Genetic Epidemiology of Cancer and its

Risk FactorsHermine MaesCancer Control

March 2006

Scandinavian Twin RegistriesLichtenstein et al. 2000 NEJM 343:78-85

• Swedish Twin Registry– Born 1886-1925: N=10,503p Ncancer=4490– Born 1926-1958: N=12,883p Ncancer=1157– Swedish Mortality Registry/ Swedish Cancer Registry

• Danish Twin Registry– Born 1870-1930: N=8461p Ncancer=3572– Central register of Deaths/ Danish Cancer Registry

• Finnish Twins– Born 1880-1958: N=12,941p Ncancer=1584– Central Population Register/ Finnish Cancer Registry

Types of cancer and concordance by sex/zygosity in 44,788 pairs of twins from Sweden, Denmark and Finland

Lichtenstein et al. 2000 NEJM 343:78-85sex sex

MZ DZ MZ DZ MZ DZ MZ DZ MZ DZ MZ DZLip M 0 0 27 57 0 0 Prostate M 40 20 299 584 0.21 0.06

F 0 0 4 8 0 0 Testis M 1 0 22 38 0.08 0Oral cavity M 0 0 10 20 0 0 Kidney M 0 0 61 108 0 0

F 0 0 6 24 0 0 F 0 0 48 99 0 0Pharynx M 0 0 11 19 0 0 Bladder M 5 2 146 253 0.06 0.02

F 0 0 7 5 0 0 F 0 0 43 76 0 0Esophagus M 0 1 16 50 0 0.04 Skin M 0 2 49 78 0 0.05

F 0 0 17 31 0 0 F 1 0 58 105 0.03 0Stomach M 6 8 131 256 0.08 0.06 Brain, ONS M 1 0 65 112 0.03 0

F 5 4 92 198 0.1 0.04 F 0 1 66 142 0 0.01Colorectum M 10 17 202 393 0.09 0.08 Thyroid M 0 0 10 19 0 0

F 20 15 214 453 0.16 0.06 F 0 0 29 44 0 0Liver M 0 1 30 44 0 0.04 Bone M 0 0 5 0

F 0 1 23 35 0 0.05 F 0 0 2 6 0 0Galbladder M 0 0 16 25 0 0 Soft Tissue M 0 0 12 27 0 0

F 1 1 51 81 0.04 0.02 F 0 0 14 23 0 0Pancreas M 2 1 64 127 0.06 0.03 Non-Hodgkin's M 0 0 36 99 0 0

F 1 0 59 127 0.03 0 lymphoma F 0 0 45 84 0 0Larynx M 2 1 22 36 0.15 0.05 Hodgkin's M 0 0 14 19 0 0

F 0 0 3 11 0 0 F 0 0 18 12 0 0Lung M 15 24 233 436 0.11 0.1 Multiple myeloma M 1 0 36 57 0.05 0

F 3 1 63 185 0.09 0.01 F 0 0 28 38 0 0Breast M 0 0 2 5 0 0 Leukemia M 2 1 51 105 0.07 0.02

F 42 52 505 1023 0.14 0.09 F 0 1 52 93 0 0.02Cervix uteri F 1 3 107 201 0.02 0.03Corpus uteri F 1 5 122 245 0.02 0.04 All sites M 262 356 1252 2459 0.29 0.22Ovary F 3 1 125 230 0.05 0.01 F 265 408 1487 3023 0.26 0.21

discordant affected

concordanceconcordant affected

discordant affected

concordance concordant affected

Genetic Epidemiology of Cancers Lichtenstein et al. 2000 NEJM 343:78-85

Genetic Epidemiology of CancersLichtenstein et al. 2000 NEJM 343:78-85

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

stomach

colorectum

pancreas

lung

breast

cervix uteri

corpus uteri

ovary

prostate

bladder

leukemia

additive genetic shared environment

Correlations Mammography densityBoyd et al. 2002 NEJM 347:886-894

Heritability Mammography densityBoyd et al. 2002 NEJM 347:886-894

Familial Risk for CancerSwedish Family-Cancer Database

Standardized incidence ratioHemminki et al. 2001 Br J Cancer 84:388-391

Population Attributable FractionHemminki & Czene 2002 CEBP 11:1638-1644

Risk Factors for Cancer

• Obesity

• Exercise / Physical Activity

• Smoking

• Alcohol / Drug Use

Obesity

Cancer Mortality due to BMI -menCalle et al. 2003 NEJM 348:1625-1638

Cancer Mortality due to BMI -womenCalle et al. 2003 NEJM 348:1625-1638

Population Attributable FractionCalle et al. 2003 NEJM 348:1625-1638

Cancer-attributable deaths EUBanegas et al. 2003 Eur J Clin Nutr 57:201-208

All-cause deaths to excess weightBanegas et al. 2003 Eur J Clin Nutr 57:201-208

Reviews on Genetics of Obesity

• Price, 1987; Bouchard & Pérusse, 1988; Stunkard, 1991; Meyer and Stunkard, 1993; Sorensen and Stunkard, 1994; Meyer and Stunkard, 1994; Bouchard and Pérusse, 1994; Sorensen, 1995, Meyer, 1995; Maes et al. 1997; ….

