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Vol. 58. Issue 4.
Pages 311-322 (April 2022)
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Vol. 58. Issue 4.
Pages 311-322 (April 2022)
Original Article
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Radon, Tobacco Exposure and Non-Small Cell Lung Cancer Risk Related to BER and NER Genetic Polymorphisms
El radón, la exposición al tabaco y el riesgo de desarrollar cáncer de pulmón de células no pequeñas en relación con polimorfismos genéticos de BER y NER
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José Ramón Enjo-Barreiroa,b,c, Alberto Ruano-Ravinab,c,d,
Corresponding author
alberto.ruano@usc.es

Corresponding author.
, Mónica Pérez-Ríosb,c,d, Karl Kelseye, Leonor Varela-Lemab, María Torres-Duránf, Isaura Parente-Lamelasg, Mariano Provencio-Pullah, Iria Vidal-Garcíai, María Piñeiro-Lamasc, José A. Fernández-Villarg, Juan M. Barros-Diosa,b,c
a Service of Preventive Medicine, University Complex of Santiago de Compostela, Spain
b Department of Preventive Medicine, Santiago de Compostela University Teaching Hospital Complex, Santiago de Compostela, Spain
c Consortium for Biomedical Research in Epidemiology and Public Health (CIBER en Epidemiología y Salud Pública, CIBERESP), Spain
d Health Research Institute of Santiago de Compostela (Instituto de Investigación Sanitaria de Santiago de Compostela–IDIS), Santiago de Compostela, Spain
e Department of Epidemiology, Brown School of Public Health, Brown University, Providence, Rhode Island, USA
f Service of Neumology, University Hospital Complex of Vigo, Spain
g Service of Neumology, University Hospital Complex of Ourense, Spain
h Service of Medical Oncology, Puerta del Hierro University Hospital of Madrid, Spain
i Service of Neumology, University Hospital Complex of A Coruña, Spain
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Tables (4)
Table 1. Sample description broken down by case–control status.
Table 2. Lung cancer association broken down by the different polymorphisms analyzed.
Table 3. Lung cancer association broken down by smoking status for the different polymorphisms analyzed.*
Table 4. Lung cancer association broken down by radon exposure for the different polymorphisms analyzed.*
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Abstract
Introduction

Tobacco consumption and radon exposure are considered the first and second most common causes of lung cancer, respectively. The aim of this study was to analyze both whether selected genetic polymorphisms in loci that are in DNA repair pathways, are related to non-small-cell lung cancer (NSCLC) and whether they may modulate the association between residential radon exposure and lung cancer in both smokers and never smokers.

Methods

A multicentre, hospital-based, case–control study with 826 cases and 1201 controls was designed in a radon-prone area. Genotyping was determined in whole blood and residential radon exposure was measured in participants’ dwellings.

Results

Attending to tobacco exposure, the variant in the gene NBN (rs1805794) was associated with lung cancer in never smokers (OR 2.72; 95%1.44–5.2) and heavy smokers (OR 3.04; 95%CI 1.21–7.69). The polymorphism with the highest lung cancer association was OGG1 (rs125701), showing an OR of 8.04 (95%CI 1.64–58.29) for its homozygous variant genotype in heavy smokers. Attending to indoor radon exposure (>200Bq/m3), rs1452584, for its homozygous variant genotype, showed the highest association (OR 3.04 (95%CI 1.15–8.48).

Conclusion

The genes analyzed seem to have no association with the fully adjusted model, but they might modulate lung cancer association when different categories of tobacco consumption are considered (i.e. heavy smokers). This association may similarly be elevated for those individuals having high indoor radon exposures, though at a minor extent.

Keywords:
Non-small cell lung cancer
Smokers
Non-smokers
Genetic polymorphisms
Radon
Resumen
Introducción

El consumo de tabaco y la exposición al radón se consideran la primera y la segunda causa más frecuentes de cáncer de pulmón, respectivamente. El objetivo de este estudio fue analizar si determinados polimorfismos genéticos en los loci que forman parte de la cascada de reparación del ADN se asocian con el cáncer de pulmón de célula no pequeña, y también si es posible que modifiquen la asociación entre la exposición al radón en el hogar y el cáncer de pulmón tanto en fumadores como en no fumadores.

Métodos

Se diseñó un estudio multicéntrico hospitalario de casos y controles con 826 casos y 1.201 controles en un área proclive a la presencia de radón. Se determinó el genotipo en sangre y se midió la exposición al radón en el lugar de residencia de los participantes.

Resultados

Analizando la exposición al tabaco, la variante del gen NBN (rs1805794) se asoció con el cáncer de pulmón en no fumadores (OR 2,72; IC 95% 1,44-5,2) y grandes fumadores (OR 3,04; IC 95% 1,21-7,69). El polimorfismo con mayor asociación con el cáncer de pulmón fue OGG1 (rs125701), con una OR de 8,04 (IC 95% 1,64-58,29) para la variante genotípica en homocigosis en grandes fumadores. En cuanto a la exposición al radón en interiores (>200Bq/m3), rs1452584 en homocigosis mostró la asociación más fuerte (OR 3,04; IC 95% 1,15-8,48).

Conclusión

Los genes que se analizaron no muestran asociación con el modelo completamente ajustado, pero podrían modificar la asociación con el cáncer de pulmón cuando se consideran diferentes categorías de consumo de tabaco (esto es, grandes fumadores). Esta asociación podría aumentar de forma similar en aquellos individuos que están expuestos al radón en interiores, aunque en menor medida.

