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. 1997 Sep;61(3):678–690. doi: 10.1086/515507

Interactions between genetic and reproductive factors in breast cancer risk in a French family sample.

N Andrieu 1, F Demenais 1
PMCID: PMC1715946  PMID: 9326334

Abstract

Considerable progress has been made in the characterization of the genetic component of breast cancer (BC). However, BC still remains a complex disease involving a genetic component and many other risk factors essentially linked to reproductive-life factors. To search for interactions between genetic and reproductive-life factors in the etiology of BC, a systematic family study was performed in two French hospitals from December 1987 to January 1990 and led to recruitment of 288 families, the IGRC data ("IGRC" refers to the Institut Gustave Roussy and Institut Curie, where the data were obtained). Detailed information on reproductive factors was recorded for probands and female first-degree relatives. Segregation analysis of BC was conducted by taking into account a variable age at onset of disease, by use of the class D regressive logistic model, as implemented in the REGRESS computer program. Segregation analyses of BC in IGRC data showed evidence for the segregation of a dominant gene and additional sister-sister dependence, both when reproductive factors were ignored and when they were included. A significant interaction was detected between the dominant gene and age when reproductive factors were taken into account. Among the reproductive factors included in segregation analysis, parity was found to interact with the dominant-gene effect, and there was an indication of an interaction, albeit not significant, between the dominant gene and age at menarche. Whereas the usual protective effect conferred on breast-cancer risk by high parity remained in nonsusceptible women, it disappeared in susceptible women. The increased BC risk associated with a late age at menarche was higher in susceptible women than in nonsusceptible women. Interactions between inherited predisposition to BC and reproductive factors were detected here for the first time by segregation analysis. It would be of major interest to confirm these results by family studies in other populations.

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Selected References

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  1. Abel L., Bonney G. E. A time-dependent logistic hazard function for modeling variable age of onset in analysis of familial diseases. Genet Epidemiol. 1990;7(6):391–407. doi: 10.1002/gepi.1370070602. [DOI] [PubMed] [Google Scholar]
  2. Abel L., Garcia A., Demenais F. Complex segregation analysis of familial diseases with variable age of onset: comparison of different methods by a simulation study. Genet Epidemiol. 1995;12(3):231–249. doi: 10.1002/gepi.1370120302. [DOI] [PubMed] [Google Scholar]
  3. Abel L., Golmard J. L., Mallet A. An autologistic model for the genetic analysis of familial binary data. Am J Hum Genet. 1993 Oct;53(4):894–907. [PMC free article] [PubMed] [Google Scholar]
  4. Andrieu N., Clavel F., Auquier A., Lê M. G., Gairard B., Piana L., Brémond A., Lansac J., Flamant R., Renaud R. Variations in the risk of breast cancer associated with a family history of breast cancer according to age at onset and reproductive factors. J Clin Epidemiol. 1993 Sep;46(9):973–980. doi: 10.1016/0895-4356(93)90164-v. [DOI] [PubMed] [Google Scholar]
  5. Andrieu N., Demenais F., Martinez M. Genetic analysis of human breast cancer: implications for family study designs. Genet Epidemiol. 1988;5(4):225–233. doi: 10.1002/gepi.1370050404. [DOI] [PubMed] [Google Scholar]
