A major lung cancer susceptibility locus maps to chromosome 6q23-25

J. E. Bailey-Wilson, C. I. Amos, S. M. Pinney, G. M. Petersen, M. De Andrade, J. S. Wiest, P. Fain, A. G. Schwartz, M. You, W. Franklin, C. Klein, A. Gazdar, H. Rothschild, D. Mandal, T. Coons, J. Slusser, J. Lee, C. Gaba, E. Kupert, A. PerezX. Zhou, D. Zeng, Q. Liu, Q. Zhang, D. Seminara, J. Minna, Marshall W. Anderson

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Abstract

Lung cancer is a major cause of death in the United States and other countries. The risk of lung cancer is greatly increased by cigarette smoking and by certain occupational exposures, but familial factors also clearly play a major role. To identify susceptibility genes for familial lung cancer, we conducted a genomewide linkage analysis of 52 extended pedigrees ascertained through probands with lung cancer who had several first-degree relatives with the same disease. Multipoint linkage analysis, under a simple autosomal dominant model, of all 52 families with three or more individuals affected by lung, throat, or laryngeal cancer, yielded a maximum heterogeneity LOD score (HLOD) of 2.79 at 155 cM on chromosome 6q (marker D6S2436). A subset of 38 pedigrees with four or more affected individuals yielded a multipoint HLOD of 3.47 at 155 cM. Analysis of a further subset of 23 multigenerational pedigrees with five or more affected individuals yielded a multipoint HLOD score of 4.26 at the same position. The 14 families with only three affected relatives yielded negative LOD scores in this region. A predivided samples test for heterogeneity comparing the LOD scores from the 23 multigenerational families with those from the remaining families was significant (P = .007). The 1-HLOD multipoint support interval from the multigenerational families extends from C6S1848 at 146 cM to 164 cM near D6S1035, overlapping a genomic region that is deleted in sporadic lung cancers as well as numerous other cancer types. Parametric linkage and variance-components analysis that incorporated effects of age and personal smoking also supported linkage in this region, but with somewhat diminished support. These results localize a major susceptibility locus influencing lung cancer risk to 6q23-25.

Original languageEnglish (US)
Pages (from-to)460-474
Number of pages15
JournalAmerican Journal of Human Genetics
Volume75
Issue number3
DOIs
StatePublished - Sep 2004

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Lung Neoplasms
Chromosomes
Pedigree
Smoking
Laryngeal Neoplasms
Occupational Exposure
Pharynx
Genetic Markers
Cause of Death
Analysis of Variance
Genes
Neoplasms

ASJC Scopus subject areas

  • Genetics

Cite this

Bailey-Wilson, J. E., Amos, C. I., Pinney, S. M., Petersen, G. M., De Andrade, M., Wiest, J. S., ... Anderson, M. W. (2004). A major lung cancer susceptibility locus maps to chromosome 6q23-25. American Journal of Human Genetics, 75(3), 460-474. https://doi.org/10.1086/423857

A major lung cancer susceptibility locus maps to chromosome 6q23-25. / Bailey-Wilson, J. E.; Amos, C. I.; Pinney, S. M.; Petersen, G. M.; De Andrade, M.; Wiest, J. S.; Fain, P.; Schwartz, A. G.; 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, Marshall W.

In: American Journal of Human Genetics, Vol. 75, No. 3, 09.2004, p. 460-474.

Research output: Contribution to journalArticle

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', American Journal of Human Genetics, vol. 75, no. 3, pp. 460-474. https://doi.org/10.1086/423857
Bailey-Wilson JE, Amos CI, Pinney SM, Petersen GM, De Andrade M, Wiest JS et al. A major lung cancer susceptibility locus maps to chromosome 6q23-25. American Journal of Human Genetics. 2004 Sep;75(3):460-474. https://doi.org/10.1086/423857
Bailey-Wilson, J. E. ; Amos, C. I. ; Pinney, S. M. ; Petersen, G. M. ; De Andrade, M. ; Wiest, J. S. ; Fain, P. ; Schwartz, A. G. ; 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, Marshall W. / A major lung cancer susceptibility locus maps to chromosome 6q23-25. In: American Journal of Human Genetics. 2004 ; Vol. 75, No. 3. pp. 460-474.
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AU - Amos, C. I.

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AU - De Andrade, M.

AU - Wiest, J. S.

AU - Fain, P.

AU - Schwartz, A. G.

AU - You, M.

AU - Franklin, W.

AU - Klein, C.

AU - Gazdar, A.

AU - Rothschild, H.

AU - Mandal, D.

AU - Coons, T.

AU - Slusser, J.

AU - Lee, J.

AU - Gaba, C.

AU - Kupert, E.

AU - Perez, A.

AU - Zhou, X.

AU - Zeng, D.

AU - Liu, Q.

AU - Zhang, Q.

AU - Seminara, D.

AU - Minna, J.

AU - Anderson, Marshall W.

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N2 - Lung cancer is a major cause of death in the United States and other countries. The risk of lung cancer is greatly increased by cigarette smoking and by certain occupational exposures, but familial factors also clearly play a major role. To identify susceptibility genes for familial lung cancer, we conducted a genomewide linkage analysis of 52 extended pedigrees ascertained through probands with lung cancer who had several first-degree relatives with the same disease. Multipoint linkage analysis, under a simple autosomal dominant model, of all 52 families with three or more individuals affected by lung, throat, or laryngeal cancer, yielded a maximum heterogeneity LOD score (HLOD) of 2.79 at 155 cM on chromosome 6q (marker D6S2436). A subset of 38 pedigrees with four or more affected individuals yielded a multipoint HLOD of 3.47 at 155 cM. Analysis of a further subset of 23 multigenerational pedigrees with five or more affected individuals yielded a multipoint HLOD score of 4.26 at the same position. The 14 families with only three affected relatives yielded negative LOD scores in this region. A predivided samples test for heterogeneity comparing the LOD scores from the 23 multigenerational families with those from the remaining families was significant (P = .007). The 1-HLOD multipoint support interval from the multigenerational families extends from C6S1848 at 146 cM to 164 cM near D6S1035, overlapping a genomic region that is deleted in sporadic lung cancers as well as numerous other cancer types. Parametric linkage and variance-components analysis that incorporated effects of age and personal smoking also supported linkage in this region, but with somewhat diminished support. These results localize a major susceptibility locus influencing lung cancer risk to 6q23-25.

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