Palabras clave:
Cáncer de pulmón de células no pequeñas
Fumadores
No fumadores
Polimorfismos genéticos
Radón
Full Text
Introduction

Worldwide, lung cancer represents 11.4% of overall cancer diagnoses. It is also the leading cause of cancer death, accounting for 18% of all cancer deaths. It is the most frequently occurring cancer among men and the third most frequent in women. Lung cancer is the leading cause of cancer death among men and the second most common fatal cancer in women, comprising 21.5 and 13.7% of all cancer deaths, respectively.1,2 Tobacco consumption is the main association factor of this disease followed by exposure to indoor radon.2

Radon is classified as the main cause of lung cancer in never smokers and the second most common in ever-smokers by the United States Environmental Protection Agency (USEPA) and the World Health Organization (WHO).3–5 The molecular mechanism of radon carcinogenesis is not fully understood, and lack of knowledge remains regarding the precise molecular carcinogenic pathways for tobacco exposure. Genetic susceptibility may play an important role and explains why some people develop lung cancer and others do not, given the same tobacco or indoor radon exposures.6,7

Tobacco smoke, despite damaging DNA, has an additional effect in DNA repair pathway activity, reducing the detectable amount of some repair proteins, (including XPC, OGG1 and OGG2) in pulmonary tissue in mouse models.8 Tobacco smoke exposure induces bulky DNA adducts, which have a linear relationship with carcinogenesis at low exposure, but with high doses may reach a steady state, possibly due to DNA repair pathway saturation and increased apoptosis.9,10

Low capacity in DNA repair is related with an increased association with lung cancer.11,12 There are three major types of DNA repair mechanisms: nucleotide excision repair (NER), the main route in mammals which repair DNA damaged by ultraviolet light, environmental mutagens and chemotherapy12; base excision repair (BER) that repairs DNA damaged by oxidation, deamination and alkylation. It protects from ageing, neurodegeneration and cancer13; and mismatch repair (MMR) that blocks recombination between non identical DNA.14 Published studies have focused in genes involved in NER such as ERCC1 and ERCC2, BER such as XRCC1 and OGG1, and MMR such as XRCC3.15 Nevertheless, no study has analyzed the potential interplay between these molecular pathways and indoor radon exposure.

The aim of this study was to analyze if selected genetic polymorphisms in genes playing a role in these molecular pathways are associated with an increased association of NSCLC. As a secondary objective, we have analyzed the effect of these genes taking into account the different amount of tobacco consumption and indoor radon exposure, to ascertain a potential modulating effect for the polymorphisms analyzed.

Subjects and methodsDesign, subjects and settings

A multicentre, hospital-based, case–control study was conducted in 12 Spanish hospitals located in four different regions. The population was insured by the National Health Service. Lung cancer diagnosis was pathologically confirmed in their respective hospitals of reference. Cases and controls were recruited between January 2011 and October 2018. All patients had to be at least 30 years old, with no upper limit to participant age. Subjects with a previously history of cancer were excluded. To be included as a case, the patient had to have a pathologically confirmed primary lung cancer. Small Cell Lung Cancer patients were excluded. Controls were individuals undergoing minor, non-oncological, ambulatory surgery not related to tobacco consumption. Controls were recruited using frequency-based age and sex matching with cases in order to ensure a similar distribution between cases and controls. We have used this approach previously.6,16 The study protocol was approved by the Santiago de Compostela Committee of Research Ethics (reference 2010/295 and 2013/364). Written informed consent was obtained for all participants.

Data collection and radon measurements

All participants answered a questionnaire administered through personal interview regarding their lifestyle, with especial emphases on smoking habit and indoor radon. A detailed smoking history was obtained through interview. Radon was measured in the dwellings of participants. The return rate of radon devices was higher than 87% for both cases and controls. The Galician Radon Laboratory (www.radon.gal; School of Medicine, University of Santiago de Compostela, Galicia, Spain) read the detectors. This is one of three laboratories certified by the National Entity of Accreditation to measure indoor radon ins Spain.

Laboratory methods

Twenty-four single nucleotide polymorphisms (SNP) in fifteen genes and one SNP in a non-protein-coding RNA (ncRNA) region of chromosome 18 involved in DNA repair were investigated. The genes analyzed involved in DNA repair were: ERCC1 (rs11615, rs3212986), ERCC2 (rs13181, rs1799793), ERCC3 (rs3738948, rs4150459), ERCC5 (rs1047768, rs2094258), OGG1 (rs1052133, rs2072668, rs2472037, rs125701), APEX1 (rs1130409, rs3136817), XRCC1 (rs25487), XRCC3 (rs861539), MUTYH (rs3219489), NBN (rs1805794), RRM1 (rs12806698), XPC (rs2228001), KLH4 (rs5922437) and FATS (rs11245007). In addition, we included in this study the single-nucleotide variation in intronic region rs1452584, located in chromosome 18, q21.33, which is in a ncRNA gene, these regions might have regulatory functions.17

Genetic polymorphisms in the studied genes (were analyzed from DNA extracted from 3ml of whole blood donated by the participants. Genotyping was performed at the CeGen, which is one of the three genotyping core facilities of the National Genotyping Centre (belonging to the University of Santiago de Compostela).

SNPs were studied with MassARRAY® System developed by Agena Bioscience Inc., a technology which make possible the investigation of the presence of punctual variants of DNA.18

Statistical analysis

A bivariate descriptive analysis was performed comparing the characteristics of cases and controls. We performed a multiple logistic regression in which the dependent variable was the case or control status of the participants and the main independent variables were the SNPs studied. Results were adjusted by age and sex in the first model. Tobacco consumption and indoor radon exposure were added to the previous variables creating a fully adjusted model. The homozygote polymorphism genotype of the common allele (wild type) was used as the reference group.

To assess the existence of a relationship between selected genetic polymorphisms and tobacco consumption, we stratified smoking habit in three categories (never smokers, moderate smokers (second tercile: 34–66 packs-years) and heavy smokers (third tercile: >66 packs-year) and each polymorphism in three different genotypes (homozygous for the common allele (wild type), heterozygous and homozygous for the mutation). In addition, we studied whether lung cancer association was modified between the same polymorphisms and radon indoor exposure stratifying this variable in two categories (≤200Bq/m3 and >200Bq/m3). Stratification at 200Bq/m3 was applied since previous studies have demonstrated that the association of lung cancer was increased at this dose.19,20 All statistical results are expressed as Odds Ratios (OR) with their 95% confidence intervals. Statistical analyses were performed with IBM SPSS v22 (IBM, Armonk, NY, USA). We included in the tables the p-values and we corrected them applying the False Discovery Rate because to reduce the possibility of false positive results due to multiple comparisons.