  6. Andrieu N., Duffy S. W., Rohan T. E., Lê M. G., Luporsi E., Gerber M., Renaud R., Zaridze D. G., Lifanova Y., Day N. E. Familial risk, abortion and their interactive effect on the risk of breast cancer--a combined analysis of six case-control studies. Br J Cancer. 1995 Sep;72(3):744–751. doi: 10.1038/bjc.1995.404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Andrieu N., Goldstein A. M. Use of relatives of cases as controls to identify risk factors when an interaction between environmental and genetic factors exists. Int J Epidemiol. 1996 Jun;25(3):649–657. doi: 10.1093/ije/25.3.649. [DOI] [PubMed] [Google Scholar]
  8. Bain C., Speizer F. E., Rosner B., Belanger C., Hennekens C. H. Family history of breast cancer as a risk indicator for the disease. Am J Epidemiol. 1980 Mar;111(3):301–308. doi: 10.1093/oxfordjournals.aje.a112901. [DOI] [PubMed] [Google Scholar]
  9. Bonney G. E., Lathrop G. M., Lalouel J. M. Combined linkage and segregation analysis using regressive models. Am J Hum Genet. 1988 Jul;43(1):29–37. [PMC free article] [PubMed] [Google Scholar]
  10. Brind J., Chinchilli V. M., Severs W. B., Summy-Long J. Induced abortion as an independent risk factor for breast cancer: a comprehensive review and meta-analysis. J Epidemiol Community Health. 1996 Oct;50(5):481–496. doi: 10.1136/jech.50.5.481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Brinton L. A., Hoover R., Fraumeni J. F., Jr Interaction of familial and hormonal risk factors for breast cancer. J Natl Cancer Inst. 1982 Oct;69(4):817–822. [PubMed] [Google Scholar]
  12. Byrne C., Brinton L. A., Haile R. W., Schairer C. Heterogeneity of the effect of family history on breast cancer risk. Epidemiology. 1991 Jul;2(4):276–284. doi: 10.1097/00001648-199107000-00007. [DOI] [PubMed] [Google Scholar]
  13. Claus E. B., Risch N. J., Thompson W. D. Age at onset as an indicator of familial risk of breast cancer. Am J Epidemiol. 1990 Jun;131(6):961–972. doi: 10.1093/oxfordjournals.aje.a115616. [DOI] [PubMed] [Google Scholar]
  14. Colditz G. A., Rosner B. A., Speizer F. E. Risk factors for breast cancer according to family history of breast cancer. For the Nurses' Health Study Research Group. J Natl Cancer Inst. 1996 Mar 20;88(6):365–371. doi: 10.1093/jnci/88.6.365. [DOI] [PubMed] [Google Scholar]
  15. Colditz G. A., Willett W. C., Hunter D. J., Stampfer M. J., Manson J. E., Hennekens C. H., Rosner B. A. Family history, age, and risk of breast cancer. Prospective data from the Nurses' Health Study. JAMA. 1993 Jul 21;270(3):338–343. [PubMed] [Google Scholar]
  16. Demenais F. M., Laing A. E., Bonney G. E. Numerical comparisons of two formulations of the logistic regressive models with the mixed model in segregation analysis of discrete traits. Genet Epidemiol. 1992;9(6):419–435. doi: 10.1002/gepi.1370090605. [DOI] [PubMed] [Google Scholar]
  17. Demenais F. M. Regressive logistic models for familial diseases: a formulation assuming an underlying liability model. Am J Hum Genet. 1991 Oct;49(4):773–785. [PMC free article] [PubMed] [Google Scholar]
  18. Demenais F., Martinez M., Bonaïti-Pellié C., Clerget-Darpoux F., Feingold N. Segregation analysis of the Jacobsen data. Genet Epidemiol Suppl. 1986;1:49–54. doi: 10.1002/gepi.1370030708. [DOI] [PubMed] [Google Scholar]
  19. Easton D. F., Bishop D. T., Ford D., Crockford G. P. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1993 Apr;52(4):678–701. [PMC free article] [PubMed] [Google Scholar]
  20. Easton D. F., Ford D., Bishop D. T. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995 Jan;56(1):265–271. [PMC free article] [PubMed] [Google Scholar]
