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Epidemiology

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    Epidemiology Epidemiology Presentation Transcript

    • Epidemiology and Oncology Translational Research in Clinical Oncology 2009 Neil Caporaso, MD Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute
    • DCEG
    • Outline 1. What is the point of epidemiology? 2. What causes cancer? 3. Why don’t we know what causes cancer? 4. How have epidemiology investigations evolved? 5. Why lung cancer? 6. 7 questions about lung cancer I can’t answer 7. Why bother studying genetics in a disease caused by smoking? 8. Where are the missing genes? 9. Tell me something I don’t know 10. What next?
    • Outline 1. What is the point of epidemiology? 2. What causes cancer? 3. Why don’t we know what causes cancer? 4. How have epidemiology investigations evolved? 5. Why lung cancer? 6. 7 questions about lung cancer I can’t answer 7. Why bother studying genetics in a disease caused by smoking? 8. Where are the missing genes? 9. Tell me something I don’t know 10. What next?
    • Domain of epidemiology Epidemiology = causes of health and disease in human populations = epi (upon) + demos (the people) + logia (talk about) An OBSERVATIONAL science (like astronomy, evolutionary biology) Contrast with experimental Investigator does NOT get to pick who is exposed or unexposed Free-living people make choices about participating…possible BIAS Study of individuals with and without disease (unlike Clinical Research)
    • What are the goals of epidemiology ? 1. Identify the causes of cancer 2. Quantify risks 3. Identify risk groups 4. Understand mechanisms Public health and health services 6. Identify syndromes
    • Prevention Primary = directed to susceptibility stage Example: Needle exchange to prevent AIDS, HPV vaccine Secondary = directed to subclinical stage Example: Screen for cervical cancer with Pap Smear Tertiary = directed to clinical stage Example: Treat diabetic retinopathy to prevent blindness
    • Epidemiologist as a “crusher of dreams” Question you want the epidemiologist to answer: = What is the p value? What the epidemiologist is thinking….. Your study design is what? Your controls came from where? Did you consider bias? Did you consider confounding? What was your original hypothesis? Did you consider the power of your study? etc.
    • Outline 1. What is the point of epidemiology? 2. What causes cancer? 3. Why don’t we know what causes cancer? 4. How have epidemiology investigations evolved? 5. Why lung cancer? 6. 7 questions about lung cancer I can’t answer 7. Why bother studying genetics in a disease caused by smoking? 8. Where are the missing genes? 9. Tell me something I don’t know 10. What next?
    • SEER
      • SEER Surveillance, Epidemiology, and End Results (SEER) Program 26% of US population incidence and survival, patient demographics, primary tumor site, tumor morphology and stage at diagnosis, first course of treatment, and follow-up for vital status comprehensive source of population-based information
    • CANCER RATES These are RATES not numbers of events KEY DIFFERENCE Rates take into account age and size of population
    • Cancer Incidence Rates*, All Sites Combined, All Races, 1975-2000 Both Sexes Men Women Rate Per 100,000
    • Men cancer rates 75% increase due to PSA screening
    • Cancer Incidence Rates* for Women, US, 1975-2000 *Age-adjusted to the 1970 US standard population. Source: Surveillance, Epidemiology, and End Results Program, 1973-1998, Division of Cancer Control and Population Sciences, National Cancer Institute, 2001. Breast Lung Uterine corpus Ovary Rate Per 100,000 Colon & rectum
    • Cancer Incidence Rates* by Race and Ethnicity, 1996-2000 Rate Per 100,000
    • Cancer incidence rates
    • Cancer death rates Why are cancer death rates leveling off?
    • Lung cancer death rates … ..because the most common cause of cancer death is declining……
    • Men cancer death rates
    • Women cancer death rates
    • Per-Capita Consumption of Different Forms of Tobacco in The U.S. 1880-2003 Data Source USDA
    • Prevalence of cancer # of people diagnosed with cancer Includes those ‘cured’ and those living with the disease > 10 million Americans
    • Men lifetime mortality
    • Women lifetime mortality
    • Childhood cancer
    • Childhood Cancers (< 14 ys) Incidence 8,600 new cases/yr 12,400 (0 – 19 ys) Mortality 1,500 deaths/yr 2,300 (0 – 19 ys) rates  50% since 1973 Etiology -- poorly understood
    • Trends in Survival, Children 0-14 Years, All Sites Combined, 1974-1999 1. For children of age 0-4 the 5 year survival rate was 56.5% in 1975 and 77.3% in 1995. 2. For children of age 5-9 the 5 year survival rate was 55.3% in 1975 and 77.6% in 1995. 3. For children 10-14 years of age, the 5 year survival rate was 55.2% in 1975 and 77.6% in 1995.
