Polymorphisms in XPC, XPD, XRCC1, and XRCC3 DNA repair genes and lung cancer risk in a population of northern Spain.
BACKGROUND
Polymorphisms in DNA repair genes have been associated to repair DNA lesions, and might contribute to the individual susceptibility to develop different types of cancer. Nucleotide excision repair (NER), base excision repair (BER), and double-strand break repair (DSBR) are the main DNA repair pathways. We investigated the relationship between polymorphisms in two NER genes, XPC (poly (AT) insertion/deletion: PAT-/+) and XPD (Asp312Asn and Lys751Gln), the BER gene XRCC1 (Arg399Gln), and the DSBR gene XRCC3 (Thr241Met) and the risk of developing lung cancer.


METHODS
A hospital-based case-control study was designed with 516 lung cancer patients and 533 control subjects, matched on ethnicity, age, and gender. Genotypes were determined by PCR-RFLP and the results were analysed using multivariate unconditional logistic regression, adjusting for age, gender and pack-years.


RESULTS
Borderline association was found for XPC and XPD NER genes polymorphisms, while no association was observed for polymorphisms in BER and DSBR genes. XPC PAT+/+ genotype was associated with no statistically significant increased risk among ever smokers (OR = 1.40; 95%CI = 0.94-2.08), squamous cell carcinoma (OR = 1.44; 95%CI = 0.85-2.44), and adenocarcinoma (OR = 1.72; 95%CI = 0.97-3.04). XPD variant genotypes (312Asn/Asn and 751Gln/Gln) presented a not statistically significant risk of developing lung cancer (OR = 1.52; 95%CI = 0.91-2.51; OR = 1.38; 95%CI = 0.85-2.25, respectively), especially among ever smokers (OR = 1.58; 95%CI = 0.96-2.60), heavy smokers (OR = 2.07; 95%CI = 0.74-5.75), and adenocarcinoma (OR = 1.88; 95%CI = 0.97-3.63). On the other hand, individuals homozygous for the XRCC1 399Gln allele presented no risk of developing lung cancer (OR = 0.87; 95%CI = 0.57-1.31) except for individuals carriers of 399Gln/Gln genotype and without family history of cancer (OR = 0.57; 95%CI = 0.33-0.98) and no association was found between XRCC3 Thr241Met polymorphism and lung cancer risk (OR = 0.92; 95%CI = 0.56-1.50), except for the 241Met/Met genotype and squamous cell carcinoma risk (OR = 0.47; 95%CI = 0.23-1.00).