  21. Elston R. C., Sobel E. Sampling considerations in the gathering and analysis of pedigree data. Am J Hum Genet. 1979 Jan;31(1):62–69. [PMC free article] [PubMed] [Google Scholar]
  22. Elston R. C., Stewart J. A general model for the genetic analysis of pedigree data. Hum Hered. 1971;21(6):523–542. doi: 10.1159/000152448. [DOI] [PubMed] [Google Scholar]
  23. Essioux L., Abel L., Bonaïti-Pellié C. Genetic epidemiology of breast cancer: interest of survival analysis methods. Ann Hum Genet. 1995 Jul;59(Pt 3):271–282. doi: 10.1111/j.1469-1809.1995.tb00747.x. [DOI] [PubMed] [Google Scholar]
  24. Ford D., Easton D. F., Peto J. Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet. 1995 Dec;57(6):1457–1462. [PMC free article] [PubMed] [Google Scholar]
  25. Gilligan S. B., Borecki I. B. Examination of heterogeneity in 200 Danish breast cancer pedigrees. Genet Epidemiol Suppl. 1986;1:67–72. doi: 10.1002/gepi.1370030711. [DOI] [PubMed] [Google Scholar]
  26. Goldgar D. E., Fields P., Lewis C. M., Tran T. D., Cannon-Albright L. A., Ward J. H., Swensen J., Skolnick M. H. A large kindred with 17q-linked breast and ovarian cancer: genetic, phenotypic, and genealogical analysis. J Natl Cancer Inst. 1994 Feb 2;86(3):200–209. doi: 10.1093/jnci/86.3.200. [DOI] [PubMed] [Google Scholar]
  27. Goldstein A. M., Amos C. I. Segregation analysis of breast cancer from the cancer and steroid hormone study: histologic subtypes. J Natl Cancer Inst. 1990 Dec 19;82(24):1911–1917. doi: 10.1093/jnci/82.24.1911. [DOI] [PubMed] [Google Scholar]
  28. Goldstein A. M., Haile R. W., Hodge S. E., Paganini-Hill A., Spence M. A. Possible heterogeneity in the segregation pattern of breast cancer in families with bilateral breast cancer. Genet Epidemiol. 1988;5(2):121–133. doi: 10.1002/gepi.1370050207. [DOI] [PubMed] [Google Scholar]
  29. Goldstein A. M., Haile R. W., Marazita M. L., Paganini-Hill A. A genetic epidemiologic investigation of breast cancer in families with bilateral breast cancer. I. Segregation analysis. J Natl Cancer Inst. 1987 May;78(5):911–918. [PubMed] [Google Scholar]
  30. Greenland S., Finkle W. D. A critical look at methods for handling missing covariates in epidemiologic regression analyses. Am J Epidemiol. 1995 Dec 15;142(12):1255–1264. doi: 10.1093/oxfordjournals.aje.a117592. [DOI] [PubMed] [Google Scholar]
  31. Hall J. M., Lee M. K., Newman B., Morrow J. E., Anderson L. A., Huey B., King M. C. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990 Dec 21;250(4988):1684–1689. doi: 10.1126/science.2270482. [DOI] [PubMed] [Google Scholar]
  32. Hartge P. Abortion, breast cancer, and epidemiology. N Engl J Med. 1997 Jan 9;336(2):127–128. doi: 10.1056/NEJM199701093360209. [DOI] [PubMed] [Google Scholar]
  33. Holt J. T., Thompson M. E., Szabo C., Robinson-Benion C., Arteaga C. L., King M. C., Jensen R. A. Growth retardation and tumour inhibition by BRCA1. Nat Genet. 1996 Mar;12(3):298–302. doi: 10.1038/ng0396-298. [DOI] [PubMed] [Google Scholar]
  34. Iselius L., Slack J., Littler M., Morton N. E. Genetic epidemiology of breast cancer in Britain. Ann Hum Genet. 1991 May;55(Pt 2):151–159. doi: 10.1111/j.1469-1809.1991.tb00408.x. [DOI] [PubMed] [Google Scholar]
  35. Jensen R. A., Thompson M. E., Jetton T. L., Szabo C. I., van der Meer R., Helou B., Tronick S. R., Page D. L., King M. C., Holt J. T. BRCA1 is secreted and exhibits properties of a granin. Nat Genet. 1996 Mar;12(3):303–308. doi: 10.1038/ng0396-303. [DOI] [PubMed] [Google Scholar]
  36. Kelsey J. L., Horn-Ross P. L. Breast cancer: magnitude of the problem and descriptive epidemiology. Epidemiol Rev. 1993;15(1):7–16. doi: 10.1093/oxfordjournals.epirev.a036118. [DOI] [PubMed] [Google Scholar]
