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Paolo Vineis University of Torino and ISI Foundation, Torino, Italy e-mail address: paolo.vineis @unito.it GENE-ENVIRONM

Paolo Vineis University of Torino and ISI Foundation, Torino, Italy e-mail address: paolo.vineis @unito.it GENE-ENVIRONMENT INTERACTIONS IN CANCER.

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Paolo Vineis University of Torino and ISI Foundation, Torino, Italy e-mail address: paolo.vineis @unito.it GENE-ENVIRONM

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  1. Paolo VineisUniversity of Torino and ISI Foundation, Torino, Italye-mail address: paolo.vineis@unito.itGENE-ENVIRONMENT INTERACTIONSIN CANCER

  2. LIMITATIONS OF GENETIC DETERMINISM1. HUMANS AND MICE HAVE THE SAME ESTIMATED NUMBER OF EXPRESSED GENES2. HUMANS AND CHIMPANZEES SHARE 98% OF THE GENOME3. THE SEQUENCE INFORMATION IN DNA IS INSUFFICIENT TO DETERMINE HOW GENE PRODUCTS INTERACT TO PRODUCE AN ORGANISM

  3. 4. GENETIC PATHWAYS COMPLETELY SPECIFY ORGANISMAL FUNCTION ONLY IN RARE CASES, I.E. MONOGENIC DISEASES (SICKLE CELL ANEMIA, MUSCULAR DISTROPHY), WHEN THE CELL HAS NO COMPENSATORY MECHANISM AND ENVIRONMENTAL INFLUENCES ARE NIL – “ONE MUTANT GENE – ONE DISEASE PARADIGM”STROHMAN: “THE CELL IS STARTING TO LOOK MORE LIKE A COMPLETE ADAPTIVE SYSTEM RATHER THAN A FACTORY FLOOR OF ROBOTIC MACHINE GENES”

  4. SOME FIGURESLIFETIME RISK OF BREAST CANCER IS 12.6% IN WOMEN, OF PROSTATE CANCER IS 15.9% IN MEN, AND OF COLON CANCER IS 5.6% IN BOTH SEXESBRCA1 AND BRCA2 CONFER A RELATIVE RISK OF BREAST CANCER OF 5-10GENOTYPES AT MISMATCH REPAIR LOCI CONFER A RR OF COLON CANCER OF 9.3METABOLIC POLYMORPHISMS CONFER A RR FOR SEVERAL TYPES OF CANCER OF LESS THAN 2

  5. ABOUT 0.25% OF WOMEN CARRY BRCA1 OR BRCA2 SUSCEPTIBLE VARIANTS, AND 0.1% OF PEOPLE HAVE SUSCEPTIBLE VARIANTS FOR MISMATCH REPAIR LOCITHESE GENOTYPES ACCOUNT FOR LESS THAN 5% OF BREAST OR COLON CANCERS20% OF THE GENERAL POPULATION HAVE THE APOLIPOPROTEIN E4 ALLELE, WITH A RR OF ALZHEIMER’S DISEASE OF ABOUT 2; THIS GENE ACCOUNTS FOR 16.7% OF ALL CASES OF AD

  6. HOW MANY CANCERS ARE ATTRIBUTABLE TO GENETIC PREDISPOSITION? LICHENSTEIN ET AL, N ENGL J MED 343: 78-85, 2000 44,788 PAIRS OF TWINS STUDIED IN SCANDINAVIAN COUNTRIES ESTIMATES: PROSTATE 42% (95% CI 29-55) COLORECTAL 35% (10-48) BREAST 27% (4-54) EDITORIAL BY R. HOOVER: GENE-ENVIRONMENT INTERACTIONS ARE NOT ACCOUNTED FOR (THESE ARE PROBABLY OVERESTIMATES)

  7. ATTENTION TO DIFFERENT RISK MEASURES:ABSOLUTE RISK, E.G. LIFE-TIME CUMULATIVE RISK (50-70% OF BREAST CANCERS FROM BRCA1 MUTATIONS IN MUTATION CARRIERS)RELATIVE RISK (PENETRANCE)=5-10 TIMESARe =PROPORTION AMONG CARRIERS= 80% OF BREAST CANCERS IN CARRIERS OF BRCA1 MUTATIONS ARE DUE TO THIS GENEARp = PROPORTION IN THE POPULATION=5-10% OF ALL BREAST CANCERS ARE ATTRIBUTABLE TO BRCA1 MUTATIONS

  8. WHEN ESTIMATING THE EFFECTIVENESS OF “SCREENING” WE HAVE TO CONSIDER: (A) PREDICTIVE VALUE, THAT DEPENDS ON THE PREVALENCE OF MUTATIONS(B) PENETRANCE OF THE GENE (NNT)(C) MOST IMPORTANT, THE AVAILABILITY OF PREVENTIVE OR CURATIVE MEASURES

  9. EXAMPLE: MUTATION YES NOTEST POSITIVE 15 10NEGATIVE 5 115PREVALENCE=20/145=13.8%SENSITIVITY=15/20=0.75SPECIFICITY=115/125=0.92POSITIVE PREDICTIVE VALUE=15/25=0.60I.E. OUT OF 100 POSITIVE TESTS 60 HAVE THE MUTATION

  10. EXAMPLE: MUTATION YES NOTEST POSITIVE 15 1000NEGATIVE 5 11500PREVALENCE=20/12520=0.16%SENSITIVITY=15/20=0.75SPECIFICITY=11500/12500=0.92POSITIVE PREDICTIVE VALUE=15/1015=0.015I.E. OUT OF 1015 POSITIVE TESTS ONLY 15 HAVE THE MUTATION

