1 / 15

Lung Cancer Project update

Lung Cancer Project update. Schumacher - Kaiser November 17, 2006. Agenda. DB sample annotations Univariate and multivariate analyses (definition of classes conditions biological interpretation) Preliminary biomedical assessment of transcriptional signatures Dataset integration

lisle
Download Presentation

Lung Cancer Project update

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Lung Cancer Projectupdate Schumacher - Kaiser November 17, 2006

  2. Agenda • DB sample annotations • Univariate and multivariate analyses (definition of classes conditions biological interpretation) • Preliminary biomedical assessment of transcriptional signatures • Dataset integration • Project timeline and milestones • Ph.D. student – update • Next steps ...

  3. Transcriptional assessment of lung biopsies - approach • Novachip platform • Biopsies with at least 10% of tumor cells (score>0) • Definite diagnoses • Squamous cell carcinomas, adenocarcinomas, controls • Orthogonal Partial Least Squares Discriminant Analysis • Two classes question  OPLS-DA  ranked features • Top 500 features analyses • Pubmed and other NCBI db and tools, Ingenuity Pathway Analysis, Metacore, Medgene, Pathologene, OntoExpress, ...

  4.    NSCLC: some markers for diagnosis of primary lung adenocarcinomas from Ueno et al (2003) BJC 88:1229

  5. NSCLC: adenocarcinoma – transcriptional signatures  tumor features (1.2) • increased levels of pulmonary adenocarcinoma markers (e.g. SFTPA2, SFPTB, SFTPC, SFTPD, NASPA, TTF1) • increased cell migration (tumor cells?, endothelial cells,leukocytes??) tumor cell spreading (increased AREG, CLDN4, FN1, HPN, MET, MMP9, PLAU, THBS1, VCAM1) • no significant change of APC and other leukocytes‘ markers • chemoattraction of mononuclear leukocytes (CCL2, CCL20, CXCL13) – respiratory burst of monocytes? (increased CCL2, FN1, ICAM1, TREM1, VCAM1) • increased cell invasiveness – cell extravasation signaling? increased cell attachment(e.g. macrophages: increased FN1, ICAM, VCAM1; tumor cells: increased IGF2, PLAU, THBS1) • increased angiogenesis (increased ADAMTS1, FN1, SERPINE1, SPARC, THBS1) • increased reactive stroma - myofibroblasts (e.g. SPARC, other) • increased tumor growth (increased CCL2, CRABP2, FN1, IGF2, IL6, MET, MMP9, OLR1, PLAU, SPP1, THBS1) • increased ECM remodelling – „wound healing“ (increased MMP1, MMP9, MMP11, MMP12, MMP13) • decreased redox stress? (decreased GSTA1, GSTA2, GSTM1 - low proliferation? cell cycle?) • increased neuritogenesis (increased ABL2, GEM, NFGB, PLAU)

  6. NSCLC: adenocarcinoma – transcriptional signatures  tumor features (2.2) • tumor progression mechanisms (CTAs (MAGEs, GAGEs), TP63, TP53?) • other oncogenes, tumor suppresors relevant markers (MYC, SRC, HER/NEU, HRAS, KRAS2, CCND1; CTNNB1, VEGFC, ERBB1-3) • evidence of epigenetics? (HATs, HDACs, DNMTs, ...) • markers of poor prognosis (e.g. SPARC, more to come ...) • xenobiotic metabolism(e.g. decreased AKR1C1, GSTs, CYP4B1, ...) • serum markers? (e.g. IL6, SPP1) • relevant molecular pathways: e.g. inflammation-related • stem cell –like markers, transient amplifying compartments (KIT, POU5F1, SOXs, SCF, CD33, ABCG2)

  7.    (?) NSCLC: distinguishing pulmonary small cell carcinoma from poorly differentiated squamous cell carcinoma TTF1 TTF1 TP63 TP63 KRT CDKN2A KRT CDKN2A Small cell carcinoma Poorly differentiated squamous carcinoma from Zhang et al (2005) Modern Pathology 18:111

  8. NSCLC: poorly differentiated adenocarcinoma   TTF1 TP63  (?)  KRT CDKN2A  mucins SFTPB from Zhang et al (2005) Modern Pathology 18:111

  9. NSCLC: squamous cell carcinoma – transcriptional signatures tumor features (1.2) • increased levels of epidermal markers (development and differentiation) - relate to carcinogenesis theories: e.g. „wound that never heals“ • inflammation, leukocytic infiltration (poor), reactive stroma? • increased cell division, proliferation and survival • increased invasiveness, ECM remodelling • tumor progression mechanisms (MAGE, TP63, TP53?) • no major evidence of epigenetics? (HATs, HDACs, DNMTs, ...) • other oncogenes, tumor suppresors • markers of poor prognosis (e.g. MAGEs. GAGE1, SPP1) • mechanisms of tumor defense (?) • xenobiotic metabolism in smokers, drug treatment, solute transport, CYPs, • serum markers? (e.g. IL1A, IL6, SPP1, defensins) • relevant molecular pathways(e.g. SHH, polyamines, Ca2+ signaling) • other cancers, transient amplifying compartments, differentiation ...

  10. NSCLC: squamous cell carcinoma – transcriptional signatures tumor features (2.2) from Proksch et al (2006) J Dermatol Sci 43(3):159

  11. MAGEs, TP53, epigenetics, TP63

  12. Discussion ...

  13. Datasets integration

  14. Proposed project timeline and milestones

  15. Next steps ...

More Related