  37. Kerangueven F., Essioux L., Dib A., Noguchi T., Allione F., Geneix J., Longy M., Lidereau R., Eisinger F., Pébusque M. J. Loss of heterozygosity and linkage analysis in breast carcinoma: indication for a putative third susceptibility gene on the short arm of chromosome 8. Oncogene. 1995 Mar 2;10(5):1023–1026. [PubMed] [Google Scholar]
  38. Lalouel J. M., Morton N. E. Complex segregation analysis with pointers. Hum Hered. 1981;31(5):312–321. doi: 10.1159/000153231. [DOI] [PubMed] [Google Scholar]
  39. Lalouel J. M., Rao D. C., Morton N. E., Elston R. C. A unified model for complex segregation analysis. Am J Hum Genet. 1983 Sep;35(5):816–826. [PMC free article] [PubMed] [Google Scholar]
  40. Lathrop G. M., Lalouel J. M. Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet. 1984 Mar;36(2):460–465. [PMC free article] [PubMed] [Google Scholar]
  41. Marquis S. T., Rajan J. V., Wynshaw-Boris A., Xu J., Yin G. Y., Abel K. J., Weber B. L., Chodosh L. A. The developmental pattern of Brca1 expression implies a role in differentiation of the breast and other tissues. Nat Genet. 1995 Sep;11(1):17–26. doi: 10.1038/ng0995-17. [DOI] [PubMed] [Google Scholar]
  42. Melbye M., Wohlfahrt J., Olsen J. H., Frisch M., Westergaard T., Helweg-Larsen K., Andersen P. K. Induced abortion and the risk of breast cancer. N Engl J Med. 1997 Jan 9;336(2):81–85. doi: 10.1056/NEJM199701093360201. [DOI] [PubMed] [Google Scholar]
  43. Mettlin C., Croghan I., Natarajan N., Lane W. The association of age and familial risk in a case-control study of breast cancer. Am J Epidemiol. 1990 Jun;131(6):973–983. doi: 10.1093/oxfordjournals.aje.a115617. [DOI] [PubMed] [Google Scholar]
  44. Michels-Blanck H., Byers T., Mokdad A. H., Will J. C., Calle E. E. Menstrual patterns and breast cancer mortality in a large U.S. cohort. Epidemiology. 1996 Sep;7(5):543–546. [PubMed] [Google Scholar]
  45. Michels K. B., Willett W. C. Does induced or spontaneous abortion affect the risk of breast cancer? Epidemiology. 1996 Sep;7(5):521–528. [PubMed] [Google Scholar]
  46. Miki Y., Swensen J., Shattuck-Eidens D., Futreal P. A., Harshman K., Tavtigian S., Liu Q., Cochran C., Bennett L. M., Ding W. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994 Oct 7;266(5182):66–71. doi: 10.1126/science.7545954. [DOI] [PubMed] [Google Scholar]
  47. Narod S. A., Feunteun J., Lynch H. T., Watson P., Conway T., Lynch J., Lenoir G. M. Familial breast-ovarian cancer locus on chromosome 17q12-q23. Lancet. 1991 Jul 13;338(8759):82–83. doi: 10.1016/0140-6736(91)90076-2. [DOI] [PubMed] [Google Scholar]
  48. Narod S. A., Ford D., Devilee P., Barkardottir R. B., Lynch H. T., Smith S. A., Ponder B. A., Weber B. L., Garber J. E., Birch J. M. An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995 Jan;56(1):254–264. [PMC free article] [PubMed] [Google Scholar]
  49. Narod S. A., Goldgar D., Cannon-Albright L., Weber B., Moslehi R., Ives E., Lenoir G., Lynch H. Risk modifiers in carriers of BRCA1 mutations. Int J Cancer. 1995 Dec 20;64(6):394–398. doi: 10.1002/ijc.2910640608. [DOI] [PubMed] [Google Scholar]
  50. Negri E., La Vecchia C., Bruzzi P., Dardanoni G., Decarli A., Palli D., Parazzini F., Rosselli del Turco M. Risk factors for breast cancer: pooled results from three Italian case-control studies. Am J Epidemiol. 1988 Dec;128(6):1207–1215. doi: 10.1093/oxfordjournals.aje.a115075. [DOI] [PubMed] [Google Scholar]
