1. Genetics of Adult Lung Cancer Frederic J. Kaye, M.D. Genetics Branch, CCR, NCI and National Naval Medical Center

2. Types of Neuroendocrine Lung Tumors Small cell lung cancer (SCLC)/RB gene inactivation Pulmonary carcinoid Non-SCLC with neuroendocrine phenotype Primary undifferentiated cancer (mediastinal/thymic/lung) Primitive neuroectodermal tumors Extrapulmonary SCLC Merkel cell tumor Retinoblastoma MEN1/MEN2-like: pituitary, MTC, islet cell, pheochromocytoma ? SCLC-related non-lung tumors

3. Types of non-Neuroendocrine Lung Tumors AdenoCa, Squamous cell, Large cell, Undifferentiated Ca, BAC Non-SCLC Mesothelioma Sarcoma (chondro-, angio-, etc) Mucoepidermoid Pleuro-pulmonary blastoma

4. RB Tumor Suppressor Product Cell Cycle Arrest Repress transcription (E2F) p105 hypophosphorylated RB Cellular Differentiation Co-activate transcription (MyoD) p105 hypophosphorylated RB Apoptosis p100cl RB

5. RB functions as a tumor suppressor gene in lung cancer l >90% of neuroendocrine SCLC express mutant or absent RB protein l 10% of non-SCLC express mutant or absent RB protein l all mutations analyzed inactivate the RB binding pocket domain l ectopic expression of RB reverses tumorigenicity in vivo

6. RB/p16/cdk pathway RB phospho cell cycle arrest cell proliferation CDK:cyclin activation p16 Inactivation of Only One Component in the Pathway is Required for Tumorigenesis SCLC Non-SCLC

7. RB inactivation p16 inactivation p53 mutation K-ras mutation Telomerase activation Myc over-expression PTEN mutations Chr 3p allele loss Absent FHIT protein Elevated BCL2 ErbB1/EGFR ErbB2/neu Epigenetic silencing of many genes of ? significance 90%10% 5-10%75% 90-100%50-70% 0%30% 90-100%75% 30%10% 10-20%0-5% 100%70-100% 50%75% 80%10-30%20-40% <5%20-30% Genetic Alterations in Lung Cancer SCLCnon-SCLCgene

8. p14/Arf p53 Ras p16Myc RB Cdk:Cyclin PTEN ErbB arrest apoptosissenescencecell cycleterminal differentiation chromosomal instability telomerase activation Phosphatase genes ?? role Genetic events in lung cancer Autocrine/Paracrine Mismatch repair FHIT Other 3p genes Bcl2 activation SV40 Tag C-Kit gene many others

9. Conclusions Extrapolation of adult lung tumors to selected pediatric tumors requires consideration of: i) cell biology features ii) genetic features iii) molecular pathways targeted by the treatment This will require a case-by-case evaluation which may vary depending on the specific treatment Since our understanding of molecular pathways is still incomplete, empirical approaches may also have value