Breast Cancer Research and Treatment

, Volume 82, Issue 1, pp 17–22 | Cite as

Familial Breast Cancer: Scope for More Susceptibility Genes?

  • Kari Hemminki
  • Charlotta Granström
Article

Abstract

Purpose. The familial risk of female breast cancer is somewhat less than 2.0 when a first-degree relative is diagnosed with breast cancer, but it is not known to what extent heritable or environmental factors explain the familial clustering. Such data would be valuable for prevention and gene identification strategies.

Experimental design. We used the nation-wide Swedish Family-Cancer Database on 10.2 million individuals and 190,000 mothers' and 26,000 daughters' breast cancers to calculate familial standardised incidence ratios (SIRs), for all invasive breast cancers in daughters, who were 0–66 years old. Over 5500 familial breast cancers were recorded.

Results. The familial SIR for all invasive breast cancer was 1.71 by breast cancer in the mother only, 1.95 by breast cancer in a sister only, and 2.75 by breast cancer in both a mother and sister. The SIRs did not change when adjustments were done for period, age at first birth, parity, socio-economic status and region. Age difference between sisters showed a small variation in risk for breast cancer but the highest SIR was found for those whose age difference was from 6 to 10 years. Half sisters showed an excess of familial risks exactly half of full sisters, the SIR being 1.44.

Conclusions. These data suggest that familial aggregation of breast cancer is mainly due to heritable causes. Because the known susceptibility genes only explain about a quarter of the familial aggregation, the remaining majority offers a challenge to new genomic approaches.