    • What are the general risk factors for cancer? Increasing age Environmental factors Genetic factors Combinations of the above!
    • Relative risk A measure of the strength of the relationship between the risk factor and the cancer So, if tobacco has a RR=10 for lung cancer, smokers are 10-fold more likely to get lung cancer than non-smokers. Contrast with: odds ratio absolute risk
    • Causes of Cancer Deaths * Environmental pollution, Infectious agents, Lifestyle, Alcohol use, Occupational factors, Medicine, Radiation, Genetic susceptibility, other & unknown causes Diet ~ 30-35% Tobacco ~30-35% Other* ~30-35%
    • Skull With Cigarette van Gogh
    • Diet and cancer
    • Higher frequency of fresh red and processed meat intake increased lung cancer risks p-trend: <0.001 Fresh red meat Processed meat
    • What are some dietary risk factors? High fat Colon, breast High calories Uterine Low fiber Colon Micronutrients Lung (?) Diet contaminents Liver
    • What are alcohol-associated cancers? Oral Pharynx Esophagus Larynx Liver
    • Radiation
      • Ionizing
      • Non Ionizing
        • Ultraviolet
        • Electromagnetic
    • Ionizing Radiation Leukemia (AML, but not CLL) Breast Lung Thyroid Head and neck cancer
    • Partial list: studies implicating cancer and Ionizing Radiation Type of XRT Study Cancer Implicated A-Bomb Japan Breast, Leuk, Gastric, Thy A-Bomb Marshall Island Thyroid Medical Breast/Mastitis Breast Medical Hemangioma Breast, Thyroid Medical Hodgkin’s Breast, lung, Thyroid Medical TB-Flouroscopy Breast Radionuclides Thorotrast Leukemia, Liver (Th-232) Radionuclides Spondylytis Bones (Ra-224) Occupation Radium Dial painters Bone Occupation Rad Technicians Leukemia Occupation Chernobyl Cleanup ? Environmental Indoor radon Lung
    • Excessive sun tanning
    • Non-Ionizing Radiation (UV/sun) Basal cell Squamous cell Melanoma
    • Melanoma map
    • Indoor air pollution in China
      • 4-Aminobiphenyl Bladder
      • Arsenic Lung, skin
      • Asbestos Lung, pleura, peritoneum
      • Benzene Leukemia
      • Benzidine Bladder
      • beta-Naphthylamine Bladder
      • Coal tars and pitches Lung, skin
      • Mineral oils Skin
      • Mustard gas Pharynx, lung
      • Radon Lung
      • Soot, tars, and oils (polycyclic hydrocarbons) Lung, skin
      • Vinyl chloride Liver
      • Wood dusts (furniture) Nasal sinuses
      •  
      OCCUPATIONAL EXPOSURES -- HUMAN CARCINOGENS EXPOSURE SITE OF CANCER
    • Viruses and cancer
    • Bacteria and Stomach Cancer
      • Helicobacter pylori increases risk of stomach cancer
    • HP-associated Disease (US)
    • Genetic Epidemiology
      • Etiology, distribution, and control of disease in families and with inherited causes of disease in populations
      • Includes
        • family studies
        • molecular epi studies w/ genetic components
        • traditional cohort + case-control studies w/ family history components
    • CDKN2A Mutations in Familial Melanoma
      • CDKN2A -- major melanoma susceptibility gene
      • Frequency of mutations varies in families
        • 2 cases <5%
        • 3 – 5 cases 20 – 24%
        • >6 cases 50%
    • Cloned Familial Tumor Suppressor Genes Retinoblastoma RB1 13q14 1986 Wilms’ tumor WT1 11p13 1990 Li-Fraumeni syndrome p53 17p13 1990 Neurofibromatosis 1 NF1 17q11 1990 Neurofibromatosis 2 NF2 22q12 1993 von Hippel-Lindau VHL 3p25 1993 Familial melanoma 1 p16 9p21 1994 Familial breast 1 BRCA1 17q21 1994 Familial breast 2 BRCA2 13q12 1995 Basal cell nevus PTC 9q22 1996
    • Categories of Cancer Causation Environment - + Genes + -
    • Outline 1. What is the point of epidemiology? 2. What causes cancer? 3. Why don’t we know what causes cancer? 4. How have epidemiology investigations evolved? 5. Why lung cancer? 6. 7 questions about lung cancer I can’t answer 7. Why bother studying genetics in a disease caused by smoking? 8. Where are the missing genes? 9. Tell me something I don’t know 10. What next?
