1. 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

2. 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

3. 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

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

5. 1961-19651966-19701971-19751976-19801981-19851986-19901991-19951996-2000 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 28 55 86 88 107 79 471 480 410 343 132 7371 210 Rate per 100,000 Mesothelioma incidence in Sweden

6. 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-)

7. High-riskLow-risk Native populations Migrant populations Genetically determined disease: Rate Before After MIGRATION BeforeAfter Environmentally determined disease: Rate MIGRATION

8. SWEDISH IMMIGRANT STUDIES Sweden: 10% of population foreign-born Immigration followed epochs of world history: II WW, Hungarians, Czechs, Pinochet, Kurds, Yugoslavs We included those who had children in Sweden, mean age at entrance 23 years

9. ADVANTAGES  Multiple immigrant groups  Close and distant migration  Mixing in society  Cancers from 1 (good) cancer registry  All cancers

10. First-generation immigrants

11. IMMIGRANT STUDIES  1 st GENERATION  - Large differences  2 nd GENERATION  - Minimal differences

12. 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

13. MZ = 1.0 DZ = 0.5 1 En 1 G1G1 Es 1 Es 2 G2G2 En 2 T1T1 engesesesesg T2T2 TWIN MODEL

14. CohortCancer info from # like-sexed pairs with known zygosity # pairs with al least one member affected Sweden1886 - 19581959 - 199423 3865 225 Denmark1870 - 19301943 - 19938 4613 088 Finland1880 - 19591953 - 199612 9411 640 Total44 7889 953 SAMPLE The dataset also includes unlike-sexed twins and twins with unknown zygosity

15. Percentage of Variance Cancer in Sweden, Denmark and Finland 0 20 40 60 80 100 Stomach Colorectum Pancreas Lung Breast (female) Cervix uteri Corpus uteri Ovary Prostate Bladder Leukemia GeneticShared environmentalNonshared environmental Lichtenstein et al, 2000, NEJM %

16. RECEPTION OF TWIN DATA  USA: so much environmental, why wasting money on DNA research?  EUROPE: so much heritable (prostate, breast, CRC) !

17. 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

18. Multi-generation Register Statistics Sweden relation file Family-Cancer Database Child MotherFather Family-Cancer Database individual files Swedish Cancer Registry 1958-1998 Death Migration Statistics Sweden Censuses 1960, 70, 80, 90 Statistics Sweden

19. Family-Cancer Database on the time axis Registration of cancer cases Offspring born Parents born 1900193219581998

20. Important information on subjects  First-degree relatives Parents, Offspring, Sibling  Cancer code (ICD-7)  Histopathological type (PAD)  Socioeconomics status  Geographic regions  Birth cohort  Period

21. 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.

22. 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 1 st childbirth

23. POPULATION ATTRIBUTABLE FRACTION (PAF) Proportion of cancer due to familial causes ~ Heritable proportion PAF= FP  SIR-1 SIR FP = Familial proportion= F F+S

24. Familial SIRs

25. SIR for concordant cancer in offspring and spouses Cancer site OSIRO Upper aerodigestive tract27 1.55 321.081.09 Stomach59 2.05 187 1.16 1.11 Colorectum524 1.95 10031.021.03 Liver31 1.66 771.091.03 Pancreas33 1.70 771.061.03 Lung292 1.83 458 1.241.22 Breast1418 1.67 361.281.26 Kidney57 1.82 791.000.98 Urinary bladder103 1.66 1511.161.14 Melanoma159 2.43 781.22 Skin, squamous cell69 2.56 1101.171.19 Nervous system102 1.78 630.940.98 Endocrine glands33 2.05 191.031.00 Non-Hodgkin's lymphoma71 1.86 711.14 Leukemia52 1.80 581.031.04 All3030 1.80 2499 1.09 Bold type: 95%CI does not include 1.00. Underlining=borderline significance. Cancer in offspringCancer in husbandCancer in wife by parental cancerby wife's cancerby husband's cancer

26. Cancer site OSIRO Colorectum64 2.55 41 2.38 Lung45 2.19 26 2.04 Breast349 1.58 367 1.85 Cervix31.317 2.53 Ovary19 3.78 16 3.51 Prostate100 3.43 64 3.83 Testis13 11.53 11 6.78 Kidney14 4.46 8 3.75 Melanoma52 3.09 34 2.15 Nervous system171.4327 2.43 Thyroid gland, nonmedullary11.225 6.61 Endocrine glands13 4.20 41.39 Non-Hodgkin's lymphoma61.0517 3.30 Leukemia14 4.05 31.03 All710 2.03 630 2.13 Bold type: 95%CI does not include 1.00. No twins included. Siblings ages<5 yearsSiblings ages>=5 years SIR for cancer in siblings by age difference

27. *: 95%CI does not include 1.00.