Results

The study included 2027 participants, 826 cases and 1201 controls. Cases and controls were well balanced regarding sociodemographic variables, with an average age of 65.5, 50.5% of women. Cases and controls lived a similar number of years in the same dwelling. Residential radon exposure was available for 754 cases (91.3%) and 1010 controls (84.1%). The most frequent histological type was adenocarcinoma (69.7%). A sample description broken down by case–control status is shown in Table 1.

Table 1.

Sample description broken down by case–control status.

Variable  Cases, n (%)  Controls, n (%) 
Number of patients  826 (40.7%)  1201 (59.3%) 
Median age (range)/25-75thpercentile  67 (25–94)/59–74  64 (21–92)/56–72 
Sex
Female  417 (50.5)  553 (46) 
Male  409 (49.5)  648 (54) 
Education
No formal studies  164 (20.3)  191 (16) 
Primary School  402 (49.7)  609 (51.1) 
High School  135 (16.7)  236 (19.8) 
University degree  108 (13.3)  156 (13.1) 
Tobacco consumption
Never-smokers  428 (57.3)  708 (61.3) 
Light smokers (first tertile, 1–33 pack-years)  86 (11.5)  266 (23) 
Moderate smokers (second tertile, 34–66 pack-years)  132(17.7)  128 (11.1) 
Heavy smokers (third tertile, >66 pack-years)  101 (13.5)  53 (4.6) 
Residential radon exposure Bq/m3
≤100  190 (25.2)  300 (29.7) 
101–147  141 (18.7)  210 (20.8) 
148–199  116 (15.4)  155 (15.3) 
≥200  307 (40.7)  345 (34.2) 
Geometric mean (95% CI)  166.18 (156.94–175.96)  152.58 (145.18–160.36) 
Median (25-75th percentiles)  164.5 (99.8–280.3)  146 (90.8–254.3) 
Years (median) living in the measured dwelling/25–75th percentiles  28 (14–40)  30 (15–40) 
Histological types
Adenocarcinoma  573 (69.7)   
Squamous cell carcinoma  154 (18.7)   
Large cell carcinoma  29 (3.5)   
Other histological types  66 (8)   

Table 2 summarizes the results for the different genotypes and their distribution between cases and controls. Compared to participants with wild type gene NBN (rs1805794) showed an OR for the homozygous genotype of 1.78 (95%CI 1.23–2.58) and 1.78 (95%CI 1.15–2.75) after adjustment for age and sex and full adjustment, respectively. This result along other results for other polymorphisms showing no association are shown in Table 2.

Table 2.

Lung cancer association broken down by the different polymorphisms analyzed.

