1. Vanesa Gregorc MD Scientific Institute San Raffaele University Hospital Department of Oncology Division of Molecular Oncology Clinical research leader Thoracic Oncology Unit LUNG CANCER EPIDEMIOLOGY, PATHOLOGY AND MOLECULAR BIOLOGY

2. Ferlay J; International Journal of Cancer; 2010 New cases and deaths in men in developed and developing regions of the world

3. Ferlay J; International Journal of Cancer; 2010 New cases and deaths in women in developed and developing regions of the world

4. Ferlay J; International Journal of Cancer; 2010 Age standardized incidence and mortality rate of lung cancer around the world

5. Tobacco epidemic according to gender related prevalence

6. • Smoking • Environmental factors (radon, secondhand smoke, occupational risks) • Indoor cooking fuels • Human papilloma virus (HPV) infection Causes of lung cancer

7. Mathers CD; PLOS Medicine 2006 Projected global tobacco caused deaths by cause, 2015 Baseline scenario

8. • The duration of smoking • The number of cigarettes smoked per day • The type of cigarette smoked • The depth of inhalation • Underlying susceptibility, family history Determinants of the risk of smoking

9. • Low tar cigarette • New cigarettes designed to make the delivery of nicotine to the brain more efficient • Chemical techniques --> ↑ free nicotine --> ↑ absorption --> more addiction • Ventilated filter (low tar and nicotine, but increased depth of inhalation) • Optimal droplet size particles --> greater volumes of smoke in the periphery • Two stage blending of tobacco --> smoother, lighter cigarette --> easier to smoke • ↑ in nitrosamine content, ↓ in benzpyrene, acetaldehyde Modern cigarette design

10. Wahbah M; Annals of Diagnostic Pathology; 2007 Histologic swing to adenocarcinoma

11. Different genetic profiles

12. • Low smoking rates • Indoor air pollution from cooking with oil (rapeseed oil) Asian, Female, Adenocarcinoma

13. • HPV DNA deteted in 50% of benign bronchial squamous cell papillomas • HPV DNA detected in 21.7% of bronchial carcinomas • In vitro studies (transformation of bronchial epithelial cells by oncogenic HPV types) K J Syrjänen; J Clin Path; 2002 HPV?

14. Driver mutations in NSCLC

17. to the Both EML4 and ALK genes map to short arm of chromosome 2p, with opposite orientations Soda M; Nature; 2007 Fusion of the N-terminal EML-4 (the basic region, the HELP domain and part of the WD repeat region) Intracellular region of ALK (the tyrosine kinase domain) EML4-ALK

18. ↓ All domains of EML4 seems to contribute to the oncogenic potential of EML4-ALK, with the basic domain being the most important ➜ deletion of the Basic domain resulted in a marked (84%) decrease in the catalytic activity due to inhability to dimerize Soda M; Nature; 2007 EML4-ALK: biologic activity ➜ tumour formation, but tumours were smaller than those expressing full lenght ➜ tumour formation, but tumours were smaller than those expressing full lenght ➜ tumours were undetectable ➜ aggressive tumour formation

19. Horn; JCO; 2009 Multiple EML4-ALK variants

20. The therapeutic effect of crizotinib seems to be the inhibition of ALK Hallberg B; NEJM; 2010 Signaling pathways activated by ALK fusion proteins

21. Downstream targets of Tyrosine Kinase Receptors PI3K mutations within exon 9 and 20 ↓ constitutive or unchecked activation leads to tumour growth regardless of activation or mutation status of the RTKs PI3K-AKT-mTOR signaling

22. Activating mutations in KRAS in exon 1 and 2 ↓ irreversible binding to GTP, resulting in constitutive activation of the signaling molecule BRAF mutations in exon 11 and 15 MEK1 mutation in exon 2 RAS-RAF-MEK signaling

23. Tumour suppressor genes

24. Complexity of NSCLC pathogenesis