ABSTRACT
Although smoking is the primary risk factor for most lung cancers, genetic predisposition
may play an important role. Familial aggregation studies suggest a greater genetic
component in the risk for younger individuals developing lung cancer, for lifetime
nonsmokers, and possibly for women. Low-penetrance, high-prevalence polymorphic genes
may explain part of this genetic predisposition. Functional polymorphisms of xenobiotic
metabolism may alter the total exposure of tobacco carcinogens in the host. Subtle
alterations in the DNA repair, inflammatory, and cell cycle pathways may also alter
lung cancer susceptibility. The role of individual polymorphisms has been evaluated
for several genes including the CYP and glutathione s-transferase superfamilies, and
the NAT genes; DNA repair genes such as XPD (nucleotide excision pathway), XRCC1 (base excision pathway), and MGMT; and tumor suppressor or cell cycle genes such as p53. Molecular epidemiological studies are now focused on building larger databases from
existing smaller studies and developing strategies to simultaneously evaluate multiple
polymorphisms and genes within the same pathway.
KEYWORDS
Molecular epidemiology - polymorphism - genetic susceptibility - lung cancer
REFERENCES
- 1 American Cancer Society .Tobacco use. In: American Cancer Society, Cancer Facts
& Figures 2001 Atlanta, GA; American Cancer Society 2001: 29-32
- 2
Smith-Warner S A, Spiegelman D, Yaun S S et al..
Fruits, vegetables and lung cancer: a pooled analysis of cohort studies.
Int J Cancer.
2003;
107
1001-1011
- 3
Fabricius P, Lange P.
Diet and lung cancer.
Monaldi Arch Chest Dis.
2004;
59
207-211
- 4
Miller A B, Altenburg H P, Bueno-de-Mesquita B et al..
Fruits and vegetables and lung cancer: findings from the European Prospective Investigation
into Cancer and Nutrition.
Int J Cancer.
2004;
108
269-276
- 5
Christiani D C.
Utilization of biomarker data for clinical and environmental intervention.
Environ Health Perspect.
1996;
104(Suppl 5)
921-925
- 6
Wu X, Zhao H, Suk R, Christiani D C.
Genetic susceptibility to tobacco-related cancer.
Oncogene.
2004;
23
6500-6523
- 7 Rottman H. Uber primare Lungencarcinoma. Inaugural dissertation. Universitat Wurzburg
1898
- 8 Adler I. Primary Malignant Growths of the Lung and Bronchi. London; Longmans Green
& Co 1912
- 9
Wynder E L, Graham E A.
Tobacco smoking as a possible etiologic factor in bronchogenic carcinoma.
JAMA.
1950;
143
329-336
- 10
Doll R, Hill A B.
Smoking and carcinoma of the lung; preliminary report.
BMJ.
1950;
2
739-748
- 11 US Department of Health and Human Services .The Health Consequences of Smoking:
A Report of the Surgeon General. http://www.hhs.gov/surgeongeneral/library/smokingconsequences/
- 12
Hecht S S.
Tobacco smoke carcinogens and lung cancer.
J Natl Cancer Inst.
1999;
91
1194-1210
- 13
Miller C W, Simon K, Aslo A et al..
p53 mutations in human lung tumors.
Cancer Res.
1992;
52
1695-1698
- 14
Law M R.
Genetic predisposition to lung cancer.
Br J Cancer.
1990;
61
195-206
- 15
Hoffmann D, Hecht S S.
Nicotine-derived N-nitrosamines and tobacco-related cancer: current status and future
directions.
Cancer Res.
1985;
45
935-944
- 16
Lambert W C, Kuo H R, Lambert M W.
Xeroderma pigmentosum.
Dermatol Clin.
1995;
13
169-209
- 17
Kuper H, Adami H O, Boffetta P.
Tobacco use, cancer causation and public health impact.
J Intern Med.
2002;
251
455-466
- 18
Tokuhata G K, Lilienfeld A M.
Familial aggregation of lung cancer in humans.
J Natl Cancer Inst.
1963;
30
289-312
- 19
Ooi W L, Elston R C, Chen V W, Bailey-Wilson J E, Rothschild H.
Increased familial risk for lung cancer.
J Natl Cancer Inst.
1986;
76
217-222
- 20
Sellers T A, Ooi W L, Elston R C, Chen V W, Bailey-Wilson J E, Rothschild H.
Increased familial risk for non-lung cancer among relatives of lung cancer patients.
Am J Epidemiol.
1987;
126
237-246
- 21
Sellers T A, Elston R C, Stewart C, Rothschild H.
Familial risk of cancer among randomly selected cancer probands.