    • Outline 1. What is the point of epidemiology? 2. What causes cancer? 3. Why don’t we know what causes cancer? 4. How have epidemiology investigations evolved? 5. Why lung cancer? 6. 7 questions about lung cancer I can’t answer 7. Why bother studying genetics in a disease caused by smoking? 8. Where are the missing genes? 9. Tell me something I don’t know 10. What next?
    • 3 big gaps on the ENVIRONMENT side For many cancers, risk factors are unknown? For cancers where general ‘cause’, is understood, individual susceptibility is poorly understood How G and E work in concert is poorly understood Epidemiologists have responded by Expanding the tools of epidemiology Enhancing investigation of causation.
    • Chronic Lymphocytic Leukemia
      • Most common leukemia of Western world.
      • 30% of adult leukemia in USA
      • Less frequent in Asia and Latin America.
      • Male to female ratio is 2:1.
      • Median age at diagnosis is 65-70 years.
      • No extrinsic environmental causes known
      • Family history is the most important risk factor
    • Traditional epidemiology Exposure to tobacco leads to lung cancer
    • Molecular epidemiology Using biomarkers for both E and D Historic rationale for molecular epidemiology: We enter the black box or Gain mechanistic insight Tobacco thru an unknown mechanism leads to lung cancer
    • Molecular epidemiology Measure smoking exposure urine cotinine
    • Molecular epidemiology exposure internal dose early biological effect altered structure or function early disease disease
    • Traditional clinical trial Evaluate new treatment se me
    • Translational medicine Understand molecular pathology biomarker of disease e.g., p53 mutations, P16 methylation, telomere alterations, etc .
    • Integrative epidemiology Behavior leads to outcome exposure internal dose early biological effect altered structure or function early disease disease
    • A premise………….. Translational medicine and molecular epidemiology are natural partners. We need both to meaningfully advance prevention and treatment of major cancers. Definitions: Molecular Epidemiology using biomarkers in population studies Translational Medicine optimizing information flow between basic and clinical science (bench-bedside) Exposure disease outcome
    • Epidemiologists use 5 criteria to support causal relations …..tobacco and lung cancer High relative risk (odds ratio) Consistency Dose-response Temporal relationship Plausible mechanism
    • Lung cancer deaths occur 2 decades after smoking incidence
    • Lung cancer correlates with cigarette consumption
    • Basal cell proliferation
    • Squamous carcinoma
    • Smoking cessation
    • Outline 1. What is the point of epidemiology? 2. What causes cancer? 3. Why don’t we know what causes cancer? 4. How have epidemiology investigations evolved? 5. Why lung cancer? 6. 7 questions about lung cancer I can’t answer 7. Why bother studying genetics in a disease caused by smoking? 8. Where are the missing genes? 9. Tell me something I don’t know
    • Outline 1. What is the point of epidemiology? 2. What causes cancer? 3. Why don’t we know what causes cancer? 4. How have epidemiology investigations evolved? 5. Why lung cancer? 6. 7 questions about lung cancer I can’t answer 7. Why bother studying genetics in a disease caused by smoking? 8. Where are the missing genes? 9. Tell me something I don’t know
    • The lung cancer challenge…. 1- Drives overall cancer mortality n the US and worldwide 2- Treatment and screening pose challenges 3- Lung cancer is paradigm for genetics of complex disease 4- Clearest example of environment and gene in cancer 5- The clearest example of a genetically influenced behavior associated with the leading public health problem in the world
    • Tobacco and public health tobacco is the major cause of preventable morbidity and mortality in the Western world 1 in 5 US deaths (450,000 USA, 3M worldwide/yr) 10 million tobacco related deaths/annum by 2030 (WHO estimate) 30% of all cancer, 8 major sites, all difficult to treat - tobacco related disease costs Medicare $10B/yr and Medicaid $13B/yr In spite of widespread knowledge of the health consequences of smoking - rates in US adolescents are stable or increasing - declines in adults have leveled off - individual smoking cessation difficult
    • Outline 1. What is the point of epidemiology? 2. What causes cancer? 3. Why don’t we know what causes cancer? 4. How have epidemiology investigations evolved? 5. Why lung cancer? 6. 7 questions about lung cancer I can’t answer 7. Why bother studying genetics in a disease caused by smoking? 8. Where are the missing genes? 9. Tell me something I don’t know
    • Seven questions in lung cancer Why begin to smoke? Why persist in smoking? Why can’t people quit smoking? What determines who gets lung cancer? What genetic lesions characterize LC? Can we effectively screen LC? Can we effectively treat LC?