Polymorphism Allele  Cases, n (%)  Controls, n (%)  ORa (95%CI)  pc  p-cd  ORb (95%CI)  pc  p-cd 
ERCC5_rs1047768
TC  220 (49.3)  312 (46.1)  1 (–)      1 (–)     
CC  150 (33.6)  229 (33.8)  0.94 (0.73–1.2)  0.6269  0.6697  0.98 (0.74–1.31)  0.9121  0.7469 
TT  76 (17)  136 (20.1)  0.71 (0.52–0.96)  0.0271  0.1141  0.71 (0.49–1.01)  0.0583  0.1943 
OGG1_Ser326Cys_rs1052133
CC  391 (62.2)  577 (61)  1 (–)      1 (–)     
CG  209 (33.2)  307 (32.5)  0.92 (0.75–1.12)  0.4076  0.5687  0.99 (0.79–1.24)  0.9288  0.7503 
GG  29 (4.6)  62 (6.6)  0.66 (0.43–1.01)  0.0598  0.1974  0.63 (0.39–1.02)  0.0638  0.2055 
FATS_C10orf90_rs11245007
CT  207 (46.4)  301 (44.4)  1 (–)      1 (–)     
CC  205 (46)  311 (45.9)  0.98 (0.78–1.24)  0.8933  0.7429  0.92 (0.70–1.21)  0.5505  0.6404 
TT  34 (7.6)  66 (9.7)  1.01 (0.68–1.5)  0.9683  0.758  0.78 (0.48–1.25)  0.3116  0.502 
APEX1_rs1130409
GT  208 (46.6)  329 (48.5)  1 (–)      1 (–)     
TT  125 (28)  187 (27.6)  1.02 (0.78–1.33)  0.8805  0.7401  1.17 (0.86–1.6)  0.3074  0.4986 
GG  113 (25.3)  162 (23.9)  1.03 (0.78–1.36)  0.8138  0.7247  1.14 (0.83–1.58)  0.4147  0.5729 
ERCC1_rs11615
CC  153 (24.2)  226 (23.9)  1 (–)      1 (–)     
CT  248 (39.3)  413 (43.6)  1.01 (0.79–1.28)  0.9469  0.7539  0.91 (0.69–1.2)  0.4948  0.6155 
TT  230 (36.5)  308 (32.5)  1.25 (0.97–1.61)  0.0838  0.2435  1.16 (0.87–1.54)  0.3188  0.5077 
OGG1_rs125701
GG  328 (73.5)  497 (73.4)  1 (–)      1 (–)     
AG  103 (23.1)  165 (24.4)  0.89 (0.68–1.16)  0.3889  0.5571  0.93 (0.69–1.26)  0.6522  0.6784 
AA  15 (3.4)  15 (2.2)  1.65 (0.84–3.28)  0.1466  0.3362  1.62 (0.73–3.57)  0.2321  0.4288 
RRM1_rs12806698
CC  248 (55.6)  388 (57.2)  1 (–)      1 (–)     
CA  170 (38.1)  252 (37.2)  0.99 (0.78–1.24)  0.9033  0.745  1.01 (0.77–1.32)  0.9587  0.7562 
AA  28 (6.3)  38 (5.6)  0.97 (0.59–1.57)  0.8909  0.7424  1.08 (0.62–1.87)  0.7764  0.7152 
ERCC2_Lys751Gln_rs13181
TT  272 (43.1)  426 (45)  1 (–)      1 (–)     
GT  281 (44.5)  416 (43.9)  1.09 (0.9–1.33)  0.388  0.5565  1.05 (0.84–1.32)  0.6465  0.6765 
GG  78 (12.4)  105 (11.1)  1.17 (0.87–1.57)  0.3074  0.4986  1.1 (0.78–1.55)  0.6004  0.6601 
rs1452584
AA  281 (63)  465 (68.6)  1 (–)      1 (–)     
GA  183 (30.9)  189 (27.9)  1.08 (0.85–1.38)  0.52  0.6271  1.17 (0.88–1.55)  0.2936  0.4871 
GG  27 (6.1)  24 (3.5)  1.45 (0.85–2.48)  0.1687  0.3624  1.61 (0.87–2.98)  0.126  0.3089 
ERCC2_Asp312Asn_rs1799793
TT  265 (59.4)  419 (61.9)  1 (–)      1 (–)     
CT  157 (35.2)  224 (33.1)  1.15 (0.91–1.46)  0.2468  0.4439  1.2 (0.91–1.58)  0.1948  0.3897 
CC  24 (5.4)  34 (5)  1.04 (0.63–1.69)  0.8741  0.7387  1.03 (0.57–1.86)  0.9137  0.7472 
NBN_rs1805794
CC  188 (42.2)  313 (46.2)  1 (–)      1 (–)     
GC  202 (45.3)  304 (44.8)  1.06 (0.83–1.34)  0.6549  0.6793  1.09 (0.83–1.43)  0.5338  0.6332 
GG  56 (12.6)  61 (9)  1.78 (1.23–2.58)  0.0022  0.0152  1.78 (1.15–2.75)  0.0102  0.0578 
OGG1_C7G_rs2072668
CC  274 (61.4)  405 (59.9)  1 (–)      1 (–)     
CG  150 (33.6)  228 (33.7)  0.88 (0.69–1.11)  0.2811  0.4762  0.96 (0.73–1.26)  0.7614  0.7112 
GG  22 (4.9)  43 (6.4)  0.71 (0.42–1.15)  0.1691  0.3628  0.69 (0.38–1.21)  0.2025  0.397 
ERCC5_rs2094258
CC  281 (63)  441 (65.1)  1 (–)      1 (–)     
CT  139 (31.2)  204 (30.1)  1.05 (0.83–1.34)  0.684  0.6887  1.09 (0.82–1.44)  0.5672  0.6472 
TT  26 (5.8)  32 (4.7)  0.95 (0.56–1.59)  0.8535  0.7341  1.13 (0.62–2.02)  0.6896  0.6905 
XPC_rs2228001
GT  214 (48)  332 (49)  1 (–)      1 (–)     
TT  162 (36.3)  234 (34.6)  0.99 (0.77–1.26)  0.909  0.7462  1.08 (0.81–1.44)  0.5805  0.6525 
GG  70 (15.7)  111 (16.4)  0.95 (0.68–1.31)  0.7516  0.7085  0.86 (0.59–1.24)  0.4135  0.5722 
OGG1_rs2472037
AG  202 (45.5)  317 (47.5)  1 (–)      1 (–)     
AA  175 (39.4)  262 (39.2)  0.93 (0.73–1.18)  0.5533  0.6415  0.98 (0.74–1.3)  0.8976  0.7438 
GG  67 (15.1)  89 (13.3)  1.16 (0.83–1.61)  0.3835  0.5537  1.31 (0.88–1.95)  0.1742  0.3685 
XRCC1_Gln399Arg_rs25487
GG  285 (45.2)  416 (43.9)  1 (–)      1 (–)     
AG  260 (41.2)  418 (44.1)  0.94 (0.77–1.14)  0.5226  0.6283  0.92 (0.74–1.16)  0.4951  0.6156 
AA  86 (13.6)  113 (11.9)  1.15 (0.86–1.55)  0.3487  0.5301  1.12 (0.8–1.56)  0.5084  0.6218 
APEX1_rs3136817
TT  238 (53.4)  347 (51.2)  1 (–)      1 (–)     
CT  172 (38.6)  261 (38.5)  0.96 (0.76–1.22)  0.7614  0.7112  0.87 (0.66–1.14)  0.3021  0.4942 
CC  36 (8.1)  70 (10.3)  0.73 (0.48–1.1)  0.1404  0.3284  0.75 (0.47–1.19)  0.229  0.4255 
ERCC1_rs3212986
GG  360 (57.1)  554 (58.5)  1 (–)      1 (–)     
GT  237 (37.6)  342 (36.1)  1.14 (0.94–1.39)  0.1867  0.3816  1.06 (0.85–1.33)  0.5942  0.6578 
TT  34 (5.4)  51 (5.4)  1.06 (0.7–1.59)  0.7721  0.7141  1.1 (0.68–1.76)  0.7003  0.6937 
MUTYH_rs3219489
CC  243 (54.7)  351 (51.8)  1 (–)      1 (–)     
GC  163 (36.7)  281 (41.5)  0.92 (0.73–1.16)  0.4965  0.6163  0.85 (0.65–1.12)  0.2454  0.4425 
GG  38 (8.6)  45 (6.6)  1.52 (0.98–2.35)  0.059  0.1958  1.41 (0.85–2.33)  0.1867  0.3816 
ERCC3_rs3738948
AA  268 (60.1)  406 (59.9)  1 (–)      1 (–)     
GA  150 (33.6)  242 (35.7)  0.92 (0.72–1.16)  0.4849  0.6107  1.04 (0.79–1.38)  0.7624  0.7115 
GG  28 (6.3)  30 (4.4)  1.52 (0.93–2.49)  0.097  0.2654  1.42 (0.8–2.52)  0.2326  0.4293 
ERCC3_XPB_rs4150459
CC  406 (91)  604 (89.3)  1 (–)      1 (–)     
CT  39 (8.7)  69 (10.2)  0.96 (0.65–1.39)  0.8141  0.7248  0.77 (0.49–1.19)  0.2445  0.4416 
TT  1 (0.2)  3 (0.4)  0.48 (0.02–3.78)  0.523  0.6285  0.45 (0.02–3.54)  0.4865  0.6114 
KLH4_rs5922437
GG  285 (63.9)  422 (62.3)  1 (–)      1 (–)     
AA  83 (18.6)  155 (22.9)  0.94 (0.71–1.24)  0.677  0.6865  0.88 (0.63–1.23)  0.4492  0.5923 
GA  78 (17.5)  100 (14.8)  1.04 (0.72–1.51)  0.819  0.726  0.86 (0.57–1.29)  0.4693  0.6029 
XRCC3_Thr241Met_rs861539
CC  238 (37.8)  374 (39.5)  1 (–)      1 (–)     
TG  306 (48.6)  420 (44.4)  1.13 (0.93–1.39)  0.2284  0.4249  1.24 (0.98–1.56)  0.0687  0.2149 
TT  86 (13.7)  152 (16.1)  0.91 (0.69–1.21)  0.5388  0.6354  0.89 (0.64–1.23)  0.497  0.6165 
a

Adjusted by age and sex.

b

Adjusted by age, sex, tobacco consumption and indoor radon exposure.

c

p-Values.

d

Corrected p-values.

