Paolo Vineis

University of Torino and ISI Foundation, Torino, Italy

e-mail address: paolo.vineis@unito.it

GENE-ENVIRONMENT INTERACTIONS

IN CANCER

LIMITATIONS OF GENETIC DETERMINISM

1. HUMANS AND MICE HAVE THE SAME ESTIMATED NUMBER OF EXPRESSED GENES

2. HUMANS AND CHIMPANZEES SHARE 98% OF THE GENOME

3. THE SEQUENCE INFORMATION IN DNA IS INSUFFICIENT TO DETERMINE HOW GENE

PRODUCTS INTERACT TO PRODUCE AN ORGANISM

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”

SOME FIGURES

LIFETIME 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 SEXES

BRCA1 AND BRCA2 CONFER A RELATIVE RISK OF BREAST CANCER OF 5-10

GENOTYPES AT MISMATCH REPAIR LOCI CONFER A RR OF COLON CANCER OF 9.3

METABOLIC POLYMORPHISMS CONFER A RR FOR SEVERAL TYPES OF CANCER OF LESS THAN 2

ABOUT 0.25% OF WOMEN CARRY BRCA1 OR BRCA2 SUSCEPTIBLE VARIANTS, AND 0.1% OF PEOPLE HAVE SUSCEPTIBLE VARIANTS FOR MISMATCH

REPAIR LOCI

THESE GENOTYPES ACCOUNT FOR LESS THAN 5% OF BREAST OR COLON CANCERS

20% 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

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)

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 TIMES

ARe =PROPORTION AMONG CARRIERS= 80% OF BREAST CANCERS IN CARRIERS OF BRCA1 MUTATIONS ARE DUE TO

THIS GENE

ARp = PROPORTION IN THE POPULATION=5-10% OF ALL BREAST CANCERS ARE ATTRIBUTABLE TO BRCA1

MUTATIONS

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

EXAMPLE:MUTATIONYES NO

TESTPOSITIVE 15 10

NEGATIVE 5 115

PREVALENCE=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

EXAMPLE:MUTATIONYES NO

TESTPOSITIVE 15 1000

NEGATIVE 5 11500

PREVALENCE=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

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)

WE COMPUTE THE NUMBER NEEDED TO TREAT (SCREEN), I.E. THE NUMBER OF MUTATIONS

CARRIERS WHO NEED TO UNDERGO SCREENING TO PREVENT A SINGLE CANCER

THE NNT(S) DEPENDS ON PENETRANCE PLUS THE EFFECTIVENESS OF PREVENTIVE MEASURES

WITH 58% SUCCESSES AND A RISK OF DISEASE OF 37%,THE NUMBER OF CASES DECREASES BY 22%.

THE RECIPROCAL OF 0.22 IS APPROXIMATELY 4.5

WITH A RISK OF DISEASE OF 1.4% AND 58% SUCCESSES, THE RISK DECREASES BY 0.008 AND ITS RECIPROCAL IS 1/0.008=125

I.E. WE NEED TO TREAT 4.5 SUBJECTS IN THE FIRST CASE AND 125 IN THE SECOND (NNT)

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)

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)

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)

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 afterintervention 6.5% 5% 20% 40%

Absolute risk reduction 6.5% 5% 20% 40%

Lung cancer Breast cancer

BRCA1GSTM1 null GSTM1 wild general BRCA1

population families

NNS in mutationcarriers 15 20 5 2.5

Prevalence 50% 50% 0.2% (e) 50%

NNS in wholetarget 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

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% womenLarynx 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

Disease Low penetrant genesOdds Ratio (a)

Lung cancer CYP1A1 MspI (asians) 1.73CYP1A1 MspI (caucasians) 1.04CYP1A1 Exon 7 (asians) 2.25CYP1A1 Exon 7 (caucasians) 1.30CYP2D6 1.26GSTM1 1.34

Bladder cancer NAT - 2 slow 1.37GSTM1 1.57

Colon cancer NAT - 2 rapid 1.19

(a) meta - analisys from Vineis et al, IARC Scie. Publ. No. 148, 1999

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