Genet Epidemiol.
1988;
5
381-391
- 22
Shaw G L, Falk R T, Pickle L W, Mason T J, Buffler P A.
Lung cancer risk associated with cancer in relatives.
J Clin Epidemiol.
1991;
44
429-437
- 23
Knudson Jr A G.
Mutation and cancer: statistical study of retinoblastoma.
Proc Natl Acad Sci USA.
1971;
68
820-823
- 24
Sellers T A, Bailey-Wilson J E, Elston R C et al..
Evidence for mendelian inheritance in the pathogenesis of lung cancer.
J Natl Cancer Inst.
1990;
82
1272-1279
- 25
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
- 26
Mayne S T, Buenconsejo J, Janerich D T.
Familial cancer history and lung cancer risk in United States nonsmoking men and women.
Cancer Epidemiol Biomarkers Prev.
1999;
8
1065-1069
- 27
Bailey-Wilson J E, Amos C I, Pinney S M et al..
A major lung cancer susceptibility locus maps to chromosome 6q23-25.
Am J Hum Genet.
2004;
75
460-474
- 28
Thorisson G A, Stein L D.
The SNP Consortium website: past, present and future.
Nucleic Acids Res.
2003;
31
124-127
- 29
Benhamou S, Lee W J, Alexandrie A K et al..
Meta- and pooled analyses of the effects of glutathione S-transferase M1 polymorphisms
and smoking on lung cancer risk.
Carcinogenesis.
2002;
23
1343-1350
- 30
Rutter J L, Mitchell T I, Buttice G et al..
A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates
an Ets binding site and augments transcription.
Cancer Res.
1998;
58
5321-5325
- 31
Rutter J L, Mitchell T I, Buttice G et al..
A single nucleotide polymorphism in the matrix metalloproteinase-1 promoter creates
an Ets binding site and augments transcription.
Cancer Res.
1998;
58
5321-5325
- 32
Yagil Y, Yagil C.
Candidate genes, association studies and haplotype analysis in the search for the
genetic basis of hypertension.
J Hypertens.
2004;
22
1255-1258
- 33
Wiencke J K, Kelsey K T, Varkonyi A et al..
Correlation of DNA adducts in blood mononuclear cells with tobacco carcinogen-induced
damage in human lung.
Cancer Res.
1995;
55
4910-4914
- 34
Wogan G N, Gorelick N J.
Chemical and biochemical dosimetry of exposure to genotoxic chemicals.
Environ Health Perspect.
1985;
62
5-18
- 35
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
- 36
Reszka E, Wasowicz W.
Significance of genetic polymorphisms in glutathione S-transferase multigene family
and lung cancer risk.
Int J Occup Med Environ Health.
2001;
14
99-113
- 37
Gelboin H V.
Benzo[alpha]pyrene metabolism, activation and carcinogenesis: role and regulation
of mixed-function oxidases and related enzymes.
Physiol Rev.
1980;
60
1107-1166
- 38
Hein D W, Doll M A, Rustan T D, Ferguson R J.
Metabolic activation of N-hydroxyarylamines and N-hydroxyarylamides by 16 recombinant
human NAT2 allozymes: effects of 7 specific NAT2 nucleic acid substitutions.
Cancer Res.
1995;
55
3531-3536
- 39
Lee W J, Brennan P, Boffetta P et al..
Microsomal epoxide hydrolase polymorphisms and lung cancer risk: a quantitative review.
Biomarkers.
2002;
7
230-241
- 40
Williams J A.
Single nucleotide polymorphisms, metabolic activation and environmental carcinogenesis:
why molecular epidemiologists should think about enzyme expression.
Carcinogenesis.
2001;
22
209-214
- 41
Kiyohara C, Otsu A, Shirakawa T, Fukuda S, Hopkin J M.
Genetic polymorphisms and lung cancer susceptibility: a review.
Lung Cancer.
2002;
37
241-256
- 42
Williams M D, Sandler A B.
The epidemiology of lung cancer.
Cancer Treat Res.
2001;
105
31-52
- 43
Hirvonen A.
Polymorphic NATs and cancer predisposition.
IARC Sci Publ.
1999;
148
251-270
- 44
Matakidou A, Eisen T, Houlston R S.
TP53 polymorphisms and lung cancer risk: a systematic review and meta-analysis.
Mutagenesis.
2003;
18
377-385
- 45
Feyler A, Voho A, Bouchardy C et al..
Point: myeloperoxidase-463G: a polymorphism and lung cancer risk.
Cancer Epidemiol Biomarkers Prev.
2002;
11
1550-1554
- 46
Zhou W, Liu G, Thurston S W et al..
