HEREDITARY AND ENVIRONMENTAL COMPONENTS IN CANCER

Kari Hemminki

Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany

Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden

Approaches to study heritability of cancer

Assess environmental effects, remaining effects are heritable

What proportion are mendelian syndromes of all cancer (~ 1%)

Gene-environment interactions difficult to resolve

Approaches to study heritability of cancer

Compare cancer incidence between populations, or as a function of time, within a population

Migrant studies (or other types with changing environment: widowhood, divorce)

Twin studies

Comparison of different family relationships

Age-standardized incidence of prostate cancer among Swedish men during 1961 and 1998

1961-1965 1966-1970 1971-1975 1976-1980 1981-1985 1986-1990 1991-1995 1996-2000 0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

Men

Women

23

38

2855

86 88 10779

471480

410

343

132

7371

210

Rat

e p

er 1

00,0

00

Mesothelioma incidence in Sweden

Population-based Family Studies

The Iceland Population Database 0.2 million individuals, 15 000 cases (1955-)

The Utah Population Database 1 million individuals, 42 000 cases (1966-)

Swedish Family-Cancer Database 10 million individuals, 1 million cases (1958-)

High-risk Low-risk

Native populations

Migrant populations

Genetically determined disease:

Rate

Before After

MIGRATION

Before After

Environmentally determined disease:

Rate MIGRATION

SWEDISH IMMIGRANT STUDIES

Sweden: 10% of population foreign-bornImmigration followed epochs of world history: II WW, Hungarians, Czechs, Pinochet, Kurds, YugoslavsWe included those who had children in Sweden, mean age at entrance 23 years

ADVANTAGES

Multiple immigrant groupsClose and distant migrationMixing in societyCancers from 1 (good) cancer registryAll cancers

First-generation immigrants

IMMIGRANT STUDIES

1st GENERATION

- Large differences

2nd GENERATION

- Minimal differences

first-generation immigrants: in agreement with previous studies, most of incidence rates appeared to be closer to country of origin than Sweden. second-generation immigrants: birth in Sweden sets the Swedish pattern for cancer incidence irrespective of the nationality of descent.

first 2 decades of life are important in setting the pattern for cancer development in subsequent life.

Conclusions: immigrant study

MZ = 1.0 DZ = 0.5

1

En1 G1 Es1 Es2 G2 En2

T1

en g es es g en

T2

TWIN MODEL

Cohort Cancer info from# like-sexed pairs with known zygosity

# pairs with al least one member affected

Sweden 1886 - 1958 1959 - 1994 23 386 5 225

Denmark 1870 - 1930 1943 - 1993 8 461 3 088

Finland 1880 - 1959 1953 - 1996 12 941 1 640

Total 44 788 9 953

SAMPLE

The dataset also includes unlike-sexed twins and twins with unknown zygosity

Percentage of VarianceCancer in Sweden, Denmark and Finland

0

20

40

60

80

100

Stom

ach

Colore

ctum

Pancr

eas

Lung

Breas

t (fem

ale)

Cervix

uter

i

Corpus u

teri

Ovary

Prosta

te

Bladder

Leukem

ia

Genetic Shared environmental Nonshared environmental

Lichtenstein et al, 2000, NEJM

%

RECEPTION OF TWIN DATA

USA: so much environmental, why wasting money on DNA research?

EUROPE: so much heritable (prostate, breast, CRC) !

Family-Cancer Database, 2000

Offspring born in Sweden 1932-98 with their parents

Persons: 10 million (3.2 million families)

Cancer cases: 0.8 million

Cancer in situ cases: 0.2 million

Multi-generation

Register

Statistics Sweden relation file

Family-Cancer Database

Child Mother Father

Family-Cancer Database

individual files

Swedish Cancer

Registry1958-1998

Death

Migration

Statistics Sweden

Censuses 1960, 70, 80, 90

Statistics Sweden

Family-Cancer Database on the time axis

Registration of cancer cases

Offspring born

Parents born

1900 1932 1958 1998

Important information on subjects

First-degree relatives

Parents, Offspring, Sibling Cancer code (ICD-7) Histopathological type (PAD)

Socioeconomics status Geographic regions Birth cohort Period

Genetic interpretation of the familial risks:

dominant effects are reflected in offspring risks (and in sibling risks when a parent is affected)

recessive (or X-linked) effects are signaled by sibling risks with no parent affected Consequently, only male offspring would be affected in an X-linked recessive disease.

