Human Genetics

, Volume 116, Issue 1–2, pp 121–127

Complex segregation analysis reveals a multigene model for lung cancer

  • Hongyan Xu
  • Margaret R. Spitz
  • Christopher I. Amos
  • Sanjay Shete
Original Investigation

Abstract

Lung cancer risk is largely attributed to tobacco exposure, but genetic predisposition also plays an etiologic role. Several studies have investigated the involvement of genetic predisposition in lung cancer aggregation in affected families, although with inconsistent results. Some studies have provided evidence for Mendelian inheritance, whereas others have suggested that environmental models are most appropriate for lung cancer aggregation in families. To examine the genetic basis of lung cancer, we performed segregation analysis on 14,378 individuals from 1,561 lung cancer case families, allowing for the effects of smoking, sex, and age. Both a Mendelian decreasing model and a Mendelian codominant model were found to be the best fitting models for susceptibility. However, when we modeled age-of-onset, all Mendelian models and the environmental model were rejected suggesting that multiple genetic factors (possibly multiple genetic loci and interactions) contribute to the age-of-onset of lung cancer. The results provide evidence that multiple genetic factors contribute to lung cancer and may act as a guide in further studies to localize susceptibility genes in lung cancer.

References

  1. Akaike H (1974) A new look at the statistical model identification. IEEE Trans Automat Control 19:716–723CrossRefGoogle Scholar
  2. Amos CI, Caporaso NE, Weston A (1992) Host factors in lung cancer risk: a review of interdisciplinary studies. Cancer Epidemiol Biomarkers Prev 1:505–513PubMedGoogle Scholar
  3. Bailey-Wilson JE, Amos CI, Pinney SM, Petersen GM, De Andrade M, Wiest JS, Fain P, Schwartz AG, You M, Franklin W, Klein C, Gazdar A, Rothschild H, Mandal D, Coons T, Slusser J, Lee J, Gaba C, Kupert E, Perez A, Zhou X, Zeng D, Liu Q, Zhang Q, Seminara D, Minna J, Anderson MW (2004) A major lung cancer susceptibility locus maps to chromosome 6q23-25. Am J Hum Genet 75:460–474CrossRefPubMedGoogle Scholar
  4. Bondy ML, Strom SS, Colopy MW, Brown BW, Strong LC (1994) Accuracy of family history of cancer obtained through interviews with relatives of patients with childhood sarcoma. J Clin Epidemiol 47:89–96CrossRefPubMedGoogle Scholar
  5. Bonney GE (1986) Regressive logistic models for familial disease and other binary traits. Biometrics 42:611–625PubMedGoogle Scholar
  6. Bonney GE (1998) Ascertainment corrections based on smaller family units. Am J Hum Genet 63:1202–1215CrossRefPubMedGoogle Scholar
  7. Burch PR (1980) Smoking and lung cancer. Tests of a causal hypothesis. J Chronic Dis 33:221–238CrossRefPubMedGoogle Scholar
  8. Etzel CJ, Amos CI, Spitz MR (2003) Risk for smoking-related cancer among relatives of lung cancer patients. Cancer Res 63:8531–8535PubMedGoogle Scholar
  9. Fisher RA (1938) Twins a study of heredity and environment. Ann Eugen 8:216–218Google Scholar
  10. Gauderman WJ, Morrison JL (2000) Evidence for age specific genetic relative risks in lung cancer. Am J Epidemiol 151:41–49PubMedGoogle Scholar
  11. Giovino GA (2002) Epidemiology of tobacco use in the United States. Oncogene 21:7326–7340CrossRefPubMedGoogle Scholar
  12. Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ, Thun MJ (2004) Cancer statistics, 2004. CA Cancer J Clin 54:8–29PubMedGoogle Scholar