Table 3 shows the association of the different polymorphisms studied with lung cancer at varying tobacco exposure categories (never-smokers, moderate-smokers and heavy-smokers). Lung cancer association increases when participants are heavy smokers for almost all the polymorphisms analyzed. Compared with never-smokers, the highest OR corresponded to homozygous genotype in heavy smokers for: OGG1 (rs125701) (OR 8.04; 95%CI 1.64–58.29), OGG1 (rs2472037) (OR 6.1; 95%CI 2.3–17.5) and ERCC1 (rs32112986) (OR 5.92; 95%CI 1.59–28.18). Only ERCC3 (rs4150459) in its homozygous type expressed an increased association with NSCLC in moderate smokers compared with never smokers with wild type (OR 2.9; 95%CI 1.96–4.33). NBN (rs1805794) in its homozygous genotype showed a higher association with lung cancer in never smokers (OR 2.72; 95%CI 1.44–5.2).

Table 3.

Lung cancer association broken down by smoking status for the different polymorphisms analyzed.*

Polymorphisms  Cases, controls; ORa (95%CI)
  Never-smokers  pb  p-cc  Moderate smokers  pb  p-cc  Heavy smokers  pb  p-cc 
ERCC5_rs1047768
TC  92, 136      34, 106      56, 51     
  1 (–)      0.79 (0.48–1.3)  0.3592  0.5374  2.82 (1.7–4.71)  0.0001  0.0012 
CC  62, 113      32, 71      29, 34     
  0.87 (0.57–1.34)  0.525  0.6294  1.1 (0.65 –1.87)  0.7174  0.6988  2.1 (1.15–3.84)  0.0156  0.0789 
TT  25, 57      9, 50      21, 18     
  0.58 (0.33–1.02)  0.0628  0.2035  0.45 (0.19–0.94)  0.0437  0.1604  2.64 (1.29–5.47)  0.0083  0.0491 
OGG1_Ser326Cys_rs1052133
CC  225, 353      41, 136      74, 60     
  1 (–)      0.7 (0.46–1.4)  0.0837  0.2433  2.82 (1.87–4.26)  <0.001  <0.001 
CG  120, 183      30, 74      29, 38     
  0.98 (0.73–1.31)  0.876  0.7391  0.92 (0.56–1.47)  0.724  0.7008  1.77 (1.02 –3.03)  0.0387  0.1471 
GG  18, 39      2, 16      3, 5     
  0.64 (0.35–1.15)  0.147  0.3367  0.28 (0.04–1.02)  0.0975  0.2661  1.36 (0.27–5.7)  0.6809  0.6877 
FATS_C10orf90_rs11245007
CT  85, 132      37, 110      45, 43     
  1 (–)      0.84 (0.51–1.37)  0.4955  0.6158  2.74 (1.6–4.74)  0.0003  0.0027 
CC  80, 144      32, 92      54, 52     
  0.88 (0.58–1.32)  0.5222  0.6281  0.93 (0.55–1.57)  0.7944  0.7199  2.62 (1.58–4.4)  0.0002  0.002 
TT  14, 30      6, 25      7, 8     
  0.76 (0.36–1.54)  0.4158  0.5937  0.6 (0.21–1.48)  0.294  0.4874  2.27 (0.75–6.73)  0.1357  0.3222 
APEX1_rs1130409
GT  121, 176      6, 33      15, 11     
  1 (–)      0.39 (0.14–0.92)  0.2777  0.4732  3.32 (1.44–7.87)  0.0000  0.0027 
TT  139, 233      32, 110      41, 52     
  0.91 (0.66–1.26)  0.5152  0.625  0.68 (0.41–1.1)  0.724  0.7008  1.82 (1.09–3.03)  0.017  0.0836 
GG  103, 166      37, 84      50, 40     
  1.05 (0.74–1.48)  0.1551  0.3465  1.02 (0.62–1.64)  0.6638  0.6822  2.81 (1.7–4.7)  <0.001  <0.001 
ERCC1_rs11615
CC  121, 176      6, 33      15, 11     
  1 (–)      0.39 (0.14–0.92)  0.0459  0.1659  3.32 (1.44–7.87)  0.0051  0.0326 
CT  139, 233      32, 110      41, 52     
  0.91 (0.66–1.26)  0.5835  0.6537  0.68 (0.41–1.1)  0.1206  0.3011  1.82 (1.09–3.03)  0.0205  0.0952 
TT  103, 166      37, 84      50, 40     
  1.05 (0.74–1.48)  0.8032  0.7221  1.02 (0.62–1.64)  0.9504  0.745  2.81 (1.7–4.7)  0.0001  0.0012 
OGG1_rs125701
GG  129, 215      60, 172      73, 76     
  1 (–)      0.99 (0.66–1.49)  0.9734  0.7589  2.64 (1.72–4.09)  <0.001  <0.001 
AG  44, 82      13, 50      28, 25     
  0.91 (0.58–1.42)  0.6749  0.6858  0.65 (0.32–1.24)  0.2071  0.4013  3.11 (1.67–5.81)  0.0003  0.0027 
AA  6, 9      2, 4      5, 2     
  1.13 (0.35–3.44)  0.8349  0.7298  1.47 (0.2–7.77)  0.663  0.682  8.04 (1.64–58.29)  0.0158  0.0796 
RRM1_rs12806698
CC  103, 162      44, 145      57, 59     
  1 (–)      0.78 (0.5–1.23)  0.2938  0.4873  2.46 (1.51–4.01)  0.003  0.0027 
CA  64, 124      28, 73      41, 37     
  0.81 (0.53–1.22)  0.319  0.5078  1 (0.58–1.69)  0.9928  0.7625  2.91 (1.67–5.11)  0.0002  0.002 
AA  12, 20      3, 9      8, 7     
  1.01 (0.45–2.21)  0.9741  0.7591  0.82 (0.18–2.93)  0.7807  0.7163  2.99 (1.02–9.01)  0.0453  0.1644 
ERCC2_Lys751Gln_rs13181
TT  157, 263      33, 103      50, 37     
  1 (–)      0.84 (0.52–1.34)  0.4737  0.6051  3.55 (2.16–5.9)  0.0000  0.0000 
GT  165, 242      33, 104      42, 54     
  1.18 (0.89–1.57)  0.2502  0.4473  0.77 (0.48–1.21)  0.2638  0.4604  1.94 (1.2–3.13)  0.007  0.0427 
GG  41, 70      9, 20      14, 12     
  0.94 (0.61–1.49)  0.8562  0.7347  1.2 (0.5–2.68)  0.6745  0.6857  2.89 (1.27–6.68)  0.0113  0.0625 
rs1452584
AA  106, 217      45, 149      72, 74     
  1 (–)      0.99 (0.63–1.53)  0.9601  0.7564  3.06 (1.97–4.78)  <0.001  <0.001 
GA  61, 81      25, 68      31, 25     
  1.38 (0.9–2.12)  0.1367  0.3235  1.13 (0.65–1.92)  0.6691  0.684  3.88 (2.11–7.22)  <0.001  <0.001 
GG  12, 8      5, 10      3, 4     
  2.36 (0.91–6.42)  0.0794  0.2356  1.29 (0.38–3.92)  0.6656  0.6828  2.49 (0.47–11.89)  0.2484  0.4455 
ERCC2_Asp312Asn_rs1799793
TT  119, 193      41, 132      62, 61     
  1 (–)      0.83 (0.52–1.29)  0.4088  0.5694  2.68 (1.68–4.28)  <0.001  <0.001 
CT  53, 94      32, 87      36, 35     
  0.97 (0.63–1.49)  0.8854  0.7412  1.03 (0.62–1.68)  0.9225  0.749  2.9 (1.65–5.1)  0.0002  0.002 
CC  7, 19      2, 8      8, 6     
  0.62 (0.23–1.54)  0.3232  0.5111  0.64 (0.09–2.75)  0.5925  0.6571  3.64 (1.18–11.81)  0.0249  0.1082 
NBN_rs1805794
CC  74, 144      35, 106      38, 44     
