Most common malignant disease in western hemisphere In the United States, 89,300 men and 67,600 women die yearly from lung cancer Etiology: Tobacco

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2 Most common malignant disease in western hemisphere In the United States, 89,300 men and 67,600 women die yearly from lung cancer Etiology: Tobacco use (primary cause) Occupation Air pollution Radon Asbestos Viruses (Klein, Kotb and Peterson, 2009) Genetic component (Haiman,et al.,2006)

3 Most common Shortness of breath Cough Weight loss Fatigue

4 Lung cancer may be seen on Chest XRAY and CT scan. The diagnosis is confirmed with a biopsy, usually bronchoscopy or CT-guided biopsy. Treatment and prognosis depend upon 1. the histological type of cancer 2. the stage of spread 3. the patient's performance status.

5 Possible treatments include surgery, chemotherapy and radiotherapy. Depending on the stage and treatment, the five-year survival rate is 14%.

6 Non- small cell - 85% of all cancer 1. Epidermoid carcinoma (Squamous cell) % 2. Adenocarcinoma % - more likely to occur in nonsmokers 3. Large-cell carcinoma % Small-cell carcinoma - 15%

7 Only 10 to 15% of all smokers develop lung cancer 10 to 15% of all lung cancers occur among nonsmokers. This suggest that there are individual differences in susceptibility to lung carcinogens This susceptibility may be the result of genetic predisposition to lung cancer. (OMIM,2009) Taioli et al. (2007) found that a polymorphism in the MPO gene conferred resistance to lung cancer among smokers.

8 Follows a multistep oncogenic process Elaborate collection of genetic abnormalities of disrupted pathways are caused by environmental carcinogens. This results in heterogeneous nature of lung cancer (Yagui-Beltran and Jablons 2009 )

9 Proto-oncogenes are believed to turn into oncogenes when exposed to particular carcinogens. Cigarette smoking is strongly associated with mutation of the somatic K-ras gene in patients with primary adenocarcinoma of the lung. (Ahrendt,et al. 2009) Mutations in the K-Ras proto-oncogene are responsible for 10 30% of lung adenocarcinomas.

10 K-ras acts as a molecular on/off switch. Once it is turned on it recruits and activates proteins necessary for the propagation of growth factor. A single amino acid substitution is responsible for an activating mutation. The transforming protein that results is implicated in other malignancies besides lung adenocarcinoma.

11 The epidermal growth factor receptors(egfrs) regulate cell proliferation, apoptosis, angiogenesis and tumor invasion. Mutations and amplifications of EGFRs are common in non-small cell lung cancer. They provide the basis for treatment with EGFR-inhibitors.

12 Chromsomal damage leads to loss of heterozygosity, causing inactivation of tumor suppressor genes. Damage to chromosomes 3p, 5q, 13q, and 17p are common in small cell lung carcinoma. The p53 tumor suppressor gene, located on chromosome 17p, is affected in 60-75% of cases.

13 You, et al. (2009) studied 6 multigenerational families each having with at least five cases of lung cancer RESULTS: A region-wide scan across 6q23-25 found significant association between lung cancer susceptibility and three single nucleotide polymorphisms in the first intron of the RGS17 gene.

14 Patients with non-small cell lung cancer and mutations in EGRF have a significantly increased 12- month survival rate when treated with the drug gefitinib. Screening for RGS17 could be used to identify high-risk patients who may benefit from earlier, more aggressive lung cancer screening.

15 Future areas of research include : K-ras proto-oncogone Tumor suppressor gene replacement Cancer stem cell research

16 Your patient want to know what her genetic risk is for developing lung cancer. She is a former light smoker,(in adolescence), quit 30 years ago. Her grandfather and mother died from lung cancer. They were both smokers. You have at your disposal a test for lung cancer. As a health care provider, it is your responsibility to understand what kind of psychosocial impact genetic testing may have on your patient.

