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Semin Respir Crit Care Med 2003; 24(2): 197-204
DOI: 10.1055/s-2003-39018
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Genetic Susceptibility to Lung Cancer

York E. Miller1,2,3 , Pamela Fain4,5
  • 1Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado
  • 2University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado
  • 3Denver Veterans Affairs Medical Center, University of Colorado Health Sciences Center, Denver, Colorado
  • 4Division of Renal Diseases and Hypertension, University of Colorado Health Sciences Center, Denver, Colorado
  • 5Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado
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Publication History

Publication Date:
07 May 2003 (online)

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ABSTRACT

Lung cancer is the most common cause of cancer death in the world. Environmental factors, particularly cigarette smoking, are of paramount importance in determining lung cancer risk. Lung cancer and chronic obstructive lung disease are likely to share some common susceptibility genes, but these have not yet been identified. Evidence from various sources, including twin studies, segregation analyses, and case-control studies, support a heritable component to lung cancer risk in humans. As with many common diseases, susceptibility genes for lung cancer appear to be of low penetrance. Family studies of lung cancer susceptibility using linkage analysis and positional cloning have not been reported; however, a consortium is currently carrying out such studies, and results may soon be available. Association studies support lung cancer risk being partly determined by genes that control the metabolism of carcinogens found in tobacco smoke, with the heritable effects being most prominent in smokers with shorter smoking histories. Of these, the CYP1A1 and GSTM1 polymorphisms have been most consistently implicated. In the mouse, an oligonucleotide repeat polymorphism within an intron of the Ki-ras oncogene is the major lung cancer susceptibility locus; however this locus is not clearly involved in susceptibility to lung cancer in the human. Further understanding of the genetic basis of lung cancer susceptibility has many important implications, ranging from targeting prevention and screening efforts to the most highly susceptible population to developing novel chemopreventive therapies.

KEYWORDS

Lung cancer - genetic susceptibility - genomic instability - carcinogen metabolism

