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Vanesa Gregorc MD Scientific Institute San Raffaele University Hospital Department of Oncology Division of Molecular Oncol...
Ferlay J; International Journal of Cancer; 2010 New cases and deaths in men in developed and developing regions of the world
Ferlay J; International Journal of Cancer; 2010 New cases and deaths in women in developed and developing regions of the w...
Ferlay J; International Journal of Cancer; 2010 Age standardized incidence and mortality rate of lung cancer around the wo...
Tobacco epidemic according to gender related prevalence
•  Smoking •  Environmental factors (radon, secondhand smoke, occupational risks) •  Indoor cooking fuels •  Human papillo...
Mathers CD; PLOS Medicine 2006 Projected global tobacco caused deaths by cause, 2015 Baseline scenario
•  The duration of smoking •  The number of cigarettes smoked per day •  The type of cigarette smoked •  The depth of inha...
•  Low tar cigarette •  New cigarettes designed to make the delivery of nicotine to the brain more efficient •  Chemical t...
Wahbah M; Annals of Diagnostic Pathology; 2007 Histologic swing to adenocarcinoma
Different genetic profiles
•  Low smoking rates •  Indoor air pollution from cooking with oil (rapeseed oil) Asian, Female, Adenocarcinoma
•  HPV DNA deteted in 50% of benign bronchial squamous cell papillomas •  HPV DNA detected in 21.7% of bronchial carcinoma...
Driver mutations in NSCLC
In frame deletion 746-750 exon 19 Amino acid substitution L858R exon 21 Amino acid substitution L861Q exon 21 Amino acid s...
 
to the Both EML4 and ALK genes map to short arm of chromosome 2p, with opposite orientations Soda M; Nature; 2007 Fusion o...
↓ All domains of EML4 seems to contribute to the oncogenic potential of EML4-ALK, with the  basic  domain being the most i...
Horn; JCO; 2009 Multiple EML4-ALK variants
The therapeutic effect of crizotinib seems to be the inhibition of ALK Hallberg B; NEJM; 2010 Signaling pathways activated...
Downstream targets of Tyrosine Kinase Receptors PI3K mutations within exon 9 and 20 ↓ constitutive or unchecked activation...
Activating mutations in KRAS in exon 1 and 2 ↓ irreversible binding to GTP, resulting in constitutive activation of the si...
Tumour suppressor genes
Complexity of NSCLC pathogenesis
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BALKAN MCO 2011 - V. Gregorc - Epidemiology, pathology and molecular biology

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BALKAN MCO 2011 - V. Gregorc - Epidemiology, pathology and molecular biology

  1. 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. 2. Ferlay J; International Journal of Cancer; 2010 New cases and deaths in men in developed and developing regions of the world
  3. 3. Ferlay J; International Journal of Cancer; 2010 New cases and deaths in women in developed and developing regions of the world
  4. 4. Ferlay J; International Journal of Cancer; 2010 Age standardized incidence and mortality rate of lung cancer around the world
  5. 5. Tobacco epidemic according to gender related prevalence
  6. 6. • Smoking • Environmental factors (radon, secondhand smoke, occupational risks) • Indoor cooking fuels • Human papilloma virus (HPV) infection Causes of lung cancer
  7. 7. Mathers CD; PLOS Medicine 2006 Projected global tobacco caused deaths by cause, 2015 Baseline scenario
  8. 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. 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. 10. Wahbah M; Annals of Diagnostic Pathology; 2007 Histologic swing to adenocarcinoma
  11. 11. Different genetic profiles
  12. 12. • Low smoking rates • Indoor air pollution from cooking with oil (rapeseed oil) Asian, Female, Adenocarcinoma
  13. 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. 14. Driver mutations in NSCLC
  15. 15. In frame deletion 746-750 exon 19 Amino acid substitution L858R exon 21 Amino acid substitution L861Q exon 21 Amino acid substitution G719A/S exon 18 L-lysine is hydrophobic, R-arginine is a polar amino acid --> R destabilizes the inactive conformation of the receptor determining its activation <ul><li>LREA 19 enhances receptor kinase activity and it develops a longer drug binding if compared to L858R </li></ul>Lynch et al ; NEJM; 2004 Kumar; JCO; 2008 EGFR activating mutations L858 R858
  16. 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
  17. 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
  18. 19. Horn; JCO; 2009 Multiple EML4-ALK variants
  19. 20. The therapeutic effect of crizotinib seems to be the inhibition of ALK Hallberg B; NEJM; 2010 Signaling pathways activated by ALK fusion proteins
  20. 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
  21. 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
  22. 23. Tumour suppressor genes
  23. 24. Complexity of NSCLC pathogenesis

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