CONCLUSIONS
In conclusion, we analysed the association between XPC, XPD, XRCC1, and XRCC3 polymorphisms and the individual susceptibility to develop lung cancer in the Spanish population, specifically with a highly tobacco exposed population. We attempt to contribute to the discovery of which biomarkers of DNA repair capacity are useful for screening this high-risk population for primary preventing and early detection of lung cancer.
López-Cima
M Felicitas
MF
Departamento de Medicina, Facultad de Medicina, Unidad de Epidemiología Molecular del Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain. laboepic.uo@uniovi.es
González-Arriaga
Patricia
P
García-Castro
Laura
L
Pascual
Teresa
T
Marrón
Manuel G
MG
Puente
Xose S
XS
Tardón
Adonina
A
D000368:Aged; D016022:Case-Control Studies; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors; D013030:Spain / Q000453:epidemiology; D014029:Tobacco Use Disorder / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D000076105:X-ray Repair Cross Complementing Protein 1; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*
D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C110901:X-ray repair cross complementing protein 3; C000619371:XRCC1 protein, human; C086984:XPC protein, human; D051759:Xeroderma Pigmentosum Group D Protein
Trends Genet. 1993 Jun;9(6):211-7
8337762
Genes Dev. 1996 May 15;10(10):1219-32
8675009
Annu Rev Biochem. 1996;65:43-81
8811174
Mutat Res. 2004 Feb 26;546(1-2):65-74
14757194
Mutat Res. 1998 May 25;400(1-2):15-24
9685572
Environ Mol Mutagen. 1999;33(1):3-20
10037319
Cancer Epidemiol Biomarkers Prev. 2004 Nov;13(11 Pt 1):1788-93
15533908
Carcinogenesis. 2004 Dec;25(12):2433-41
15333465
Biochem Genet. 2004 Dec;42(11-12):453-60
15587988
Carcinogenesis. 2005 Jan;26(1):169-75
15471894
Breast Cancer Res Treat. 2005 Jan;89(1):15-21
15666192
Mol Carcinog. 2005 Feb;42(2):65-92
15682379
Carcinogenesis. 2002 Apr;23(4):599-603
11960912
Hum Mol Genet. 2002 Jun 1;11(12):1399-407
12023982
Oncogene. 2002 Jun 13;21(26):4176-80
12037675
Carcinogenesis. 2002 Aug;23(8):1321-5
12151350
Nucleic Acids Res. 2002 Aug 15;30(16):3624-31
12177305
Breast Cancer Res Treat. 2002 Sep;75(2):159-66
12243508
Lung Cancer. 2002 Nov;38(2):123-9
12399122
Mutat Res. 2002 Nov 30;509(1-2):165-74
12427537
Cancer Epidemiol Biomarkers Prev. 2002 Dec;11(12):1513-30
12496039
Cancer Lett. 2003 Mar 10;191(2):171-8
12618330
Front Biosci. 2003 May 1;8:d963-81
12700077
Int J Cancer. 2003 Jul 10;105(5):669-73
12740916
Carcinogenesis. 2004 May;25(5):729-34
14688016
Carcinogenesis. 2004 May;25(5):757-63
14729591
IARC Monogr Eval Carcinog Risks Hum. 2004;83:1-1438
15285078
Cancer Lett. 2004 Sep 15;213(1):67-72
15312685
Lung Cancer. 2004 Oct;46(1):1-10
15364127
Int J Hyg Environ Health. 2004 Sep;207(4):301-13
15471094
Free Radic Res. 2004 Oct;38(10):1037-54
15512792
Cancer Res. 2005 Feb 1;65(3):722-6
15705867
CA Cancer J Clin. 2005 Mar-Apr;55(2):74-108
15761078
Cancer Lett. 2005 May 10;222(1):67-74
15837542
J Natl Cancer Inst. 2005 Apr 20;97(8):567-76
15840879
Cancer Epidemiol Biomarkers Prev. 2006 Mar;15(3):536-42
16537713
Hum Mol Genet. 2006 Apr 1;15(7):1217-24
16505003
Cancer Epidemiol Biomarkers Prev. 2006 Jul;15(7):1336-40
16835333
Cancer Genet Cytogenet. 2006 Aug;169(1):27-32
16875933
Lung Cancer. 2006 Dec;54(3):267-83
16982113
Lung Cancer. 2006 Dec;54(3):285-92
17034901
Lung Cancer. 2007 May;56(2):153-60
17316890
J Clin Oncol. 2000 Jun;18(11):2309-15
10829052
Int J Cancer. 2005 Jul 10;115(5):807-13
15729698
Carcinogenesis. 2005 Jun;26(6):1085-90
15731165
Cancer Causes Control. 2005 May;16(4):389-97
15953981
Cancer Epidemiol Biomarkers Prev. 2005 Jul;14(7):1747-53
16030112
Int J Cancer. 2005 Sep 20;116(5):768-73
15849729
Nat Genet. 2005 Aug;37(8):868-72
16041375
Carcinogenesis. 2005 Sep;26(9):1536-41
15878910
Int J Mol Med. 2005 Oct;16(4):709-16
16142409
Nature. 2005 Oct 27;437(7063):1299-320
16255080
Am J Epidemiol. 2005 Nov 15;162(10):925-42
16221808
Int J Hyg Environ Health. 2006 Jan;209(1):21-9
16373199
Carcinogenesis. 2006 Mar;27(3):560-7
16195237
Cancer Lett. 2000 Oct 16;159(1):79-86
10974409
Cancer Res. 2000 Oct 15;60(20):5612-6
11059748
Am J Ind Med. 2000 Dec;38(6):644-50
11071687
Mutat Res. 2001 Jan 5;461(4):273-8
11104903
Cancer Epidemiol Biomarkers Prev. 2001 Feb;10(2):125-31
11219769
Science. 2001 Feb 16;291(5507):1284-9
11181991
Nat Genet. 2001 Mar;27(3):247-54
11242102
Cancer Res. 2001 Feb 15;61(4):1354-7
11245433
Carcinogenesis. 2001 Apr;22(4):593-7
11285194
Cancer Epidemiol Biomarkers Prev. 2001 Mar;10(3):217-22
11303590
Cancer Res. 2001 Apr 15;61(8):3321-5
11309287
Cancer Epidemiol Biomarkers Prev. 2001 Aug;10(8):911-2
11489761
Carcinogenesis. 2001 Sep;22(9):1437-45
11532866
Int J Cancer. 2001 Oct 1;94(1):121-7
11668486
Cancer Epidemiol Biomarkers Prev. 2002 Jan;11(1):23-7
11815397
Cancer Lett. 2002 Apr 25;178(2):181-6
11867203
Carcinogenesis. 2002 Feb;23(2):295-9
11872635
Cancer Res. 2002 Mar 1;62(5):1377-81
11888908
J Natl Cancer Inst. 1983 Sep;71(3):539-44
6577228
Nucleic Acids Res. 1988 Feb 11;16(3):1215
3344216
Am J Public Health. 1992 Nov;82(11):1525-30
1443304