• focus: particular type of study: adoption, twin or family • main conclusion: genetic factors play a significant role in variation of

body fatness• debate: how much is explained by genetic factors?• heritability: h2

– twin (.50-.90) > – family (.20-.80) > – adoption (.20-.60) studies

• measure: body mass index (BMI) weight (kg)/height2 (m)

MZ twins

0

0.2

0.4

0.6

0.8

1

0 500 1000 1500 2000 2500

DZ twins

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

0 500 1000 1500 2000 2500 3000

Twin correlations for BMI

Parent-Offspring

-0.1

0

0.1

0.2

0.3

0.4

0.5

0 2000 4000 6000 8000 10000 12000 14000

Siblings

0

0.1

0.2

0.3

0.4

0.5

0.6

0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000

Sibling & PO correlations for BMI

Adoptive Pairs

-0.2

-0.1

0

0.1

0.2

0.3

0.4

0 50 100 150 200 250 300 350 400 450 500

Spouses

-0.1

0

0.1

0.2

0.3

0.4

0.5

0 5000 10000 15000 20000 25000 30000

Non-biological correlations BMI

MZ twins

0

0.2

0.4

0.6

0.8

1

0 500 1000 1500 2000 2500

Parent-Offspring

-0.1

0

0.1

0.2

0.3

0.4

0.5

0 2000 4000 6000 8000 10000 12000 14000

Siblings

0

0.1

0.2

0.3

0.4

0.5

0.6

0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000

Adoptive Pairs

-0.2

-0.1

0

0.1

0.2

0.3

0.4

0 50 100 150 200 250 300 350 400 450 500

DZ twins

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

0 500 1000 1500 2000 2500 3000

Spouses

-0.1

0

0.1

0.2

0.3

0.4

0.5

0 5000 10000 15000 20000 25000 30000

Correlations between RelativesMaes et al. 1997 Behav Genet 27:325-351

• Weighted mean correlation pooled across studies: – .74 MZ twins .32 DZ twins – .24 siblings .19 parents and offspring (PO) – .12 spouses .06 adoptive relatives

• Expectations based on correlations:– 1-rMZ: specific environmental factors– rMZ > rDZ: additive genetic factors– rDZ > 1/2rMZ: shared environmental factors– rDZ < 1/2rMZ: dominance genetic factors– rDZ > rSib: twin effects– rSib > rPO: age x gene interaction, dominance– rPO > rSib: cultural transmission– rSpouse > 0: assortment– rAdoptSib/PO > 0: shared environmental factors

Twin Studies of BMIMaes et al. 1997 Behav Genet 27:325-351

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

NAS-NRC (VA)Finnish TR

Sweden SATSA mSweden SATSA f

Danish TR mDanish TR f

Norway TP mNorway TP f

TrondelagOZ NH&MRC <30yOZ NH&MRC >30y

Virginia 30k mVirginia 30k fMI MTSADA

Utah pedigreesKP TRBritain

US CAATSA

heritability adults

Twin Studies of BMIMaes et al. 1997 Behav Genet 27:325-351

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

Sweden SATSA

Britain m

Britain f

Britain

Finland,Japan

heritability twins reared apart

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

MCV TS

China

US (GA,KE,IN)

Belgium

VTSABD 8-10y

VTSABD 11-13y

VTSABD 14-16y

heritability adolescents

Longitudinal Twin Studies of BMIMaes et al. 1997 Behav Genet 27:325-351

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

NAS-NRC Y-MNAS-NRC M-L

Finnish TCMCV TS mMCV TS fVTSABD

LLTS

genetic correlations

Family & Adoption Studies of BMIMaes et al. 1997 Behav Genet 27:325-351

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

Quebec FSCanada Fitness SNorway Trondelag

NHLBI FHS

heritability family studies

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

Danish ARLondon

TOPSMontrealQuebec

IowaColorado AP sibs

Colorado AP po

heritability adoption studies

Integrated Approach

• all collateral two-generational relationships identified in kinships of twins (first and second degree relatives)– > estimate sex-dependent

contributions of genes and environment to complex traits in presence of assortative mating