    • Chain of events that must occur to result in death from lung cancer (population perspective) 1. Start smoking 2. Persist in smoking/can’t quit 3.Host susceptibility/molecular lesions 4.Can’t detect early 5. Can’t treat
    • Chain of events that must occur to result in death from lung cancer (population perspective) Traditional discipline that addresses the area 1. Economics/politics 2. Behavioral scientists 3. Genetics, Epidemiology, Molecular biologists 4. Prevention trials 5. Clinical Trials
    • It costs less to intervene early in the process………..
    • It takes longer for interventions early in the process to influence cancer rates….…
    • It is politically easier to fund treatment then public health…
    • Molecular epidemiology starting point 3. Host susceptibility
    • Outline 1. What is the point of epidemiology? 2. What causes cancer? 3. Why don’t we know what causes cancer? 4. How have epidemiology investigations evolved? 5. Why lung cancer? 6. 7 questions about lung cancer I can’t answer 7. Why bother studying genetics in a disease caused by smoking? 8. Where are the missing genes? 9. Tell me something I don’t know
    • Outline 1. What is the point of epidemiology? 2. What causes cancer? 3. Why don’t we know what causes cancer? 4. How have epidemiology investigations evolved? 5. Why lung cancer? 6. 7 questions about lung cancer I can’t answer 7. Why bother studying genetics in a disease caused by smoking? 8. Where are the missing genes? 9. Tell me something I don’t know
      • Evidence: hereditary variation in lung cancer - Lung cancer kindreds exist Tomizawa 1997 Case–control studies identify increased risks in case relatives Tokuhata 1963, Ooi 1986, Shaw 1991, Bromen 2000, Lynch 1986 Segregation analysis Sellers 1990 Population databases Cannon-Albright 1994 Twin studies (note- results mixed) Morison 1994, Paul 1987, Braun 1994,95 Animal Models Manenti 1997, 1999; Dragani 1995 Many plausible polymorphic candidate genes Rare lung cancer susceptibility gene identified in lung cancer families
    • Lung cancer risk and Family History No rel.w/LC Cont Cases * OR(95% CI) 0 466 393 1.0 1 78 119 1.7 (1.2- 2.4) 2+ 8 20 2.9 (1.2- 6.6) * Adjusted for gender, smoking, passive smoking, and the # of 1st degree relatives
    • Genes that contribute to cancer fall in 2 categories Single Susceptibility Study design family population Type linkage association Allele freq rare common # of genes one/few many D and G freq rare common Risk high low Role of E low high Attrib risk low high Concept deterministic probabilistic Type Search anonymous directed example: BRCA1 TERT/CHRN
    • To look for first category of genes you need families………. High risk kindreds like this likely harbor rare genes that confer high risk- if we knew what were they would be clinically important….