  1 (–)      1.05 (0.63–1.74)  0.8462  0.7324  2.87 (1.64–5.05)  0.0002  0.002 
GC  76, 135      31, 99      57, 48     
  1.07 (0.7–1.62)  0.7615  0.7112  1.12 (0.66–1.91)  0.6693  0.684  4.04 (2.39–6.88)  <0.001  <0.001 
GG  29, 27      9, 22      11, 11     
  2.72 (1.44–5.2)  0.0022  0.0152  1.21 (0.49–2.78)  0.6632  0.6821  3.04 (1.21–7.69)  0.0172  0.0843 
OGG1_C7G_rs2072668
CC  106, 181      43, 137      74, 60     
  1 (–)      0.87 (0.55–1.37)  0.5564  0.6428  3.41 (2.16–5.44)  <0.001  <0.001 
CG  63, 105      29, 73      29, 38     
  0.97 (0.64–1.47)  0.8773  0.7394  1.06 (0.62–1.78)  0.8262  0.7277  2.03 (1.13–3.63)  0.0175  0.0852 
GG  10, 20      3, 16      3, 5     
  0.74 (0.31–1.67)  0.4833  0.6099  0.49 (0.11–1.56)  0.2759  0.4716  1.45 (0.28–6.24)  0.6254  0.6692 
ERCC5_rs2094258
CC  118, 198      47, 144      64, 68     
  1 (–)      0.88 (0.57–1.35)  0.5622  0.6452  2.42 (1.54–3.82)  0.0001  0.0012 
CT  53, 98      25, 69      35, 28     
  0.83 (0.54–1.27)  0.3909  0.5584  0.97 (0.56–1.65)  0.9041  0.7452  3.63 (2.02 –6.59)  <0.001  <0.001 
TT  8, 10      3, 14      7, 7     
  1.12 (0.4–3.14)  0.8216  0.7266  0.51 (0.11–1.66)  0.3067  0.498  2.42 (0.77–7.56)  0.1218  0.3028 
XPC_rs2228001
GT  86, 164      36, 106      51, 48     
  1 (–)      1.02 (0.62–1.65)  0.9511  0.7547  3.29 (1.97–5.53)  <0.001  <0.001 
TT  65, 108      27, 82      37, 25     
  1.16 (0.76–1.77)  0.4977  0.6168  1.08 (0.62–1.84)  0.7911  0.719  4.78 (2.6–8.92)  <0.001  <0.001 
GG  28, 34      12, 39      18, 30     
  1.45 (0.79–2.63)  0.2258  0.4221  0.96 (0.45–1.95)  0.9217  0.7488  1.8 (0.9–3.52)  0.0904  0.2548 
OGG1_rs2472037
AG  73, 140      38, 105      54, 55     
  1 (–)      1.17 (0.7–1.93)  0.5496  0.64  3.11 (1.86–5.24)  <0.001  <0.001 
AA  75, 121      25, 84      39, 41     
  1.15 (0.75–1.77)  0.5187  0.6266  0.91 (0.51–1.58)  0.7425  0.706  2.98 (1.69–5.28)  0.0002  0.002 
GG  30, 38      11, 36      13, 7     
  1.73 (0.96–3.13)  0.0678  0.2132  1.04 (0.47–2.18)  0.9197  0.7484  6.1 (2.3–17.5)  0.0004  0.0034 
XRCC1_Gln399Arg_rs25487
GG  169, 257      32, 94      45, 45     
  1 (–)      0.78 (0.48–1.24)  0.2954  0.4886  2.28 (1.4–3.7)  0.0009  0.007 
AG  145, 247      36, 108      43, 45     
  0.89 (0.67–1.19)  0.4299  0.5817  0.74 (0.47–1.16)  0.1984  0.3932  2.16 (1.32–3.53)  0.0022  0.0152 
AA  49, 71      7, 25      18, 13     
  1.08 (0.71–1.64)  0.7276  0.7018  0.64 (0.25–1.48)  0.3272  0.5142  3.19 (1.49–7.01)  0.003  0.0203 
APEX1_rs3136817
TT  104, 151      42, 123      54, 57     
  1 (–)      0.81 (0.51–1.29)  0.3818  0.5526  2.36 (1.44–3.88)  0.0007  0.0056 
CT  63, 121      26, 81      45, 35     
  0.76 (0.5–1.15)  0.1921  0.387  0.76 (0.44–1.29)  0.3224  0.5105  2.98 (1.73– 5.19)  0.0001  0.0012 
CC  12, 34      7, 23      7, 11     
  0.54 (0.25–1.1)  0.0981  0.2671  0.76 (0.29–1.83)  0.564  0.6459  1.33 (0.46– 3.62)  0.5763  0.6508 
ERCC1_rs3212986
GG  194, 339      49, 132      62, 58     
  1 (–)      0.98 (0.65–1.45)  0.9071  0.7458  2.81 (1.82–4.35)  <0.001  <0.001 
GT  146, 202      25, 82      37, 42     
  1.27 (0.95–1.68)  0.1029  0.2743  0.79 (0.47–1.29)  0.3562  0.5353  2.31 (1.38–3.84)  0.0013  0.0097 
TT  23, 34      1, 13      7, 3     
  1.25 (0.7–2.2)  0.4423  0.5886  0.2 (0.01–1.01)  0.1188  0.2984  5.92 (1.59–28.18)  0.0118  0.0646 
MUTYH_rs3219489
CC  91, 157      35, 118      72, 55     
  1 (–)      0.83 (0.5–1.34)  0.445  0.5901  3.69 (2.29–6.01)  <0.001  <0.001 
GC  72, 126      31, 94      28, 42     
  0.95 (0.63–1.43)  0.7974  0.7206  0.91 (0.54–1.51)  0.7201  0.6996  1.93 (1.07–3.46)  0.0281  0.1166 
GG  16, 23      9, 15      6, 6     
  1.27 (0.61–2.62)  0.52  0.6271  1.93 (0.75–4.74)  0.1584  0.3505  2.16 (0.64–7.3)  0.2028  0.3973 
ERCC3_rs3738948
AA  112, 173      46, 139      59, 62     
  1 (–)      0.84 (0.54–1.3)  0.4379  0.5862  2.33 (1.46–3.74)  0.0004  0.0034 
GA  57, 119      24, 79      39, 35     
  0.79 (0.52–1.2)  0.2791  0.4744  0.83 (0.47–1.43)  0.5078  0.6216  3.17 (1.81–5.58)  0.0001  0.0012 
GG  10, 14      5, 9      8, 6     
  1.1 (0.44–2.65)  0.8375  0.7304  1.36 (0.4–4.17)  0.5948  0.658  3.5 (1.15–11.22)  0.0281  0.1166 
ERCC3_XPB_rs4150459
CC  162, 269      69, 202      98, 95     
  1 (–)      0.39 (0.13–0.99)  0.0684  0.2143  2.34 (0.82–6.72)  0.1082  0.282 
CT  17, 33      5, 24      8, 8     
  0.94 (0.48–1.78)  0.8539  0.7342  1.32 (0.05–33.83)  0.8467  0.7325  2.59 (1.89–3.55)  <0.001  <0.001 
TT  0, 2      1, 1      0, 0     
  –      2.9 (1.96–4.33)  <0.001  <0.001  –     
KLH4_rs5922437
GG  101, 172      49, 145      72, 74     
  1 (–)      0.88 (0.56–1.36)  0.5582  0.6436  2.59 (1.64–4.11)  <0.001  <0.001 
AA  26, 62      10, 62      27, 22     
  0.87 (0.5–1.5)  0.624  0.6687  0.48 (0.22–0.97)  0.0513  0.1788  3.02 (1.57–5.88)  0.001  0.0076 
GA  52, 72      16, 20      7, 7     
  0.73 (0.45–1.17)  0.1964  0.3912  1.34 (0.63–2.79)  0.439  0.5868  1.53 (0.49– 4.76)  0.4541  0.5949 
XRCC3_Thr241Met_rs861539
CC  142, 241      19, 87      41, 34     
  1 (–)      0.55 (0.31–0.94)  0.0355  0.1381  3.05 (1.81–5.2)  <0.001  <0.001 
TG  178, 243      43, 103      51, 53     
  1.32 (0.99–1.76)  0.0618  0.2015  1.12 (0.72–1.74)  0.6028  0.661  2.57 (1.61– 4.13)  0.0001  0.0012 
TT  43, 91      12, 37      14, 16     
  0.8 (0.52–1.22)  0.3042  0496  0.86 (0.41–1.69)  0.6658  0.6829  2.41 (1.1–5.22)  0.0258  0.1106 
*

