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Tracing the Innate Genetic Evolution and Spatial Heterogeneity in Treatment Naïve Lung Cancer Lesions Jihye Kim Translational Bioinformatics and Cancer.

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Presentation on theme: "Tracing the Innate Genetic Evolution and Spatial Heterogeneity in Treatment Naïve Lung Cancer Lesions Jihye Kim Translational Bioinformatics and Cancer."— Presentation transcript:

1 Tracing the Innate Genetic Evolution and Spatial Heterogeneity in Treatment Naïve Lung Cancer Lesions Jihye Kim Translational Bioinformatics and Cancer Systems Biology Laboratory Division of Medical Oncology, Dept. Medicine, School of Medicine, University of Colorado Anschutz Medical Campus

2 Backgrounds Personalized molecular targeted therapies in lung cancer is based on that “oncogenic driver mutations” are homogeneous throughout and between legions in a single patient However, cancers are composed of heterogeneous cell populations in terms of somatic mutations and dysregulated signaling pathways. Tumor heterogeneity may have impacts on cancer evolution and therapeutic resistance, a well as on biopsy strategies. There is no comprehensive study that analyzed treatment naïve inter-tumor heterogeneity focusing on intra-thoracic AND extra- thoracic lesions.

3 Previous studies of tumor heterogeneity
Ovaries vs Omentum/Peritoneum in treatment-naïve Multiple lesions in early-stage primary lung adenocarcinomas Multiple intrathoracic lesions from NSCLCs .

4 Treatment-naïve tumor heterogeneity in Lung Cancer
Our studies are about treatment- naïve inter-tumor heterogeneity focusing on intra and extra thoracic lesions, especially for patients with advanced-stage disease.

5 Samples and Methods Samples : Tumor specimens and non-cancer tissues from treatment-naïve autopsied lung cancer patients RNA-seq of 5 patients with multiple different metastasis sites 2 adenocarcinomas (AC), 2 squamous cell carcinomas (SQ), 1 small cell lung cancer (SCLC) Each patient has normal and primary Methods : Differential Expression Pathway analysis with GSEA/KEGG Mutation Detection Phylogenetic tree with mutations Dr. Kenichi Suda NFE2L2 KIF5B-RET [AC] [SQ]

6 Clustering Analysis : Gene expression excluding normal samples unsupervised, by all genes (FPKM >1)

7 KEGG Pathway analysis AC, non-smoker SQ, heavy smoker Primary
Pleura_Mediastinal Liver Lung_LLL Pleura_Visceral AC, non-smoker SQ, heavy smoker

8 Metastatic lesions vs. Primary tumors in NSCLCs
Comparison of upregulated or downregulated pathways between metastatic lesions vs. primary tumors in NSCLCs Pleural metastases vs. primary tumors Lung metastases vs. primary tumors Distant metastases vs. primary tumors (exclude lung metastases) Lymph node metastases vs. primary tumors By GSEA with KEGG pathways with Norm P < 0.05

9 Metastatic lesions vs. Primary tumors in NSCLCs
Comparison of upregulated or downregulated pathways between metastatic lesions vs. primary tumors in NSCLCs Pleural metastases vs. primary tumors Lung metastases vs. primary tumors Distant metastases vs. primary tumors (exclude lung metastases) Lymph node metastases vs. primary tumors By GSEA with KEGG pathways with Norm P < 0.05

10 # of mutations detected
Mutation Detection TCGA, Nature 2012 # of mutations detected Total Trunk Metastatic Trunk AC, non-smoker 350 51 (KIF5B-RET) 77 AC, smoker 362 81 (ERBB2) 18 SQ, heavy smoker 272 7 (PPL) 5 SQ, smoker 442 53 (NFE2L2) 11 SCLC, heavy smoker 207 2 (UBE2C) (Somatic / Non-synonymous / Detrimental / Total read counts > 20 / Mutant read counts > 5 and > 2%)

11 AC, non-smoker : By NJ method, implemented in R, phangorn package

12 SQ, heavy-smoker : By NJ method, implemented in R, phangorn package

13 SCLC, heavy-smoker : SCLC, heavy-smoker KEGG Pathway of SCLC

14 Conclusions and Discussions
Complexity of genomic alterations in lung cancers and potentially targetable genetic aberrations not able to evaluate tumor heterogeneity which would be clinically important Similarity and the heterogeneity between primary and metastatic lesions in lung cancer patients Gene expression clustered by patient and by tumor cell type, not by lesion location Tumor heterogeneity by pathways or somatic mutations were correlated with smoking- status Should be cautious when we use a metastatic lesion as a surrogate for the primary tumor In metastatic sites, especially in pleural metastases, immune-related pathways are downregulated compared with primary lesions, NSCLC may have a direct impact on the efficacy of treatment, especially for immunotherapeutic agents

15 Acknowledgements Hirsch Lab Tan Lab Kenichi Suda * Aik Choon Tan
Christopher J. Rivard Leslie Rozeboom Fred R. Hirsch Japan Team Isao Murakami Tetsuya Mitsudomi Tan Lab Aik Choon Tan Hyunmin Kim Jennifer Hintzsche Brian Jackson Ilyssa Summer Kelsey Nassar Minjae Yoo


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