REFERENCES

  • 1 Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002.  CA Cancer J Clin . 2002;  52 23-47
    CrossrefPubMedGoogle Scholar
  • 2 Patz Jr F E, Goodman P C, Bepler G. Screening for lung cancer.  N Engl J Med . 2000;  343 1627-1633
    CrossrefPubMedGoogle Scholar
  • 3 Kaneko M, Eguchi K, Ohmatsu H. et al . Peripheral lung cancer: screening and detection with low-dose spiral CT versus radiography.  Radiology . 1996;  201 798-802
    PubMedGoogle Scholar
  • 4 Henschke C I, McCauley D I, Yankelevitz D F. et al . Early Lung Cancer Action Project: overall design and findings from baseline screening.  Lancet . 1999;  354 99-105
    CrossrefPubMedGoogle Scholar
  • 5 Franklin W A. Pathology of lung cancer.  J Thorac Imaging . 2000;  15 3-12
    PubMedGoogle Scholar
  • 6 Garber M E, Troyanskaya O G, Schluens K. et al . Diversity of gene expression in adenocarcinoma of the lung.  Proc Natl Acad Sci USA . 2001;  98 13784-13789
    CrossrefPubMedGoogle Scholar
  • 7 Anbazhagan R, Tihan T, Bornman D M. et al . Classification of small cell lung cancer and pulmonary carcinoid by gene expression profiles.  Cancer Res . 1999;  59 5119-5122
    PubMedGoogle Scholar
  • 8 Miller Y E, Franklin W A. Molecular events in lung carcinogenesis.  Hematol Oncol Clin North Am . 1997;  11 215-234
    CrossrefPubMedGoogle Scholar
  • 9 Peto R, Lopez A D, Boreham J, Thun M, Heath Jr C, Doll R. Mortality from smoking worldwide.  Br Med Bull . 1996;  52 12-21
    PubMedGoogle Scholar
  • 10 Tong L, Spitz M R, Fueger J J, Amos C A. Lung carcinoma in former smokers.  Cancer . 1996;  78 1004-1010
    CrossrefPubMedGoogle Scholar
  • 11 Sellers T A, Weaver T W, Phillips B, Altmann M, Rich S S. Environmental factors can confound identification of a major gene effect: results from a segregation analysis of a simulated population of lung cancer families.  Genet Epidemiol . 1998;  15 251-262
    CrossrefPubMedGoogle Scholar
  • 12 Schwartz A G, Yang P, Swanson G M. Familial risk of lung cancer among nonsmokers and their relatives.  Am J Epidemiol . 1996;  144 554-562
    PubMedGoogle Scholar
  • 13 The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group [see comments].  N Engl J Med . 1994;  330 1029-1035
    CrossrefPubMedGoogle Scholar
  • 14 Hennekens C H, Buring J E, Manson J E. et al . Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease [see comments].  N Engl J Med . 1996;  334 1145-1149
    CrossrefPubMedGoogle Scholar
  • 15 Omenn G S, Goodman G E, Thornquist M D. et al . Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease [see comments].  N Engl J Med . 1996;  334 1150-1155
    CrossrefPubMedGoogle Scholar
  • 16 Schreinemachers D M, Everson R B. Aspirin use and lung, colon, and breast cancer incidence in a prospective study [see comments].  Epidemiology . 1994;  5 138-146
    PubMedGoogle Scholar
  • 17 Hemminki K, Lonnstedt I, Vaittinen P, Lichtenstein P. Estimation of genetic and environmental components in colorectal and lung cancer and melanoma.  Genet Epidemiol . 2001;  20 107-116
    CrossrefPubMedGoogle Scholar
  • 18 Lichtenstein P, Holm N V, Verkasalo P K. et al . Environmental and heritable factors in the causation of cancer: analyses of cohorts of twins from Sweden, Denmark, and Finland [see comments].  N Engl J Med . 2000;  343 78-85
    CrossrefPubMedGoogle Scholar
  • 19 Fearon E R. Human cancer syndromes: clues to the origin and nature of cancer.  Science . 1997;  278 1043-1050
    CrossrefPubMedGoogle Scholar
  • 20 Li F P. The 4th American Cancer Society Award for Research Excellence in Cancer Epidemiology and Prevention: Phenotypes, Genotypes, and Interventions for Hereditary Cancers.  Cancer Epidemiol Biomarkers Prev . 1995;  4 579-582
    PubMedGoogle Scholar
  • 21 Sellers T A, Chen P L, Potter J D, Bailey-Wilson J E, Rothschild H, Elston R C. Segregation analysis of smoking-associated malignancies: evidence for Mendelian inheritance.  Am J Med Genet . 1994;  52 308-314
    CrossrefPubMedGoogle Scholar