The reference category for each gene analyzed is having the wild type and being never-smoker.

a

Adjusted by age, sex and indoor radon exposure.

b

p-Values.

c

Corrected p-values.

Table 4 shows the association of these polymorphisms with lung cancer broken down by radon concentration (≤200Bq/m3 and >200Bq/m3). NSCLC associations were increased for some variants for those participants exposed to more than 200Bq/m3. rs1452584 showed the highest association for the homozygous genotype (OR 3.04; 95% CI 1.15–8.48) as well as APEX1 (rs1130409) and ERRC1 (rs11615) showed a higher association too (OR 1.68; 95% CI 1.04–2.73 and OR 1.65; 95%CI 1.1–2.48 respectively). XRCC3 (rs861539), ERCC2 (rs13181), OGG1 (rs10521333) and ERRC1 (rs3212986) showed this increase for the heterozygous form (OR 1.79; 95%CI 1.28–2.51, OR 1.56; 95%CI 1.13–2.15, OR 1.53; 95%CI 1.09–2.16 and OR 1.47; 95%CI 1.06–2.04, OR 1.47; 95% CI 1.06–2.04 respectively). In addition, NBN (rs1805794) showed an increased association for its homozygous genotype for low indoor radon exposures (OR 1.88; CI 95% (1.09–3.24). No other significant association was observed.