  11. WHAT IS THE EFFECT OF PENETRANCE?IMAGINE WE HAVE AN EFFECTIVE PREVENTIVE MEASURE THAT REDUCES THE RISK OF DISEASE IN THE SCREENEES BY 58%LET US IMAGINE THAT THE RISK OF DISEASE IS 1.4% FOR A LOW PENETRANT MUTATION AND 37% FOR A HIGHLY PENETRANT MUTATION(REALISTIC FIGURES FOR A METABOLIC POLYMORPHISM AND BRCA1, RESPECTIVELY)

  12. WE COMPUTE THE NUMBER NEEDED TO TREAT (SCREEN), I.E. THE NUMBER OF MUTATIONS CARRIERS WHO NEED TO UNDERGO SCREENING TO PREVENT A SINGLE CANCERTHE NNT(S) DEPENDS ON PENETRANCE PLUS THE EFFECTIVENESS OF PREVENTIVE MEASURES

  13. WITH 58% SUCCESSES AND A RISK OF DISEASE OF 37%,THE NUMBER OF CASES DECREASES BY 22%.THE RECIPROCAL OF 0.22 IS APPROXIMATELY 4.5WITH A RISK OF DISEASE OF 1.4% AND 58% SUCCESSES, THE RISK DECREASES BY 0.008 AND ITS RECIPROCAL IS 1/0.008=125I.E. WE NEED TO TREAT 4.5 SUBJECTS IN THE FIRST CASE AND 125 IN THE SECOND (NNT)

  14. NOW WE CAN COMBINE THE NNT AND PREVALENCETO OBTAIN THE NNS CASE 1IF WE SCREEN THE GENERAL POPULATION FOR A LOW PENETRANT GENE (NNT=125, PREVALENCE=13.8%, PPV=60%), IN ORDER TO PREVENT A CANCER WE HAVE TO MULTIPLY THE NNT BY THE RECIPROCAL OF PREVALENCE 125 X (1/0.138) = 906 SUBJECTS (WITHOUT CONSIDERING SENSITIVITY AND SPECIFICITY)

  15. CASE 2IF WE SCREEN THE GENERAL POPULATION FOR A RARE, HIGHLY PENETRANT GENE (NNT=4.5, PREVALENCE=0.16%, PPV=1.5%), IN ORDER TO PREVENT A CANCER WE HAVE TO MULTIPLY THE NNT BY THE RECIPROCAL OF PREVALENCE 4.5 X (1/0.0016) = 2813 SUBJECTS (WITHOUT CONSIDERING SENSITIVITY AND SPECIFICITY)

  16. CASE 3IF WE SCREEN FAMILIES FOR A RARE, HIGHLY PENETRANT GENE (NNT=4.5, PREVALENCE IN THE FAMILIES=0.50), IN ORDER TO PREVENT A CANCER WE HAVE TO MULTIPLY THE NNT BY THE RECIPROCAL OF PREVALENCE 4.5 X (1/0.50) = 90 SUBJECTS (WITHOUT CONSIDERING SENSITIVITY AND SPECIFICITY)

  17. Calculation of the Number Needed to Screen in the case of screening for a low penetrant gene (GSTM1 in smokers), and a highly penetrant gene (BRCA1), respectively in the general population or in families (from Vineis et al, The Lancet, 357: 709-712, 2001) Lung cancer Breast cancer in workers exposed to PAH BRCA1 BRCA1 GSTM1 null GSTM1 wild general population families Relative risk 1.34 (1.21 - 1.48) 1.0 (a) 5 10 Cumulative risk 13% 10% 40% (b) 80 % Risk reduction 50% 50% (c) 50% (Tamoxifen 50% or Raloxifene) (d) Cumulative risk after intervention 6.5% 5% 20% 40% Absolute risk reduction 6.5% 5% 20% 40%

  18. Lung cancer Breast cancer BRCA1 GSTM1 null GSTM1 wild general BRCA1 population families NNS in mutation carriers 15 20 5 2.5 Prevalence 50% 50% 0.2% (e) 50% NNS in whole target population 30 40 2,500 5 NNS in all occupationally exposed 35 (a) from Vineis et al, IARC Scie. Publ. No. 148, 1999 1999 (b) from Hopper et al, 1999 (c) theoretical maximum reduction in risk of lung cancer due to preventive action (d) theoretical benefit, based on the BCPT trial with a 45% benefit, and the Raloxifene trial with a 76% benefit (e) Coughlin et al, 1999

  19. An illustration of the principle of “one exposure - many diseases, one disease - many low penetrant genes”. Exposure Proportion attributable Tobacco smoke Lung cancer 90% Bladder cancer 70% men 30% women Larynx cancer 90% CHD 12.5% Chronic bronchitis 80% Occupational Lung cancer 4-20% (a) exposure Bladder cancer 1-10% (a) to PAH (a) depending on the areas

  20. Disease Low penetrant genes Odds Ratio (a) Lung cancer CYP1A1 MspI (asians) 1.73 CYP1A1 MspI (caucasians) 1.04 CYP1A1 Exon 7 (asians) 2.25 CYP1A1 Exon 7 (caucasians) 1.30 CYP2D6 1.26 GSTM1 1.34 Bladder cancer NAT - 2 slow 1.37 GSTM1 1.57 Colon cancer NAT - 2 rapid 1.19 (a) meta - analisys from Vineis et al, IARC Scie. Publ. No. 148, 1999

  21. MANY GENES CONTRIBUTE TO MODULATE THE RISK, AND THE CONTRIBUTION OF EACH IS MODEST ( EXCEPT IN HIGH RISK FAMILIES) ADOPTING PREVENTIVE MEASURES ONLY IN THE HIGHLY SUSCEPTIBLE WOULD IMPLY VERY LITTLE ADVANTAGES OVER PREVENTION FOR ALL

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