28. Cancer site OSIRO (sibling/parent) Stomach32 2.00 52.351.17 Colorectum269 2.23 114 2.65 1.19 Lung138 1.69 71 2.02 1.20 Breast963 1.61 728 1.73 1.07 Cervix32 1.59 101.951.23 Endometrium48 2.54 161.700.67 Ovary78 3.48 35 3.62 1.04 Prostate215 2.55 170 3.581.41 Testis10 4.33 24 8.55 1.97 Kidney34 1.92 22 3.942.05 Urinary bladder45 1.89 111.120.59 Melanoma105 2.33 86 2.59 1.11 Nervous system81 1.86 44 1.87 1.01 Endocrine glands22 2.18 17 2.81 1.29 Non-Hodgkin's lymphoma29 1.68 23 2.05 1.22 Hodgkin's disease7 3.82 33.941.03 All2108 1.88 1379 2.071.10 Bold type: 95%CI does not include 1.00. Parent onlySibling onlySIR ratio SIR for cancer in offspring of parental and sibling probands

29. SIR for cancer in siblings of parental and sibling probands

30. SIRs, familial proportions and PAFs for parental history

31. All agesParent<60yrOffspring<50yr Parent<60yr Parental proband SIR

32. All agesSibling<50yrBoth<50yr 150 Sibling proband SIR

33. All agesSibling<50yr Parent<60yr sibling<50yr Both parent and sibling proband SIR

34. SIR for cancer in offspring by SNOMED Cancer siteSNOMEDOSIR StomachAdenocarcinoma361.82 Signet-ring cell carcinoma123.45 ColonAdenocarcinoma1822.11 Mucinous adenocarcinoma182.56 LiverAdenocarcinoma151.84 Hepatocellular carcinoma82.48 LungLarge cell carcinoma292.29 Oat cell carcinoma112.00 Small cell carcinoma241.74 Squamous cell carcinoma411.78 Adenocarcinoma842.18 BreastTubular adenocarcinoma961.87 Ductal carcinoma7711.87 Lobular carcinoma1271.75 OvaryEndometrioid carcinoma123.61 Cystadenocarcinoma93.32 Serous papillary cystadenocarcinoma254.26 KidneyClear cell adenocarcinoma82.73 Renal cell carcinoma221.72

35. 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!

36. CONSTRAINS IN SNP STUDIES  Risk alleles are enriched in familial cases  Risk alleles are diluted in unselected cases  Common alleles carry normally a low risk, if any  The risk should be higher among familial cases

37. I0I0 IFIF A

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

39. SIR for histological types of lung cancer in offspring by parental lung cancer Parental lung cancerAge at diagnosisOSIRO O O O Adenocarcinoma< 5071.9810.726 3.70 161.67 50-5917 2.68 41.2261.9571.9335 1.85  60 41.9821.5511.0521.4691.40 All28 2.35 60.9981.4815 2.27 60 1.72 SCC< 5081.6210.507 3.54 41.68211.59 50-5929 2.37 13 1.98 40.6819 2.65 67 1.83  60 91.7361.788 3.32 72.0231 1.89 All46 2.06 20 1.68 19 1.85 30 2.31 119 1.80 Small cell/< 5013 1.98 7 2.66 41.6462.0133 1.91 large cell carcinoma50-5929 2.13 91.27111.71 242.94 80 1.97  60 111.949 2.414 1.5130.7731 1.71 All53 2.05 25 1.85 191.6533 2.19 144 1.89 All lung cancer< 5030 1.77 91.31111.6818 2.28 77 1.71 50-5980 2.21 31 1.62 231.3252 2.44 198 1.82  60 28 1.90 18 1.87 14 2.02 141.3980 1.70 All138 2.03 58 1.63 48 1.55 84 2.14 355 1.77 AdenocarcinomaSCCSmall cell carcinomaLarge cell carcinomaAll lung cancer

40. 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 Rate 100,000 person years 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 SIR Familial lung cancer Sporadic lung cancer

41. Age at diagnosis (years) Age-specific incidence and SIR of lung cancer in different histological types in offspring of parent with lung cancer

42. Sibling lung cancerAge at diagnosisOSIRO O O O Adenocarcinoma< 505 8.23 13.733 9.63 11 6.65 50-598 3.98 21.6510.8413 2.05  60 5 4.48 22.8111.8282.26 All18 4.82 52.2810.5441.7832 2.78 SCC< 503 9.35 2 14.67 5 5.59 50-5911.6011.4720.60  60 22.8112.2512.7611.9152.13 All52.4321.6232.7921.4712 1.83 Small cell carcinoma< 5018.53110.362 15.53 4 5.58 50-5911.1812.013 6.84 24.397 2.68  60 13.1129.1231.90 All10.6233.206 7.95 4 4.28 14 2.85 Large cell carcinoma< 5012.842 12.94 33.19 50-5931.9011.0911.2522.2381.65  60 11.5712.1030.93 All41.3721.1942.8021.12141.55 All lung cancer< 5010 5.67 22.645 6.94 5 5.61 24 5.05 50-5913 2.08 51.3441.2371.9232 1.64  60 9 2.39 52.1252.7920.7722 1.83 All32 2.72 121.7514 2.43 14 1.96 78 2.15 SCCSmall cell carcinomaLarge cell carcinomaAll lung cancerAdenocarcinoma SIR for histological types of lung cancer in siblings

43. 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 Rate per 100,000 person years 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 SIR Familial lung cancer Sporadic lung cancer

44. 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 Rate per 100,000 person years 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 SIR Adenocarcinoma SIR Familial Sporadic Age at diagnosis (years)

45. 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 AdenocarcinomaSCCSmall cell carcinoma Large cell carcinoma All SIR ratio (sibling/parent) < 50yr  50yr All ages 29.4% 13.3% 33.3% 27.9%