METHODS Person years = person-time at risk

Cancer incidence rate = Cases / Person years

Familial risk: risk in those who have an affected relative, compared to those whose relative has no cancer, given as:standardized incidence ratio (SIR), ratio between observed and expected number of cases

Data adjusted for age, period, region, socio-economic status; for women also parity and age at 1st childbirth

POPULATION ATTRIBUTABLE FRACTION (PAF)

Proportion of cancer due to familial causes

~ Heritable proportion

PAF= FP SIR-1

SIR

FP = Familial proportion= F

F+S

Col Lun Bre End Ova Pro Bla Mel Thy End0.1

1

10

100

parent

SIR

sibling

parent & sibling

Familial SIRs

SIR for concordant cancer in offspring and spouses

Cancer site

O SIR O SIR SIRUpper aerodigestive tract 27 1.55 32 1.08 1.09Stomach 59 2.05 187 1.16 1.11Colorectum 524 1.95 1003 1.02 1.03Liver 31 1.66 77 1.09 1.03Pancreas 33 1.70 77 1.06 1.03Lung 292 1.83 458 1.24 1.22Breast 1418 1.67 36 1.28 1.26Kidney 57 1.82 79 1.00 0.98Urinary bladder 103 1.66 151 1.16 1.14Melanoma 159 2.43 78 1.22 1.22Skin, squamous cell 69 2.56 110 1.17 1.19Nervous system 102 1.78 63 0.94 0.98Endocrine glands 33 2.05 19 1.03 1.00Non-Hodgkin's lymphoma 71 1.86 71 1.14 1.14Leukemia 52 1.80 58 1.03 1.04All 3030 1.80 2499 1.09 1.09Bold type: 95%CI does not include 1.00. Underlining=borderline significance.

Cancer in offspring Cancer in husband Cancer in wifeby parental cancer by wife's cancer by husband's cancer

Cancer siteO SIR O SIR

Colorectum 64 2.55 41 2.38Lung 45 2.19 26 2.04Breast 349 1.58 367 1.85Cervix 3 1.31 7 2.53Ovary 19 3.78 16 3.51Prostate 100 3.43 64 3.83Testis 13 11.53 11 6.78Kidney 14 4.46 8 3.75Melanoma 52 3.09 34 2.15Nervous system 17 1.43 27 2.43Thyroid gland, nonmedullary 1 1.22 5 6.61Endocrine glands 13 4.20 4 1.39Non-Hodgkin's lymphoma 6 1.05 17 3.30Leukemia 14 4.05 3 1.03All 710 2.03 630 2.13Bold type: 95%CI does not include 1.00. No twins included.

Siblings ages<5 years Siblings ages>=5 years

SIR for cancer in siblings by age difference

0

2

4

6

8

10

12

14

Colore

ctum

Lung

Breas

t

Cervix

Ovary

Prosta

te

Testis

Kidney

Mela

noma

Nervo

us sys

tem

Thyroid

glan

d, non

med

ullary

Endocrin

e glan

ds

Non-H

odgk

in's

lymphom

a

Leukem

ia

SIR

Ages<5yr

Ages>=5yr

* * * * * **

* * * ** *

* *

* **

*

**

*

SIR for cancer in siblings by age difference*: 95%CI does not include 1.00.

Cancer siteO SIR O SIR (sibling/parent)

Stomach 32 2.00 5 2.35 1.17Colorectum 269 2.23 114 2.65 1.19Lung 138 1.69 71 2.02 1.20Breast 963 1.61 728 1.73 1.07Cervix 32 1.59 10 1.95 1.23Endometrium 48 2.54 16 1.70 0.67Ovary 78 3.48 35 3.62 1.04Prostate 215 2.55 170 3.58 1.41Testis 10 4.33 24 8.55 1.97Kidney 34 1.92 22 3.94 2.05Urinary bladder 45 1.89 11 1.12 0.59Melanoma 105 2.33 86 2.59 1.11Nervous system 81 1.86 44 1.87 1.01Endocrine glands 22 2.18 17 2.81 1.29Non-Hodgkin's lymphoma 29 1.68 23 2.05 1.22Hodgkin's disease 7 3.82 3 3.94 1.03All 2108 1.88 1379 2.07 1.10Bold type: 95%CI does not include 1.00.

Parent only Sibling only SIR ratio

SIR for cancer in offspring of parental and sibling probands

SIR for cancer in siblings of parental and sibling probands

2.0 2.0

1.41.3 1.2 1.2 1.2 1.2 1.2 1.1 1.1 1.0 1.0 1.0

0.7 0.6

0

1

2

3

4

5

6

7

8

9

Kidney

Testis

Prosta

te

Endocr

ine g

lands

Cervix

Non-H

odgk

in's

lymph

oma

Lung

Color

ectu

m

Stom

ach

Mela

noma

Breas

t

Ovary

Hodgk

in's

diseas

e

Nervo

us sys

tem

Endom

etriu

m

Urinar

y bla

dder

SIR

0.0

0.5

1.0

1.5

2.0

2.5

SIR

rat

io (

S/P

)