    • To search for the 2nd (common) category of genes you need large populations
    • Until recently you also needed some idea of what kinds of genes to look for….. Starter paradigm for identifying candidate genes in lung cancer Smoking causes most lung cancer Carcinogens in tobacco must be metabolically activated Metabolic alteration is under genetic control CLL CLL CLL, NHL, HL NHL
    • Processing is often under hereditary control examples: tobacco nicotine (CYP2A6) aryl amines (NAT2) PAH (CYP1A1, GSTM1, others) nitrosamines (CYP2A6/13, CYP2E1)
    • Metanalyses : Lung cancer Gene studies OR (95% CI) author CYP1A1 22 1.2 (0.9-1.5) Houlson 2000 4 MspI 1.7 (1.3-2.3) d’Errico 1999 3 exon7 2.3 (1.4-3.7) d’Errico 1999 CYP2D6 16 1.3 (1.0-1.6) d’Errico 1999 13 1.3 (0.9-2.0) Christensen 1997 MPO * 6 0.7 (0.4-0.8) Kantarci 2002 GSTM1 23 1.1 (1.0-1.3) Houlson 1999 13(C) 1.2 (1.1-1.4) d’Errico 1999
    • Genetic Association Studies Hirschhorn et al Genetic Medicine 2002 - 600 reported associations (133 diseases and 268 genes) 166 studied 3 or more times only 6 consistently reproduced DVT and F5 (arg506Gln) Graves Disease and CTLA4 (Thr17Ala) Type 1 Diabetes and INS (5’ VNTR) HIV/AIDS and CCR5 (32bp ins/del) Alzheimers and APOE (e 2/3/4) Creutfeldt-Jacob and PRNP (met129val) None involving cancer
    • Some observations - In general candidate genes studies to identify the precise genes that account for the hereditary risks in complex disease have been disappointing Situation NOT unique to lung cancer An improved approach was needed to examine the genome in a systematic manner…
    • What were some challenges in finding genes involved in common cancers using candidate approach (pre-2007)? - type 1 error (false positives) - population stratification - multiple comparisons - inadequate power (type 2 error) - design issues - failure to consider gene-environment failure to consider pathways failure to consider genetic architecture
    • Where genes might operate to influence disease risk... 1 PAH CYP1A1, AHR, GSTM1, GSTP1, EH, NQO1, MPO 2 nitrosamines CYP2E1, CYP2D6, CYP2A6 3 aromatic amines CYP1A2, NAT1, NAT2 4 nicotine CYP2A6, CYP2A13, CYP2D6
    • Where genes might operate to influence disease risk. 1 dopamine DRD2, DRD4, SLC6A3, TH, DBH 2 serotonin 5HTT, CYP2D6, receptors 3 nicotine CYP2A6, CYP2A13, nicotinic receptors..
    • Multiple Comparisons The problem: 1. Many gene families and many genes within each family 2. Many SNPs within each gene Technical capacity to test 1000s of genes Low prior probability that any given SNP is truly associated with the cancer…….. Therefore because the number of true associations is limited………………
    • Multiple Comparisons The vast majority of observed ‘significant’ associations will be FALSE POSITIVE Suppose we test 5 SNPs for each of 20,000 genes or 100,000 SNPs….assume that 100 SNPs have a true ‘disease’ relation….. only 100/5100 or 2% of nominally significant associations will be ‘true positives’.
    • A problem.What we investigate: One gene leads to one disease. The biological reality is tha one gene has many effects (pleiotropy). Many genes cause one disease.
    • Outline 1. What is the point of epidemiology? 2. What causes cancer? 3. Why don’t we know what causes cancer? 4. How have epidemiology investigations evolved? 5. Why lung cancer? 6. 7 questions about lung cancer I can’t answer 7. Why bother studying genetics in a disease caused by smoking? 8. Where are the missing genes? 9. Tell me something I don’t know 10. What next?
    • Outline 1. What is the point of epidemiology? 2. What causes cancer? 3. Why don’t we know what causes cancer? 4. How have epidemiology investigations evolved? 5. Why lung cancer? 6. 7 questions about lung cancer I can’t answer 7. Why bother studying genetics in a disease caused by smoking? 8. Where are the missing genes? 9. Tell me something I don’t know 10. What next?
    • WISH LIST in 2005 to identify genes in lung cancer MUCH MUCH larger study Technology to look at all genes in an ‘agnostic’ screen
    • EAGLE website
    • Study Design Population-based Catchment's area: 5 cities and 216 municipalities Cases: from 13 hospitals Controls: randomly sampled from the area Matched by age, sex, and residence
    • Study description 2348 incident lung cancer cases 2012 population-based controls Participation rate, Cases = 85%; Controls = 73%; 1. Questionnaires CAPI, Demographics, Smoking, Family history, Medical history, Reproductive history, Occupational exposures, Self-administered, Behavior, Diet, 2. Clinical Data Path reports, Diagnostic procedures, Imaging, 3. Biospecimens Blood/buccal, WB, PBMC, RBC, Serum, Plasma, Buffy coat, DNA, RNA, Blood cards, Tissue Fresh frozen, Paraffin blocks, Paraffin slides 4. caBIG Participation rate, Cases=85%; Controls=73%
    • Pilot studies: participation rate A 30% participation rate was obtained by Survey and Phone A 49% participation rate was obtained by Invitation letter, Follow-up by phone, In hospital, Advertisements, Cash award, Physicians’ letter and Home/hospital. A 73% participation rate was obtained by New interviewers, Physicians’ call, Gas coupon, TV ads, New invitation letter, Mayor’s letter, Toll-free phone line Total number of subjects in pilot investigations: 156 Cases - 212 Controls Clinical data: 99% Questionnaires: 87% Biospecimens: 97%
    • Why Population Controls ? Gold standard Representative of the population from which cases derive Can calculate absolute rates Reduces selection bias IMPLIES Defined population in time and space Specified eligibility and exclusion criteria Defined and high response rate
    • Study design: controls 35% never smokers 30% former 35% current n=700 n=600 n=700 Test for Test for Test for smoking initiation smoking initiation smoking persistence smoking persistence
    • Lung Cancer Case Control
    • GENEVA Overview Gene Environment Association Studies. Part of NIH-wide Genes, Environment and Health Initiative (GEI). GENEVA aims: use whole genome technology: Identify genetic variants related to common, complex diseases. Identify variations in gene-trait associations related to environmental exposures. Address potential pathways to outcomes in various populations.