  51. Newman B., Austin M. A., Lee M., King M. C. Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families. Proc Natl Acad Sci U S A. 1988 May;85(9):3044–3048. doi: 10.1073/pnas.85.9.3044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Ottman R., Pike M. C., King M. C., Casagrande J. T., Henderson B. E. Familial breast cancer in a population-based series. Am J Epidemiol. 1986 Jan;123(1):15–21. doi: 10.1093/oxfordjournals.aje.a114209. [DOI] [PubMed] [Google Scholar]
  53. Parazzini F., Negri E., La Vecchia C., Restelli C., Franceschi S. Family history of reproductive cancers and ovarian cancer risk: an Italian case-control study. Am J Epidemiol. 1992 Jan 1;135(1):35–40. doi: 10.1093/oxfordjournals.aje.a116199. [DOI] [PubMed] [Google Scholar]
  54. Phelan C. M., Rebbeck T. R., Weber B. L., Devilee P., Ruttledge M. H., Lynch H. T., Lenoir G. M., Stratton M. R., Easton D. F., Ponder B. A. Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus. Nat Genet. 1996 Mar;12(3):309–311. doi: 10.1038/ng0396-309. [DOI] [PubMed] [Google Scholar]
  55. Rookus M. A., van Leeuwen F. E. Induced abortion and risk for breast cancer: reporting (recall) bias in a Dutch case-control study. J Natl Cancer Inst. 1996 Dec 4;88(23):1759–1764. doi: 10.1093/jnci/88.23.1759. [DOI] [PubMed] [Google Scholar]
  56. Sellers T. A., Kushi L. H., Potter J. D., Kaye S. A., Nelson C. L., McGovern P. G., Folsom A. R. Effect of family history, body-fat distribution, and reproductive factors on the risk of postmenopausal breast cancer. N Engl J Med. 1992 May 14;326(20):1323–1329. doi: 10.1056/NEJM199205143262004. [DOI] [PubMed] [Google Scholar]
  57. Sellers T. A., Potter J. D., Severson R. K., Bostick R. M., Nelson C. L., Kushi L. H., Folsom A. R. Difficulty becoming pregnant and family history as interactive risk factors for postmenopausal breast cancer: the Iowa Women's Health Study. Cancer Causes Control. 1993 Jan;4(1):21–28. doi: 10.1007/BF00051710. [DOI] [PubMed] [Google Scholar]
  58. Sobol H., Birnbaum D., Eisinger F. Evidence for a third breast-cancer susceptibility gene. Lancet. 1994 Oct 22;344(8930):1151–1152. doi: 10.1016/s0140-6736(94)90655-6. [DOI] [PubMed] [Google Scholar]
  59. Theis B., Boyd N., Lockwood G., Tritchler D. Accuracy of family cancer history in breast cancer patients. Eur J Cancer Prev. 1994 Jul;3(4):321–327. doi: 10.1097/00008469-199407000-00004. [DOI] [PubMed] [Google Scholar]
  60. Weed D. L., Kramer B. S. Induced abortion, bias, and breast cancer: why epidemiology hasn't reached its limit. J Natl Cancer Inst. 1996 Dec 4;88(23):1698–1700. doi: 10.1093/jnci/88.23.1698. [DOI] [PubMed] [Google Scholar]
  61. Williams W. R., Anderson D. E. Genetic epidemiology of breast cancer: segregation analysis of 200 Danish pedigrees. Genet Epidemiol. 1984;1(1):7–20. doi: 10.1002/gepi.1370010104. [DOI] [PubMed] [Google Scholar]
  62. Wooster R., Bignell G., Lancaster J., Swift S., Seal S., Mangion J., Collins N., Gregory S., Gumbs C., Micklem G. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995 Dec 21;378(6559):789–792. doi: 10.1038/378789a0. [DOI] [PubMed] [Google Scholar]
  63. Wooster R., Neuhausen S. L., Mangion J., Quirk Y., Ford D., Collins N., Nguyen K., Seal S., Tran T., Averill D. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science. 1994 Sep 30;265(5181):2088–2090. doi: 10.1126/science.8091231. [DOI] [PubMed] [Google Scholar]
  64. Wu A. H., Ziegler R. G., Pike M. C., Nomura A. M., West D. W., Kolonel L. N., Horn-Ross P. L., Rosenthal J. F., Hoover R. N. Menstrual and reproductive factors and risk of breast cancer in Asian-Americans. Br J Cancer. 1996 Mar;73(5):680–686. doi: 10.1038/bjc.1996.118. [DOI] [PMC free article] [PubMed] [Google Scholar]

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