Parent only

Sibling only

0

2

4

6

8

10

12

14

16

Col Lun Bre End Ova Pro Bla Mel Thy End

SIR Proportion % PAF %

SIRs, familial proportions and PAFs for parental history

012345678

Stom

ach

Color

ectu

m

Lung

Breas

t

Cervix

Endomet

rium

Ova

ry

Prosta

te

Testis

Kid

ney

Mela

noma

Nervo

us sys

tem

Thyroid

glan

d, non

med

ullary

Endocrin

e glan

ds

Hod

gkin

's dise

ase

All ages Parent<60yr Offspring<50yrParent<60yr

ParentalprobandSIR

1

10

100

Stom

ach

Colore

ctum

Lung

Breas

t

Endometr

ium

Ovary

Prosta

te

Testis

Kidney

Urinar

y blad

der

Mela

noma

Nervo

us sys

tem

Endocrin

e glan

ds

Hodgk

in's

diseas

e

All ages Sibling<50yr Both<50yr

150

Sibling proband

SIR

1

10

100

Stom

ach

Colore

ctum

Lung

Breas

t

Endometr

ium

Ovary

Prosta

te

Urinar

y blad

der

Mela

noma

Nervo

us sys

tem

Endocrin

e glan

ds

All ages Sibling<50yr Parent<60yrsibling<50yr

Both parent andsibling probandSIR

SIR for cancer in offspring by SNOMEDCancer site SNOMED O SIRStomach Adenocarcinoma 36 1.82

Signet-ring cell carcinoma 12 3.45

Colon Adenocarcinoma 182 2.11Mucinous adenocarcinoma 18 2.56

Liver Adenocarcinoma 15 1.84Hepatocellular carcinoma 8 2.48

Lung Large cell carcinoma 29 2.29Oat cell carcinoma 11 2.00

Small cell carcinoma 24 1.74

Squamous cell carcinoma 41 1.78

Adenocarcinoma 84 2.18

Breast Tubular adenocarcinoma 96 1.87Ductal carcinoma 771 1.87

Lobular carcinoma 127 1.75

Ovary Endometrioid carcinoma 12 3.61Cystadenocarcinoma 9 3.32

Serous papillary cystadenocarcinoma 25 4.26

Kidney Clear cell adenocarcinoma 8 2.73Renal cell carcinoma 22 1.72

GENOTYPES ARE INHERITED!

Person with a risk allele has inherited it from a parent

An inherited gene can predispose to cancer only if that cancer shows a familial risk

For recessive effects, familial risk only among sibling

Check familial risk before SNP analysis!

CONSTRAINS IN SNP STUDIES

Risk alleles are enriched in familial cases

Risk alleles are diluted in unselected casesCommon alleles carry normally a low risk, if anyThe risk should be higher among familial cases

h 1-h

I0

IF

A

0

2

4

6

8

10

12

14

16

18

20

1958-1969 1970-1979 1980-1989 1990-1996

Diagnosis year

Inci

den

ce r

ate/

100,

000

per

son

yea

rs

AdenocarcinomaSCCOthersAll lung cancer

0

5

10

15

20

25

30

35

40

1958-1969 1970-1979 1980-1989 1990-1996

Diagnosis year

Inci

denc

e ra

te/1

00,0

00 p

erso

n ye

ars

AdenocarcinomaSCC

OthersAll lung cancer

MEN WOMEN

Age-adjusted incidence trends of lung cancer in men and women by histological type

SIR for histological types of lung cancer in offspring byparental lung cancer

Parental lung cancer Age atdiagnosis O SIR O SIR O SIR O SIR O SIR

Adenocarcinoma < 50 7 1.98 1 0.72 6 3.70 16 1.6750-59 17 2.68 4 1.22 6 1.95 7 1.93 35 1.85 60 4 1.98 2 1.55 1 1.05 2 1.46 9 1.40

All 28 2.35 6 0.99 8 1.48 15 2.27 60 1.72

SCC < 50 8 1.62 1 0.50 7 3.54 4 1.68 21 1.5950-59 29 2.37 13 1.98 4 0.68 19 2.65 67 1.83 60 9 1.73 6 1.78 8 3.32 7 2.02 31 1.89

All 46 2.06 20 1.68 19 1.85 30 2.31 119 1.80

Small cell/ < 50 13 1.98 7 2.66 4 1.64 6 2.01 33 1.91large cell carcinoma 50-59 29 2.13 9 1.27 11 1.71 24 2.94 80 1.97

60 11 1.94 9 2.41 4 1.51 3 0.77 31 1.71All 53 2.05 25 1.85 19 1.65 33 2.19 144 1.89

All lung cancer < 50 30 1.77 9 1.31 11 1.68 18 2.28 77 1.7150-59 80 2.21 31 1.62 23 1.32 52 2.44 198 1.82 60 28 1.90 18 1.87 14 2.02 14 1.39 80 1.70