  13. Lee PN, Forey BA (1996) Misclassification of smoking habits as a source of bias in the study of environmental tobacco smoke and lung cancer. Stat Med 15:581–605CrossRefPubMedGoogle Scholar
  14. Martinez ME, Reid M, Jiang R, Einspahr J, Alberts DS (2004) Accuracy of self-reported smoking status among participants in a chemoprevention trial. Prev Med 38:492–497CrossRefPubMedGoogle Scholar
  15. McMurray MA, Gottschling DE (2003) An age-induced switch to a hyper-recombinational state. Science 301:1908–1911CrossRefPubMedGoogle Scholar
  16. Nyberg F, Agudo A, Boffetta P, Fortes C, Gonzalez CA, Pershagen G (1998) A European validation study of smoking and environmental tobacco smoke exposure in nonsmoking lung cancer cases and controls. Cancer Causes Control 9:173–182CrossRefPubMedGoogle Scholar
  17. Osann KE, Anton-Culver H, Kurosaki T, Taylor T (1993) Sex differences in lung-cancer risk associated with cigarette smoking. Int J Cancer 54:44–48PubMedGoogle Scholar
  18. SAGE (1998) Computer program package from the Department of Epidemiology and Biostatistics, Rammelkamp Center for Education and Research, MetroHealth Campus, Case Western Reserve University, Cleveland, http://www.sagenet.org/
  19. Sellers TA, Bailey-Wilson JE, Elston RC, Wilson AF, Elston GZ, Ooi WL, Rothschild H (1990) Evidence for mendelian inheritance in the pathogenesis of lung cancer. J Natl Cancer Inst 82:1272–1279PubMedGoogle Scholar
  20. Sellers TA, Bailey-Wilson JE, Potter JD, Rich SS, Rothschild H, Elston RC (1992) Effect of cohort differences in smoking prevalence on models of lung cancer susceptibility. Genet Epidemiol 9:261–271PubMedGoogle Scholar
  21. Shopland DR, Eyre HJ, Pechacek TF (1991) Smoking-attributable cancer mortality in 1991: is lung cancer now the leading cause of death among smokers in the United States. J Natl Cancer Inst 83:1142–1148PubMedGoogle Scholar
  22. Thun MJ, Lally CA, Flannery JT, Calle EE, Flanders WD, Heath CWJ (1997) Cigarette smoking and changes in the histopathology of lung cancer. J Natl Cancer Inst 89:1580–1586CrossRefPubMedGoogle Scholar
  23. Tokuhata GK, Lilienfeld AM (1963) Familial aggregation of lung cancer in humans. J Natl Cancer Inst 30:289–312PubMedGoogle Scholar
  24. Wood ME, Kelly K, Mullineaux LG, Bunn PAJ (2000) The inherited nature of lung cancer: a pilot study. Lung Cancer 30:135–144CrossRefPubMedGoogle Scholar
  25. Yang P, Schwartz AG, McAllister AE, Aston CE, Swanson GM (1997) Genetic analysis of families with nonsmoking lung cancer probands. Genet Epidemiol 14:181–197CrossRefPubMedGoogle Scholar
  26. Yang P, Schwartz AG, McAllister AE, Swanson GM, Aston CE (1999) Lung cancer risk in families of nonsmoking probands: heterogeneity by age at diagnosis. Genet Epidemiol 17:253–273CrossRefPubMedGoogle Scholar
  27. Zang EA, Wynder EL (1996) Differences in lung cancer risk between men and women: examination of the evidence. J Natl Cancer Inst 88:183–192PubMedGoogle Scholar
  28. Ziogas A, Anton-Culver H (2003) Validation of family history data in cancer family registries. Am J Prev Med 24:190–198CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Hongyan Xu
    • 1
  • Margaret R. Spitz
    • 1
  • Christopher I. Amos
    • 1
  • Sanjay Shete
    • 1
  1. 1.Department of Epidemiology, Unit 189The University of Texas M. D. Anderson Cancer CenterHoustonUSA

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