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HEREDITARY AND ENVIRONMENTAL COMPONENTS IN CANCER

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.

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HEREDITARY AND ENVIRONMENTAL COMPONENTS IN CANCER

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  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. 2.2 480 471 2.0 410 1.8 343 Men 1.6 1.4 Rate per 100,000 1.2 210 1.0 0.8 132 Women 0.6 71 73 107 88 86 0.4 79 55 28 23 0.2 38 0.0 1961-1965 1966-1970 1971-1975 1976-1980 1981-1985 1986-1990 1991-1995 1996-2000 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. Migrant populations Genetically determined disease: MIGRATION Rate Before After Environmentally determined disease: Rate MIGRATION Before After Native populations High-risk Low-risk

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

  12. Conclusions: immigrant study • 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.

  13. T1 T2 MZ = 1.0 DZ = 0.5 TWIN MODEL 1 En1 G1 En2 Es1 G2 Es2 en g es es g en

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

  15. Nonshared environmental Percentage of VarianceCancer in Sweden, Denmark and Finland Genetic Shared environmental % 100 80 60 40 20 0 Lung Ovary Bladder Prostate Stomach Leukemia Pancreas Cervix uteri Colorectum Corpus uteri Breast (female) 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. Swedish Cancer Registry 1958-1998 Death Migration Statistics Sweden Censuses 1960, 70, 80, 90 Statistics Sweden individual files Multi-generation Register Statistics Sweden relation file Family-Cancer Database Family-Cancer Database Child Mother Father

  19. Family-Cancer Database on the time axis Registration of cancer cases Offspring born Parents born 1900 1932 1958 1998

  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 effectsare 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 maleoffspring 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 1st childbirth

  23. POPULATION ATTRIBUTABLE FRACTION (PAF)

  24. Familial SIRs

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

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

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

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

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

  30. SIRs, familial proportions and PAFs for parental history

  31. All ages Parent<60yr Offspring<50yr Parent<60yr Parental proband SIR

  32. All ages Sibling<50yr Both<50yr 150 Sibling proband SIR

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

  34. SIR for cancer in offspring by SNOMED

  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. A IF I0

  38. 40 Adenocarcinoma SCC Others 35 All lung cancer 30 25 20 Incidence rate/100,000 person years 15 10 MEN 5 0 1958-1969 1970-1979 1980-1989 1990-1996 Diagnosis year Age-adjusted incidence trends of lung cancer in men and women by histological type WOMEN

  39. SIR for histological types of lung cancer in offspring by parental lung cancer Parental lung cancer Age at Adenocarcinoma SCC Small cell carcinoma Large cell carcinoma All lung cancer diagnosis O SIR O SIR O SIR O SIR O SIR 3.70 Adenocarcinoma < 50 7 1.98 1 0.72 6 16 1.67 2.68 1.85 50-59 17 4 1.22 6 1.95 7 1.93 35  60 4 1.98 2 1.55 1 1.05 2 1.46 9 1.40 2.35 2.27 1.72 All 28 6 0.99 8 1.48 15 60 3.54 SCC < 50 8 1.62 1 0.50 7 4 1.68 21 1.59 2.37 1.98 2.65 1.83 50-59 29 13 4 0.68 19 67 3.32 1.89  60 9 1.73 6 1.78 8 7 2.02 31 2.06 1.68 1.85 2.31 1.80 All 46 20 19 30 119 1.98 2.66 1.91 Small cell/ < 50 13 7 4 1.64 6 2.01 33 2.13 24 2.94 1.97 large cell carcinoma 50-59 29 9 1.27 11 1.71 80 2.41 4 1.71  60 11 1.94 9 1.51 3 0.77 31 2.05 1.85 2.19 1.89 All 53 25 19 1.65 33 144 1.77 2.28 1.71 All lung cancer < 50 30 9 1.31 11 1.68 18 77 2.21 1.62 2.44 1.82 50-59 80 31 23 1.32 52 198 1.90 1.87 2.02 1.70  60 28 18 14 14 1.39 80 2.03 1.63 1.55 2.14 1.77 All 138 58 48 84 355

  40. 180 3.5 Familial lung cancer 160 3.0 SIR 140 2.5 120 2.0 100 SIR Rate 100,000 person years 80 1.5 60 1.0 40 0.5 Sporadic lung cancer 20 0 0.0 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-68 Age-specific incidence and SIR of lung cancer in offspring of parent with lung cancer Age at diagnosis (years)

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

  42. SIR for histological types of lung cancer in siblings Sibling lung cancer Age at Adenocarcinoma SCC Small cell carcinoma Large cell carcinoma All lung cancer diagnosis O SIR O SIR O SIR O SIR O SIR 8.23 9.63 6.65 Adenocarcinoma < 50 5 1 3.73 3 11 3.98 2.05 50-59 8 2 1.65 1 0.84 13 4.48  60 5 2 2.81 1 1.82 8 2.26 4.82 2.78 All 18 5 2.28 1 0.54 4 1.78 32 9.35 14.67 5.59 SCC < 50 3 2 5 50-59 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 1.83 All 5 2.43 2 1.62 3 2.79 2 1.47 12 15.53 5.58 Small cell carcinoma < 50 1 8.53 1 10.36 2 4 6.84 2.68 50-59 1 1.18 1 2.01 3 2 4.39 7  60 1 3.11 2 9.12 3 1.90 7.95 4.28 2.85 All 1 0.62 3 3.20 6 4 14 12.94 Large cell carcinoma < 50 1 2.84 2 3 3.19 50-59 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 5.67 6.94 5.61 5.05 All lung cancer < 50 10 2 2.64 5 5 24 2.08 1.64 50-59 13 5 1.34 4 1.23 7 1.92 32 2.39 1.83  60 9 5 2.12 5 2.79 2 0.77 22 2.72 2.43 1.96 2.15 All 32 12 1.75 14 14 78

  43. 250 7.0 6.0 200 SIR 5.0 150 4.0 Rate per 100,000 person years SIR 3.0 100 Familial lung cancer 2.0 50 1.0 Sporadic lung cancer 0 0.0 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-68 Age-specific incidence and SIR in siblings Age at diagnosis (years)

  44. 100 8.0 Adenocarcinoma 90 7.0 80 6.0 SIR 70 Familial 5.0 60 Rate per 100,000 person years SIR 50 4.0 40 3.0 30 2.0 20 1.0 10 Sporadic 0 0.0 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-68 Age at diagnosis (years) Age at diagnosis (years) Age-specific incidence and SIR of lung cancer in different histological types in siblings

  45. 4.0 < 50yr 29.4%  50yr 3.5 All ages 33.3% 27.9% 3.0 33.3% 2.5 SIR ratio (sibling/parent) 2.0 13.3% 1.5 1.0 0.5 0.0 Adenocarcinoma SCC Small cell Large cell All carcinoma carcinoma SIR ratio for lung cancer in offspring of parental and sibling probands

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