All 138 2.03 58 1.63 48 1.55 84 2.14 355 1.77

Adenocarcinoma SCC Small cell carcinoma Large cell carcinoma All lung cancer

Age-specific incidence and SIR of lung cancer in offspring of parent with lung cancer

Age at diagnosis (years)

0

20

40

60

80

100

120

140

160

180

15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-68

Rat

e 10

0,00

0 p

erso

n y

ears

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

SIR

SIRFamilial lung cancer

Sporadic lung cancer

Age at diagnosis (years)

Age at diagnosis (years)

Age-specific incidence and SIR of lung cancer in different histological types in offspring of parent with lung cancer

0

5

10

15

20

25

30

35

25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-68

Rat

e pe

r 10

0,00

0 pe

rson

yea

rs

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

SIR

SIR

SCC

Familial

Sporadic

0

5

10

15

20

25

30

35

40

45

25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-68

Rat

e pe

r 10

0,00

0 pe

rson

yea

rs

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

SIR

SIR

Large cell carcinoma

Familial

Sporadic

0

5

10

15

20

25

30

25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-68

Rat

e pe

r 10

0, 0

00 p

erso

n ye

ars

0.0

0.5

1.0

1.5

2.0

2.5

3.0

SIR

Small cell carcinoma

SIR

Sporadic

Familial

0

10

20

30

40

50

60

70

25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-68

Rat

e pe

r 10

0,00

0 pe

rson

yea

rs

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

SIR

SIR

Familial

Sporadic

Adenocarcinoma

Sibling lung cancer Age atdiagnosis O SIR O SIR O SIR O SIR O SIR

Adenocarcinoma < 50 5 8.23 1 3.73 3 9.63 11 6.6550-59 8 3.98 2 1.65 1 0.84 13 2.05 60 5 4.48 2 2.81 1 1.82 8 2.26

All 18 4.82 5 2.28 1 0.54 4 1.78 32 2.78

SCC < 50 3 9.35 2 14.67 5 5.5950-59 1 1.60 1 1.47 2 0.60 60 2 2.81 1 2.25 1 2.76 1 1.91 5 2.13

All 5 2.43 2 1.62 3 2.79 2 1.47 12 1.83

Small cell carcinoma < 50 1 8.53 1 10.36 2 15.53 4 5.5850-59 1 1.18 1 2.01 3 6.84 2 4.39 7 2.68 60 1 3.11 2 9.12 3 1.90

All 1 0.62 3 3.20 6 7.95 4 4.28 14 2.85

Large cell carcinoma < 50 1 2.84 2 12.94 3 3.1950-59 3 1.90 1 1.09 1 1.25 2 2.23 8 1.65 60 1 1.57 1 2.10 3 0.93

All 4 1.37 2 1.19 4 2.80 2 1.12 14 1.55

All lung cancer < 50 10 5.67 2 2.64 5 6.94 5 5.61 24 5.0550-59 13 2.08 5 1.34 4 1.23 7 1.92 32 1.64 60 9 2.39 5 2.12 5 2.79 2 0.77 22 1.83

All 32 2.72 12 1.75 14 2.43 14 1.96 78 2.15

SCC Small cell carcinoma Large cell carcinoma All lung cancerAdenocarcinoma

SIR for histological types of lung cancer in siblings

Age-specific incidence and SIR in siblings

Age at diagnosis (years)

0

50

100

150

200

250

15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-68

Rat

e p

er 1

00,0

00 p

erso

n y

ears

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

SIR

SIR

Familial lung cancer

Sporadic lung cancer

Age-specific incidence and SIR of lung cancer in different histological types in siblings

0

10

20

30

40

50

60

70

80

90

100

25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-68

Rat

e p

er 1

00,0

00 p

erso

n y

ears

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

SIR

Adenocarcinoma

SIR

Familial

Sporadic

0

10

20

30

40

50

60

70

80

25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-68

Rat

e pe

r 10

0,00

0 pe

rson

yea

rs

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0

10.0

SIR

SIR

SCC

Familial

Sporadic

0

5

10

15

20

25

30

25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-68

Rat

e pe

r 10

0,00

0 pe

rson

yea

rs

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

SIR

Large cell carcinoma

SIRFamilial

Sporadic

0

10

20

30

40

50

60

70

80

25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-68

Rat

e pe

r 10

0,00

0 pe

rson

yea

rs

0.0

2.0

4.0

6.0

8.0

10.0

12.0

SIR

Small cell carcinoma

SIR Familial

Sporadic

Age at diagnosis (years)Age at diagnosis (years)

SIR ratio for lung cancer in offspring of parental and sibling probands

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

Adenocarcinoma SCC Small cellcarcinoma

Large cellcarcinoma

All

SIR

rat

io (

sib

lin

g/p

aren

t)

< 50yr 50yrAll ages

29.4%

13.3%

33.3%

33.3%

27.9%