familial risk half sisters risk factors sibling risk 

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References

  1. 1.
    Pharoah P, Day N, Duffy S, Easton D, Ponder B: Family history and the risk of breast cancer: a systematic review and meta-analysis. Int J Cancer 71: 800-809, 1997Google Scholar
  2. 2.
    Collaborative Group on Hormonal Factors in Breast Cancer: Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet 358: 1389-1399, 2001Google Scholar
  3. 3.
    Hemminki K, Granström C: Familial breast cancer risks by morphology: a nation-wide epidemiologic study from Sweden. Cancer 94: 3063-3070, 2002Google Scholar
  4. 4.
    Hemminki K, Granström C, Czene K: Attributable risks for familial breast cancer by proband status and morphology: a nation-wide epidemiological study from Sweden. Int J Cancer 100: 214-219, 2002Google Scholar
  5. 5.
    Easton D: How many more breast cancer predisposition genes are there? Breast Cancer Res 1: 14-17, 1999Google Scholar
  6. 6.
    Cui J, Antoniou AC, Dite GS, Southey MC, Venter DJ, Easton DF, Giles GG, McCredie MR, Hopper JL: After BRCA1 and BRCA2-what next? Multifactorial segregation analyses of three-generation, population-based Australian families affected by female breast cancer. Am J Hum Genet 68: 420-431, 2001Google Scholar
  7. 7.
    Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N, Easton D, Evans C, Deacon J, Stratton M: Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst 91: 943-949, 1999Google Scholar
  8. 8.
    Syrjäkoski K, Vahteristo P, Eerola H, Tamminen A, Kivinummi K, Sarantaus L, Holli K, Blomqvist C, Kallioniemi O-P, Kainu T, Nevanlinna H: Population-based study of BRCA1 and BRCA2 mutations in 1035 unselected Finnish breast cancer patients. J Natl Cancer Inst 92: 1529-1531, 2000Google Scholar
  9. 9.
    Shih HA, Couch FJ, Nathanson KL, Blackwood MA, Rebbeck TR, Armstrong KA, Calzone K, Stopfer J, Seal S, Stratton MR, Weber BL: BRCA1 and BRCA2 mutation frequency in women evaluated in a breast cancer risk evaluation clinic. J Clin Oncol 20: 994-999, 2002Google Scholar
  10. 10.
    Kainu T, Hank Juo S-H, Desper R, Schäffer A, Gillanders E, Rozenblum E, Freas-Lutz D, Weaver D, Stephan D, Bailey-Wilson J, Kallioniemi O-P: Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus. Proc Natl Acad Sci 97: 9603-9608, 2000Google Scholar
  11. 11.
    Thompson D, Szabo CI, Mangion J, Oldenburg RA, Odefrey F, Seal S, Barfoot R, Kroeze-Jansema K, Teare D, Rahman N, Renard H, Consortium K, Mann G, Hopper JL, Buys SS, Andrulis IL, Senie R, Daly MB, West D, Ostrander EA, Offit K, Peretz T, Osorio A, Benitez J, Nathanson KL, Sinilnikova OM, Olah E, Bignon YJ, Ruiz P, Badzioch MD, Vasen HF, Futreal AP, Phelan CM, Narod SA, Lynch HT, Ponder BA, Eeles RA, Meijers-Heijboer H, Stoppa-Lyonnet D, Couch FJ, Eccles DM, Evans DG, Chang-Claude J, Lenoir G, Weber BL, Devilee P, Easton DF, Goldgar DE, Stratton MR: Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple case families from the Breast Cancer Linkage Consortium. Proc Natl Acad Sci USA 99: 827-831, 2002Google Scholar
  12. 12.
    Olsen J, Hahnemann J, Börresen-Dale A-L, Bröndum-Nielsen K, Hammarström L, Kleinerman R, Kääriäinen H, Lönnqvist T, Sankila R, Seesholm N, Tretli S, Yuen J, Boice J, Tucker M: Cancer in patients with ataxia-telangiectasia and in their relatives in the Nordic countries. J Natl Cancer Inst 93: 121-127, 2001Google Scholar
  13. 13.
    Meijers-Heijboer H, van Den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, Hollestelle A, Houben M, Crepin E, van Veghel-Plandsoen M, Elstrodt F, van Duijn C, Bartels C, Meijers C, Schutte M, McGuffog L, Thompson D, Easton DF, Sodha N, Seal S, Barfoot R, Mangion J, Chang-Claude J, Eccles D, Eeles R, Evans DG, Houlston R, Murday V, Narod S, Peretz T, Peto J, Phelan C, Zhang HX, Szabo C, Devilee P, Goldgar D, Futreal PA, Nathanson KL, Weber BL, Rahman N, Stratton MR: Low-penetrance susceptibility to breast cancer due to CHEK2* 1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 2002Google Scholar
  14. 14.
    Domchek SM, Weber BL: Recent advances in breast cancer biology. Curr Opin Oncol 14: 589-593, 2002Google Scholar
  15. 15.
    Pharoah PD, Antoniou A, Bobrow M, Zimmern RL, Easton DF, Ponder BA: Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31: 33-36, 2002Google Scholar
  16. 16.
    Lichtenstein P, Holm N, Verkasalo P, Illiado A, Kaprio J, Koskenvuo M, Pukkala E, Skytthe A, Hemminki K: Environmental and heritable factors in the causation of cancer. N Engl J Med 343: 78-85, 2000Google Scholar
  17. 17.
    Vaittinen P, Hemminki K: Risk factors and age-incidence relationships for contralateral breast cancer. Int J Cancer 88: 998-1002, 2000Google Scholar
  18. 18.
    Peto J, Mack TM: High constant incidence in twins and other relatives of women with breast cancer. Nat Genet 26: 411-414, 2000Google Scholar
  19. 19.
    Dong C, Hemminki K: Multiple primary cancers at colon, breast and skin (melanoma) as models for polygenic cancers. Int J Cancer 92: 883-887, 2001Google Scholar
  20. 20.
    Czene K, Lichtenstein P, Hemminki K: Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish Family-Cancer Database. Int J Cancer 99: 260-266, 2002Google Scholar
  21. 21.
    Hopper JL, Carlin JB: Familial aggregation of a disease consequent upon correlation between relatives in a risk factor measured on a continuous scale. Am J Epidemiol 136: 1138-1147, 1992Google Scholar
  22. 22.
    Hemminki K, Dong C, Vaittinen P: Cancer risks to spouses and offspring in the Family-Cancer Database. Genet Epidemiol 20: 247-257, 2001Google Scholar
  23. 23.
    Hemminki K, Jiang Y: Cancer risks among long-standing spouses. Br J Cancer 86: 1737-1740, 2002Google Scholar
  24. 24.
    Hemminki K, Li X, Plna K, Granström C, Vaittinen P: The nation-wide Swedish Family-Cancer Database: updated structure and familial rates. Acta Oncol 40: 772-777, 2001Google Scholar
  25. 25.
    Hemminki K: Genetic epidemiology: science and ethics on familial cancers. Acta Oncol 40: 439-444, 2001Google Scholar
  26. 26.
    Hemminki K, Li X: Familial carcinoid tumors and subsequent cancers: a nation-wide epidemiological study from Sweden. Int J Cancer 94: 444-448, 2001Google Scholar
  27. 27.
    Hemminki K, Granström C: Risk for familial breast cancer increases with age. Nat Genet 32: 233, 2002Google Scholar
  28. 28.
    Hemminki K, Vaittinen P, Dong C, Easton D: Sibling risks in cancer: clues to recessive or X-linked genes? Br J Cancer 84: 388-391, 2001Google Scholar
  29. 29.
    Hemminki K, Granström C: Morphological types of breast cancer in family members and multiple primary tumours: is morphology genetically determined? Breast Cancer Res 4: R7, 2002Google Scholar
  30. 30.
    Risch N: The genetic epidemiology of cancer: interpreting family and twin studies and their implications for molecular genetic approaches. Cancer Epidemiol Biomarkers Prev 10: 733-741, 2001Google Scholar
  31. 31.
    Hemminki K: Genetic epidemiology of cancer: interpreting family and twin studies and their implications for molecular genetic approaches. Cancer Epidemiol Biomarkers Prev 11: 423, 2002Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Kari Hemminki
    • 1
    • 2
  • Charlotta Granström
    • 1
  1. 1.Department of Biosciences at NovumKarolinska InstituteHuddingeSweden
  2. 2.Division of Molecular Genetic EpidemiologyGerman Cancer Research Center (DKFZ)HeidelbergGermany

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