17 Test must justified by serious disease, with effective prevention or treatment. Highly sensitive and specific Reality is: Many tests available commercially We can anticipate many more tests becoming available in the future Marteau and Croyle (1998) noted: As genetic testing extends beyond testing for single gene disorders to testing large sections of the population for genes associated with common disorders, it is important to consider what effect this will have on individuals and on society as a whole

18 Predictive genetic testing, such as that for the cancer predisposition genes, presents an especially important challenge in this regard. Results of genetic testing stay with patient throughout life. Some patients use the information to be proactive about addressing any risk that may be identified. Others find the quoted risks frightening, and serious psychosocial complications such as depression or anxiety may result.( Ensenauer, Michaels and Reinke,2005)

19 Increased anxiety; Depression; Guilt; The burden of carrying such knowledge with constant vigilance for the onset of symptoms; Damage to self-esteem Stigmatization. (James,et al. 2003)

20 RESULTS: Genetic counseling and testing appear to produce psychological benefits and to improve accuracy of risk perception Carriers of mutations in cancer predisposition genes did not experience significant increases in depression and anxiety Non-carriers experienced significant relief. Being tested but declining to learn results seemed to increase risk of a worse psychological outcome. (Butow, et al, 2003)

21 Does revealing increased genetic risk for lung cancer increase rate of smoking cessation? There is only limited evidence of increased motivation, no evidence of successful behavior change in the few studies that observed individuals who were told that they have increased genetic risk. Motivation may be reduced because it may induce a sense of powerlessness and fatalism.(marcy, et al2002)

22 Ethical issues patient autonomy (right to know) vs nonmaleficence. In this case, no. Difficult to know how much risk increases with positive result. May induce undue worry, the disease is multifactorial, patient is a nonsmoker. adds additional health care costs.

23 Points for discussion: Patient s motivation for test Benefits and limitations of testing Meaning of both a positive and negative result should be explored in detail. Impact of a test result on medical management

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25 Ahrent,S.A., Decker,P.A.,Alawi,E.A,Zhu,Y.R.,Sanchez- Cespedes,M.,Yang, S.C., et al. (2009). Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer Research, 69, doi: / CAN Butow, P.N., Lobb, E.A., Meiser, B., Barratt, A., &Tucker, K.M.(2003). Psychological outcomes and risk perception after genetic testing and counseling in breast cancer: A systematic review. Medical Journal of Australia 178(2): Retrieved from Pub Med. Ensenauer,R.E., Michels,V.V.&, Reinke,S.S.(2005). Genetic testing: practical, ethical, and counseling considerations. Mayo Clinic Proceedings,80(1): Retrieved from PubMed] Haiman, C. A., Stram, D. O., Wilkens, L. R., Pike, M. C., Kolonel, L. N., Henderson, B. E., et al. (2006). Ethnic and racial differences in the smoking-related risk of lung cancer. New England Journal of Medicine. 354,(4), Retrieved from PubMed. James, M.A., Lu,Y., Liu,Y., Vikis,H.G. &You, M. (2005). Clinical ethics: Ethical considerations in presymptomatic testing for variant CJD.Journal of medical ethics,31: doi: /jme

26 Lo, B. (2009). Resolving Ethical Dilemmas: A guide for clinicians. 4th Ed. Lippincott, Williams, & Wilkins: Baltimore, MD. Lung cancer # (n.d.). In Online Mendelian Inheritance in Man. Retrieved from Marcy,T.W.,Stefanek,M,.Thompson,K.M.(2002.) Genetic testing for lung cancer risk: If physicians can do it, should they? General Internal Medicine (12): Doi: /j Marteau,T.M. and Croyle, R.T. (1998)The new genetics: Psychological responses to genetic testing. British Medical Journal 316(7132): Spiro,S.G. (2003). Lung Cancer. In A. Warrell, E. Benz, J. Firth, T. Cox, Eds. Oxford Textbook of Medicine. Oxford/New York. Oxford University Press. Retrieved STAT!Ref Online Electronic Medical Library.

27 Taioli, E., Benhamou, S., Bouchardy, C., Cascorbi, I., Cajas-Salazar, N., Dally, H.,et al.(2007) Myeloperoxidase G-463A polymorphism and lung cancer: a HuGE genetic susceptibility to environmental carcinogens pooled analysis. Genetics Medicine. 9: Yagui-Beltran, A. and Jablans,D.M.(2009) A translational approach to lung cancer research: From EGFRs to Wnt and cancer stem cells. Annuals of Thoracic Cardiovascular Surgery.;15(4): Retrieved from Pubmed. You,M.,Wang,D.,Liu,P.,Vikas,H.,James,M.,Lu,Y. et al.(2009) Fine mapping of chromosome 6q23-25 region in familial lung cancer families reveals RGS17 as a likely candidate gene. Clinical Cancer Research. 15(8): Retrieved from PubMed.