– > resolve genetic and cultural transmission, and both special MZ and special DZ twin environment effects

• Stealth Eaves, 1999; ET-model Maes, 2006

CA B

T F

a f c f

CA B

T M

b m c m

i

on

CA B

P F

a f c f

CA B

P M

a m b m c m

m p

a m

K

l f

L

k m k f

lm

L

Kk f

l f

L

Kk m

lm

L

r vs

euqr v

s

euq

y

eu*q* eu*q*

1

1

1

1

1

1

1

K

1

d

Ttm t fT

w

1 1

Ttm

1t f T

1

.5 .5 .5.5.5 .5.5 .5

Virginia 30,000

• Structure of the Virginia 30,000 Sample– pedigrees: twins + parents, siblings, spouses, children– > 80 sex-specific two-generation relationships

• Ascertainment of the Virginia 30,000 Sample– questionnaires on 14,763 twins, ascertained from 2 sources:– N=5287 families <Virginia Twin Registry– N=9476 twins <American Association of Retired Persons

• BMI– log transformed, corrected for the linear and quadratic effects of

age, sex, twin status, source of ascertainment (Virginia vs. AARP), and interactions between these terms

ET Model Results

• proportions of variance for most parsimonious model– additive genes: 35% males 39% females– genetic effects of assortative mating: 2% – dominance: 31% males 26% females

> broad heritabilities of .66 males .65 females– special twin environment: 7-8%– unique environmental: remaining 27%– special MZ twin environment, non-scalar sex limitation, cultural

transmission, non-parental shared environment not significant • confidence intervals: quite narrow < large sample sizes• < relative simplicity of model which accounts for

covariation in 88 different familial relationships with only 10 parameters

Summary

• convergent results for wide variety of relationship– studies with smaller sample sizes: greater variability in estimates

of correlation between relatives

• > substantial role for genetic factors in the etiology of individual differences in BMI

• why higher heritability estimates in twin vs family studies:– separate special twin environment for MZs &DZs – significance of dominance variance– twins controlled for age effects– maternal effect (intrauterine effects on growth of fetus with

lasting differences)– special MZ twin environment– epistatic effects from interaction of genes at two or more loci

GenomeEUtwin ProjectSchousbou et al. 2003 Twin Res 6:409-421

Genetic Epidemiology of BMISchousbou et al. 2003 Twin Res 6:409-421

Human Obesity Gene MapPerusse et al. 2004 Obes Res 13:381-490

Heritability of change in weight/fatBouchard & Tremblay 1997 J Nutr 127:943S-947S

Heritability of fat mass and BMIFaith et al. 1999 Pediatrics 104:61-67

Heritability of eating patternsvan den Bree et al. 1999, Am J Clin Nutr 70:456-465

Heritability of food intakeHeitmann et al. 1999 Am J Clin Nutr 69:597-602

Exercise

Physical activity and CancerFriedenreich & Orenstein 2002 J Nutr 132:3456S-3464S

Biological Mechanisms of activity Friedenreich & Orenstein 2002 J Nutr 132:3456S-3464S

Framework PEACEFriedenreich & Orenstein 2002 J Nutr 132:3456S-3464S

Twin Studies of ExerciseStubbe & de Geus, 2006 Handbook of Behavior Genetics

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

Canada

Dutch 14-20y

Dutch 13-22y

Portugal m

Portugal f

Dutch 13-22y

Belgium 15y m

Belgium 15y f

Dutch 13-14y

Dutch 15-16y

Dutch 17-18y

Dutch 19-20y

addtive genetic shared environment adolescents

Twin Studies of ExerciseStubbe & de Geus, 2006 Handbook of Behavior Genetics

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

Australia

VETS

Dutch 14-20y

Dutch 13-22y

Danish

Dutch 35-62

GenomeEUtwin m

GenomeEUtwin f

addtive genetic shared environment adults

Twin Studies of Physical ActivityStubbe & de Geus, 2006 Handbook of Behavior Genetics

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

Finland >18y

Canada 15y

Finland 16y m

Finland 16y f

Portugal 12-25y m

Portugal 12-25y f

Finland 24-60y va

Finland 24-60y la

US (AZ) 4-10y paee

US (AZ) 4-10y tee

addtive genetic shared environment

Genetics of Exercise BehaviorStubbe & de Geus, 2006 Handbook of Behavior Genetics