    • Study Investigators – Phase I The first round of GENEVA grants funded eight Study Investigators in 2007. PI Institution Title Frank Hu, MD, PhD Harvard University Type 2 Diabetes William Lowe, MD Northwestern University Maternal Metabolism-Birth Weight Interactions Mary Marazita, PhD 1 University of Pittsburgh Dental Caries Jeffrey Murray, MD University of Iowa Prematurity and its Complications Terri Beaty, PhD 1 Johns Hopkins University Oral Clefts Laura Bierut, MD 2 Washington University Addiction Eric Boerwinkle, PhD 3 The University of Texas Health Science Center at Houston CHD Neil Caporaso, MD National Cancer Institute Lung Cancer Study
    • Our Aims Find genes related to: Lung Cancer Smoking Survival
    • EAGLE Environment And Genetics in Lung Cancer Etiology PLCO Cancer Screening Trial Prostate, Lung, Colon, Ovary Initial design included ~5800 subjects but we sought collaborators from other lung cancer studies to have additional power to find genes…..
    • Power Calculation _ Lung Cancer Revision= Phase 1: EAGLE + PLCO (n=~5,500)
    • Data Sharing
      • For EAGLE, PLCO, ATBC
      • Lung cancer
        • Age
        • Gender
        • Family history of lung cancer
        • Case/control status
        • Histology
        • Stage
      • Smoking phenotype
        • Smoking status (never/ever/former)
        • Pack years
        • Fagerstrom (available in EAGLE only)
    • Outline 1. What is the point of epidemiology? 2. What causes cancer? 3. Why don’t we know what causes cancer? 4. How have epidemiology investigations evolved? 5. Why lung cancer? 6. 7 questions about lung cancer I can’t answer 7. Why bother studying genetics in a disease caused by smoking? 8. Where are the missing genes? 9. Tell me something I don’t know 10. What next?
    • Outline 1. What is the point of epidemiology? 2. What causes cancer? 3. Why don’t we know what causes cancer? 4. How have epidemiology investigations evolved? 5. Why lung cancer? 6. 7 questions about lung cancer I can’t answer 7. Why bother studying genetics in a disease caused by smoking? 8. Where are the missing genes? 9. Tell me something I don’t know 10. What next?
    • Major difference in chr 5 SNP by histology
    • Outline 1. What is the point of epidemiology? 2. What causes cancer? 3. Why don’t we know what causes cancer? 4. How have epidemiology investigations evolved? 5. Why lung cancer? 6. 7 questions about lung cancer I can’t answer 7. Why bother studying genetics in a disease caused by smoking? 8. Where are the missing genes? 9. Tell me something I don’t know 10. What next?
    • WISH LIST in 2009 to identify genes (in lung cancer and other cancer) MUCH MUCH larger study Technology to look at more genes in an ‘agnostic’ screen Go from 500,000 SNPs>>>millions Include CNVs Include rare genes Eventually need sequencing
    • Next Priorities Role of chr 15 in lung Cancer/Smoking Genomics: Outcome Key subgroups
    • Large studies provide key advantages : - incorporate new technologies and disciplines test diverse hypotheses lower marginal costs bring interdisciplinary expertise to bear use resources efficiently get full scientific value from large study ‘platforms’ Large studies should do everything possible to incorporate multiple ‘domains’ to create a setting for the best science.