3182352a45 Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Identification of six subgroups in the Erasmus MC NSCLC cohort. Six subgroups are indicated by G1 to G6. A, Correlation view of gene expression in the 90 Erasmus MC NSCLC samples. Pairwise correlations between any two samples are displayed. The colors of the cells represent Pearson's correlation coefficient values between any two samples, with deeper red indicating higher positive and deeper blue lower negative correlations. The red diagonal line displays the self-to-self comparison of each sample. B, Relative expression levels of TYMS, cell proliferation genes, and neuroendocrine genes are shown for each of the six identified NSCLC subgroups. Boxes show the distribution of gene expression in each subgroup, with dots representing outliers. The dashed line shows the median expression of that gene across all NSCLC samples. NSCLC, non-small cell lung cancer; G1, group1; G6, group6; TYMS, thymidylate synthase. Journal of Thoracic Oncology 2012 7, 105-114DOI: (10.1097/JTO.0b013e3182352a45) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Relative expression of TYMS in relation to classical NSCLC histology. Relative expression levels of TYMS in histology signature-assigned NSCLC groups.15 A, Erasmus MC cohort and (B) Duke Cohort. Boxes show the distribution of TYMS expression in each subgroup with crosses representing outliers. The band in the box shows the median expression of TYMS in that group. TYMS, thymidylate synthase; NSCLC, non-small cell lung cancer. Journal of Thoracic Oncology 2012 7, 105-114DOI: (10.1097/JTO.0b013e3182352a45) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Predicted Pemetrexed sensitivity in NSCLC subgroups and NSCLC cell lines. A, NSCLC cases predicted to be resistant (NR) or sensitive (R) to Pemetrexed are correlated to expression profiling-based subgroups (G1 to G6). B, Validation of Pemetrexed resistance signature using NSCLC cell lines. Predicted sensitivity to Pemetrexed for NSCLC cell lines is compared with experimentally established sensitivity. For each cell line, data from two independent microarrays were used (number of cases). C, Performance of the Pemetrexed-resistance prediction signature on the Duke NSCLC Cohort. The 96 primary NSCLC cases were classified into subgroups using the group signature genes (indicated by G1 to G6). The predicted response to Pemetrexed by the 25-probe set resistance signature and its correlation to the subgroups are displayed. NSCLC, non-small cell lung cancer; NR, nonresponder; R, responder; G1, group1; G6, group6. Journal of Thoracic Oncology 2012 7, 105-114DOI: (10.1097/JTO.0b013e3182352a45) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Utility of routine IHC markers to identify putative NR and R to Pemetrexed therapy. The expression of eight IHC markers in 68 of 90 NSCLC and two normal lung tissues (G0) was detected by TMA and used for cluster analysis. High staining is shown in red and low staining is shown in green. Failed IHC staining is shown in purple. NSCLC cases are annotated with predominantly present expression profile-assigned subgroup(s) (G1 to G6) on the right and predicted Pemetrexed responsiveness (resistant case [NR]: gray; sensitive case [R]: orange) on the left. IHC, immunohistochemistry; NR, nonresponder; R, responder; NSCLC, non-small cell lung cancer. Journal of Thoracic Oncology 2012 7, 105-114DOI: (10.1097/JTO.0b013e3182352a45) Copyright © 2012 International Association for the Study of Lung Cancer Terms and Conditions