Country N twin pairs

male female male femaleAustralia 2,728 64% 56% 48% 48%Denmark 9,456 43% 33% 52% 52%Finland 8,842 37% 29% 62% 62%The Netherlands 2,681 58% 55% 67% 67%Norway 3,995 55% 51% 27% 56%Sweden 8,927 37% 23% 62% 62%United Kingdom 422 - 53% - 70%

percentage exercisers

heritability estimates

Heritability of exercise by ageStubbe et al. 2005 Med Sci Sports Exerc 37:563-570

Genetic Epidemiology Studies

• Advantages & Disadvantages

Classical Twin Study I

MZ & DZ twins reared together age matching

– > age-dependent influences of genes or environment

sex limitation (male/female same + opposite sex twins)– > magnitude/source of effects of genes and environment

twins versus singletons– not generalizable if twins not representative of population

• twins not significantly different from singletons• birth / first years of life, but twins ‘catch up’ by age 8

self-report zygosity measures (difficulty being told apart)– discrepant MZ twins more likely classified as DZ twins– > increasing heritability estimates

Classical Twin Study II

equal environment assumption– MZ/DZs equal proportion of salient environmental factors

• similarity > contact > more shared environmental experiences (Lykken et al., 1990)

• parents respond to, rather than create differences (Lytton , 1977)

– genetic factors control degree to which ‘environmental’ factors are shared by twins

special twin environment– twins/sibs equal proportion of salient environmental factors

intrauterine effects on the growth of the fetus– siblings < twins (dichorionic < monochorionic twins)

• correlating intrapair differences in birth weight with those in adult BMI > intra-uterine period not a critical period for development of adiposity (Allison et al., 1995)

Classical Twin Study III

GE correlation– genetic and environmental factors not independent

• particular genetic make-up limits choice of environment• common source for genes & environment: parent’s phenotype >

offspring’s environment > combined genetic & cultural transmission• different genotypes actively select different environment

– ‘eliciting’ = genetic effect - with environmental pathway

GxE interaction– sensitivity to unique environment genotype-dependent– GxE interaction = specific environmental effect

random mating– assortment of partners < significant marital correlation– > h2 overestimated in AE, underestimated in ACE model

• spouse corr significant but low, c2 not significant > h2 overestimated

Twins Reared Apart

prenatal environment post-natal environment (age of separation) representativeness

– parents who put children up for adoption: representative?– parents who adopt: representative?– > sampling of both genotypes and environments suspect

random placement– no correlation between biological and adoptive parents– > independence of genetic and cultural transmission

generalizability of twin data GxE interaction random mating no test of common environment

Family Studies

Nuclear Family Design: parent-offspring, sibling & spouse pairs

no separation of genetic and environmental transmission– significant correlations < shared genes or environments

(siblings: cultural transmission/ non-parental shared env)– > measured indices of the environment > construct

environmental index free from any genetic background?

Twin Parent Design: classical twin design with parents separation of genetic and environmental transmission

– 5 parameters: heritability, non-parental shared env., cultural transmission, assortative mating, unique env.

• model with sex differences applied to sum of skinfolds from LLTS (Maes et al., 1996) h2 .79 males .90 females, genetic effects of assortment 2%, no shared environment

Extended Family Design

separation of genetic and cultural transmission– addition of second-degree relatives (over first-degree relatives)– > estimation of additional parameters, such as dominance

assortative mating– estimate of assortment <marital correlation

• assortative mating more likely explanation than cohabitation/marital interaction (Allison et al., 1996; Knuiman et al., 1996)

age x genotype interaction– children & parents or siblings measured at different ages– > different genetic/environmental factors at different ages >

parent-offspring & sibling correlations reduced > reduced h2

• higher correlations of sibs close in age than further apart (Mueller & Malina, 1980; Tambs et al.,1991)

• longitudinal twin studies: genetic correlations between twins measured at different ages > mostly same genetic factors, but new genetic factors switch on at various ages

– > discrepancies between results from family & twin studies

Adoption Studies I

Complete Adoption Design: adopted/natural children & adoptive/biological parents

resolution of effects from genes and shared environment– correlation of adopted children - biological parents > estimate of

genetic transmission– correlation of adopted children - adoptive parents > estimate of

cultural transmission

assortment age effects selective placement

– adopted parents not selected based on any characteristic of adopted child or biological parents of adopted child

– > separation of genetic and environmental pathways

prenatal environment/ early postnatal environment– > genotype-environment covariance

Adoption Studies II

Partial Adoption Design: adopted children & adoptive parents

estimate of cultural transmission not confounded with genetic transmission– adoptive versus regular parent-offspring correlations– > estimate of the genetic transmission by subtracting and

doubling adoptive parent-offspring correlation from biological parent-offspring correlation

assortment age effects selective placement prenatal environment/ early postnatal environment