  • 22 Yang P, Schwartz A G, McAllister A E, Swanson G M, Aston C E. Lung cancer risk in families of nonsmoking probands: heterogeneity by age at diagnosis.  Genet Epidemiol . 1999;  17 253-273
    CrossrefPubMedGoogle Scholar
  • 23 Schwartz A G, Siegfried J M, Weiss L. Familial aggregation of breast cancer with early onset lung cancer.  Genet Epidemiol . 1999;  17 274-284
    CrossrefPubMedGoogle Scholar
  • 24 Malkinson A M. Primary lung tumors in mice: an experimentally manipulable model of human adenocarcinoma.  Cancer Res . 1992;  52(suppl 9) S2670-S2676
    PubMedGoogle Scholar
  • 25 Malkinson A M. Molecular comparison of human and mouse pulmonary adenocarcinomas.  Exp Lung Res . 1998;  24 541-555
    PubMedGoogle Scholar
  • 26 Chen B, Johanson L, Wiest J S, Anderson M W, You M. The second intron of the K-ras gene contains regulatory elements associated with mouse lung tumor susceptibility.  Proc Natl Acad Sci USA . 1994;  91 1589-1593
    PubMedGoogle Scholar
  • 27 Malkinson A M. Inheritance of pulmonary adenoma susceptibility in mice.  Prog Exp Tumor Res . 1999;  35 78-94
    PubMedGoogle Scholar
  • 28 Dragani T A, Hirohashi S, Juji T. et al . Population-based mapping of pulmonary adenoma susceptibility 1 locus.  Cancer Res . 2000;  60 5017-5020
    PubMedGoogle Scholar
  • 29 Sherrill D L, Lebowitz M D, Knudson R J, Burrows B. Longitudinal methods for describing the relationship between pulmonary function, respiratory symptoms and smoking in elderly subjects: the Tucson Study [see comments].  Eur Respir J . 1993;  6 342-348
    PubMedGoogle Scholar
  • 30 Lomas D A, Silverman E K. The genetics of chronic obstructive pulmonary disease.  Respir Res . 2001;  2 20-26
    CrossrefPubMedGoogle Scholar
  • 31 Tockman M S, Anthonisen N R, Wright E C, Donithan M G. Airways obstruction and the risk for lung cancer.  Ann Intern Med . 1987;  106 512-518
    PubMedGoogle Scholar
  • 32 Cohen B H, Diamond E L, Graves C G. et al . A common familial component in lung cancer and chronic obstructive pulmonary disease.  Lancet . 1977;  2 523-526
    PubMedGoogle Scholar
  • 33 Malkinson A M, Radcliffe R A, Bauer A K. Quantitative trait locus mapping of susceptibilities to butylated hydroxytoluene-induced lung tumor promotion and pulmonary inflammation in CXB mice.  Carcinogenesis . 2002;  23 411-417
    CrossrefPubMedGoogle Scholar
  • 34 Malkinson A M, Bauer A, Meyer A. et al . Experimental evidence from an animal model of adenocarcinoma that chronic inflammation enhances lung cancer risk.  Chest . 2000;  117(5 suppl 1) 228S
    CrossrefPubMedGoogle Scholar
  • 35 Yang P, Wentzlaff K A, Katzmann J A. et al . Alpha1-antitrypsin deficiency allele carriers among lung cancer patients.  Cancer Epidemiol Biomarkers Prev . 1999;  8 461-465
    PubMedGoogle Scholar
  • 36 Nicoletto M O, Donach M, De Nicolo A, Artioli G, Banna G, Monfardini S. BRCA-1 and BRCA-2 mutations as prognostic factors in clinical practice and genetic counselling.  Cancer Treat Rev . 2001;  27 295-304
    CrossrefPubMedGoogle Scholar
  • 37 Muller A, Fishel R. Mismatch repair and the hereditary nonpolyposis colorectal cancer syndrome (HNPCC).  Cancer Invest . 2002;  20 102-109
    CrossrefPubMedGoogle Scholar
  • 38 Bowcock A M. Molecular cloning of BRCA1: a gene for early onset familial breast and ovarian cancer.  Breast Cancer Res Treat . 1993;  28 121-135
    CrossrefPubMedGoogle Scholar
  • 39 Cannon-Albright L A, Skolnick M H. The genetics of familial breast cancer.  Semin Oncol . 1996;  23(1 suppl 2) 1-5
    PubMedGoogle Scholar
  • 40 Peltomaki P T. Genetic basis of hereditary nonpolyposis colorectal carcinoma (HNPCC).  Ann Med . 1994;  26 215-219
    PubMedGoogle Scholar
  • 41 Collins F S. Positional cloning: let's not call it reverse anymore.  Nat Genet . 1992;  1 3-6
    PubMedGoogle Scholar
  • 42 Collins F S. Identifying human disease genes by positional cloning.  Harvey Lect . 1990;  86 149-164
    PubMedGoogle Scholar
  • 43 Kinzler K W, Vogelstein B. Cancer-susceptibility genes: gatekeepers and caretakers.  Nature . 1997;  386 761-763
    CrossrefPubMedGoogle Scholar