Genetic polymorphisms in N-acetyltransferase-2 and microsomal epoxide hydrolase, cumulative
cigarette smoking, and lung cancer.
Cancer Epidemiol Biomarkers Prev.
2002;
11
15-21
- 47
Berwick M, Vineis P.
Markers of DNA repair and susceptibility to cancer in humans: an epidemiologic review.
J Natl Cancer Inst.
2000;
92
874-897
- 48
Wei Q, Cheng L, 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
- 49
Duell E J, Wiencke J K, Cheng T J et al..
Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells.
Carcinogenesis.
2000;
21
965-971
- 50
Ratnasinghe D, Yao S X, Tangrea J A et al..
Polymorphisms of the DNA repair gene XRCC1 and lung cancer risk.
Cancer Epidemiol Biomarkers Prev.
2001;
10
119-123
- 51
Chen S, Tang D, Xue K et al..
DNA repair gene XRCC1 and XPD polymorphisms and risk of lung cancer in a Chinese population.
Carcinogenesis.
2002;
23
1321-1325
- 52
Park J Y, Lee S Y, Jeon H S et al..
Polymorphism of the DNA repair gene XRCC1 and risk of primary lung cancer.
Cancer Epidemiol Biomarkers Prev.
2002;
11
23-27
- 53
David-Beabes G L, London S J.
Genetic polymorphism of XRCC1 and lung cancer risk among African-Americans and Caucasians.
Lung Cancer.
2001;
34
333-339
- 54
Misra R R, Ratnasinghe D, Tangrea J A et al..
Polymorphisms in the DNA repair genes XPD, XRCC1, XRCC3, and APE/ref-1, and the risk of lung cancer among male smokers in Finland.
Cancer Lett.
2003;
191
171-178
- 55
Hung R J, Brennan P, Canzian F et al..
Large-scale investigation of base excision repair genetic polymorphisms and lung cancer
risk in a multicenter study.
J Natl Cancer Inst.
2005;
97
567-576
- 56
Zhou W, Liu G, Miller D P et al..
Polymorphisms in the DNA repair genes XRCC1 and ERCC2, smoking, and lung cancer risk.
Cancer Epidemiol Biomarkers Prev.
2003;
12
359-365
- 57
Benhamou S, Sarasin A.
ERCC2/XPD gene polymorphisms and lung cancer: a HuGE review.
Am J Epidemiol.
2005;
161
1-14
- 58
Johnson E S.
Nested case-control study of lung cancer in the meat industry.
J Natl Cancer Inst.
1991;
83
1337-1339
- 59
Zhou W, Liu G, Park S et al..
Gene-smoking interaction associations for the ERCC1 polymorphisms in the risk of lung cancer.
Cancer Epidemiol Biomarkers Prev.
2005;
14
491-496
- 60
Wu X, Zhao H, Wei Q et al..
XPA polymorphism associated with reduced lung cancer risk and a modulating effect on
nucleotide excision repair capacity.
Carcinogenesis.
2003;
24
505-509
- 61
Butkiewicz D, Popanda O, Risch A et al..
Association between the risk for lung adenocarcinoma and a (-4) G-to-A polymorphism
in the XPA gene.
Cancer Epidemiol Biomarkers Prev.
2004;
13
2242-2246
- 62
Park J Y, Park S H, Choi J E et al..
Polymorphisms of the DNA repair gene xeroderma pigmentosum group A and risk of primary
lung cancer.
Cancer Epidemiol Biomarkers Prev.
2002;
11
993-997
- 63
Kaur T B, Travaline J M, Gaughan J P et al..
Role of polymorphisms in codons 143 and 160 of the O6-alkylguanine DNA alkyltransferase
gene in lung cancer risk.
Cancer Epidemiol Biomarkers Prev.
2002;
9
339-342
- 64
Cohet C, Borel S, Nyberg F et al..
Exon 5 polymorphisms in the O6-alkylguanine DNA alkyltransferase gene and lung cancer
risk in nonsmokers exposed to secondhand smoke.
Cancer Epidemiol Biomarkers Prev.
2004;
13
320-323
- 65
Krzesniak M, Butkiewicz D, Samojedny A, Chorazy M, Rusin M.
Polymorphisms in TDG and MGMT genes: epidemiological and functional study in lung
cancer patients from Poland.
Ann Hum Genet.
2004;
68
300-312
Geoffrey LiuM.D.
Harvard Medical School, Harvard School of Public Health
Massachusetts General Hospital Cancer Center, Yawkey 7B, 55 Fruit St.
Boston, MA 02115
Email: gliu1@partners.org