  • 44 Sard L, Accornero P, Tornielli S. et al . The tumor-suppressor gene FHIT is involved in the regulation of apoptosis and in cell cycle control.  Proc Natl Acad Sci USA . 1999;  96 8489-8492
    CrossrefPubMedGoogle Scholar
  • 45 Shields P G, Harris C C. Cancer risk and low-penetrance susceptibility genes in gene-environment interactions.  J Clin Oncol . 2000;  18 2309-2315
    PubMedGoogle Scholar
  • 46 Lengauer C, Kinzler K W, Vogelstein B. Genetic instabilities in human cancers.  Nature . 1998;  396 643-649
    CrossrefPubMedGoogle Scholar
  • 47 Vessey C J, Norbury C J, Hickson I D. Genetic disorders associated with cancer predisposition and genomic instability.  Prog Nucleic Acid Res Mol Biol . 1999;  63 189-221
    PubMedGoogle Scholar
  • 48 Kolodner R D, Putnam C D, Myung K. Maintenance of genome stability in Saccharomyces cerevisiae Science .  2002;  297 552-557
    PubMedGoogle Scholar
  • 49 Kinzler K W, Vogelstein B. Landscaping the cancer terrain.  Science . 1998;  280 1036-1037
    CrossrefPubMedGoogle Scholar
  • 50 Bartsch H, Nair U, Risch A, Rojas M, Wikman H, Alexandrov K. Genetic polymorphism of CYP genes, alone or in combination, as a risk modifier of tobacco-related cancers.  Cancer Epidemiol Biomarkers Prev . 2000;  9 3-28
    PubMedGoogle Scholar
  • 51 Stucker I, deWaziers I, Cenee S. et al . GSTM1, smoking and lung cancer: a case-control study.  Int J Epidemiol . 1999;  28 829-835
    CrossrefPubMedGoogle Scholar
  • 52 Qingyi W, Lie C, Amos C I. et al . Repair of tobacco carcinogen-induced DNA adducts and lung cancer risk: a molecular epidemiologic study.  J Natl Cancer Inst . 2000;  92 1764-1772
    CrossrefPubMedGoogle Scholar
  • 53 Wu X, Hudmon K S, Detry M A, Chamberlain R M, Spitz M R. D2 dopamine receptor gene polymorphisms among African-Americans and Mexican-Americans: a lung cancer case-control study.  Cancer Epidemiol Biomarkers Prev . 2000;  9 1021-1026
    PubMedGoogle Scholar
  • 54 Lerman C, Caporaso N E, Audrain J. et al . Evidence suggesting the role of specific genetic factors in cigarette smoking.  Health Psychol . 1999;  18 14-20
    PubMedGoogle Scholar
  • 55 Lerman C, Caporaso N, Main D. et al . Depression and self-medication with nicotine: the modifying influence of the dopamine D4 receptor gene.  Health Psychol . 1998;  17 56-62
    CrossrefPubMedGoogle Scholar
  • 56 Chan J M, Stampfer M J, Giovannucci E. et al . Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study [see comments].  Science . 1998;  279 563-566
    CrossrefPubMedGoogle Scholar
  • 57 Wu X, Yu H, Amos C I, Hong W K, Spitz M R. Joint effect of insulin-like growth factors and mutagen sensitivity in lung cancer risk.  J Natl Cancer Inst . 2000;  92 737-743
    CrossrefPubMedGoogle Scholar
  • 58 Pollak M. Insulin-like growth factor physiology and cancer risk.  Eur J Cancer . 2000;  36 1224-1228
    CrossrefPubMedGoogle Scholar
  • 59 Harrela M, Koistinen H, Kaprio J. et al . Genetic and environmental components of interindividual variation in circulating levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3.  J Clin Invest . 1996;  98 2612-2615
    PubMedGoogle Scholar
  • 60 Hong Y, Pedersen N L, Brismar K, Hall K, de Faire U. Quantitative genetic analyses of insulin-like growth factor I (IGF-I), IGF-binding protein-1, and insulin levels in middle-aged and elderly twins.  J Clin Endocrinol Metab . 1996;  81 1791-1797
    CrossrefPubMedGoogle Scholar
  • 61 Cohen A J, Bunn P A, Franklin W. et al . Neutral endopeptidase: variable expression in human lung, inactivation in lung cancer, and modulation of peptide-induced calcium flux.  Cancer Res . 1996;  56 831-839
    PubMedGoogle Scholar
  • 62 Ganju R K, Sunday M, Tsarwhas D G, Card A, Shipp M A. CD10/NEP in non-small cell lung carcinomas: relationship to cellular proliferation.  J Clin Invest . 1994;  94 1784-1791
    PubMedGoogle Scholar
  • 63 Cohen A J, Franklin W A, Magill C, Sorenson J, Miller Y E. Low neutral endopeptidase levels in bronchoalveolar lavage fluid of lung cancer patients.  Am J Respir Crit Care Med . 1999;  159 907-910
    PubMedGoogle Scholar