Table 4.

Lung cancer association broken down by radon exposure for the different polymorphisms analyzed.*

Polymorphisms  Cases, controls; ORa (95%CI)
  Indoor radon exposure (Bq/m3)
  ≤200  pb  p-cc  >200  pb  p-cc 
ERCC5_rs1047768
TC  131, 208      89, 104     
  1 (–)      1.39 (0.94–2.04)  0.0972  0.2657 
CC  86, 146      64, 83     
  0.98 (0.68–1.41)  0.9136  0.7472  1.34 (0.88–2.05)  0.1737  0.3679 
TT  51, 86      25, 50     
  0.87 (0.55–1.34)  0.5236  0.6288  0.66 (0.37–1.16)  0.1506  0.3411 
OGG1_Ser326Cys_rs1052133
CC  231, 374      160, 203     
  1 (–)      1.27 (0.97–1.68)  0.0843  0.2444 
CG  117, 211      92, 96     
  0.87 (0.65–1.17)  0.3637  0.5405  1.53 (1.09–2.16)  0.0145  0.075 
GG  18, 42      11, 20     
  0.64 (0.35–1.15)  0.146  0.3355  0.78 (0.34–1.69)  0.5404  0.6361 
FATS_C10orf90_rs11245007
CT  134, 198      73, 103     
  1 (–)      1.03 (0.69–1.53)  0.8875  0.7416 
CC  118, 202      87, 109     
  0.82 (0.59–1.15)  0.2559  0.4529  1.14 (0.77–1.67)  0.515  0.6249 
TT  16, 41      18, 25     
  0.57 (0.29–1.08)  0.092  0.2574  1.22 (0.6–2.43)  0.5814  0.6528 
APEX1_rs1130409
GT  135, 206      73, 123     
  1 (–)      1 (0.68–1.47)  0.7598  0.7638 
TT  71, 125      54, 62     
  1.06 (0.71–1.56)  0.7868  0.7179  1.4 (0.89–2.22)  0.1458  0.3352 
GG  62, 110      51, 52     
  0.94 (0.63–1.42)  0.7834  0.717  1.68 (1.04–2.73)  0.0341  0.1341 
ERCC1_rs11615
CC  90, 159      63, 67     
  1 (–)      1.73 (1.1–2.59)  0.0155  0.0785 
CT  137, 261      111, 152     
  0.97 (0.69–1.38)  0.8823  0.7405  1.34 (0.92–1.94)  0.1257  0.3085 
TT  140, 208      90, 100     
  1.24 (0.87–1.77)  0.2274  0.4238  1.65 (1.1–2.48)  0.0158  0.0796 
OGG1_rs125701
GG  194, 331      134, 166     
  1 (–)      1.42 (1.04–1.94)  0.0294  0.1198 
AG  68, 101      35, 64     
  1.1 (0.75–1.6)  0.6224  0.6681  0.95 (0.59–1.53)  0.8417  0.7314 
AA  6, 8      9, 7     
  2.03 (0.63–6.25)  0.2185  0.4141  1.73 (0.6–5.12)  0.3085  0.4995 
RRM1_rs12806698
CC  156, 245      92, 143     
  1 (–)      1.05 (0.74–1.5)  0.7816  0.7166 
CA  97, 174      73, 78     
  0.87 (0.61–1.22)  0.4099  0.57  1.42 (0.94–2.14)  0.0934  0.257 
AA  15, 22      13, 16     
  1.02 (0.48–2.1)  0.9553  0.7555  1.24 (0.55–2.77)  0.6022  0.6608 
ERCC2_Lys751Gln_rs13181
TT  158, 283      114, 143     
  1 (–)      1.4 (1.01–1.94)  0.0428  0.1581 
GT  160, 275      121, 141     
  1.02 (0.77–1.36)  0.8886  0.7419  1.56 (1.13–2.15)  0.0074  0.0447 
GG  49, 70      29, 35     
  1.18 (0.77–1.81)  0.4376  0.586  1.35 (0.77–2.35)  0.2909  0.4848 
rs1452584
AA  162, 298      119, 167     
  1 (–)      1.27 (0.91–1.75)  0.1543  0.3456 
GA  92, 127      46, 62     
  1.23 (0.86–1.75)  0.2559  0.4529  1.35 (0.85–2.13)  0.2007  0.3954 
GG  14, 16      13, 8     
  1.19 (0.54–2.6)  0.6604  0.6811  3.04 (1.15–8.48)  0.0273  0.1146 
ERCC2_Asp312Asn_rs1799793
TT  153, 280      112, 139     
  1 (–)      1.52 (1.08–2.14)  0.0162  0.0809 
CT  101, 137      56, 87     
  1.47 (1.04–2.9)  0.0295  0.1201  1.31 (0.86–2.01)  0.2065  0.4008 
CC  14, 23      10, 11     
  1.2 (0.56–2.51)  0.6323  0.6716  1.32 (0.51–3.38)  0.5595  0.6441 
NBN_rs1805794
CC  112, 202      76, 111     
  1 (–)      1.12 (0.75–1.68)  0.565  0.6463 
GC  121, 199      81, 105     
  0.98 (0.69–1.39)  0.9223  0.7489  1.46 (0.98–2.18)  0.0658  0.2094 
GG  35, 40      21, 21     
  1.88 (1.09–3.24)  0.0231  0.1031  1.91 (0.94–3.88)  0.0724  0.2223 
OGG1_C7G_rs2072668
CC  165, 258      109, 147     
  1 (–)      1.18 (0.84–1.65)  0.3477  0.5293 
CG  88, 153      62, 75     
  0.88 (0.62–1.25)  0.4729  0.6047  1.28 (0.84–1.94)  0.25  0.4471 
GG  15, 28      7, 15     
  0.76 (0.38–1.51)  0.4483  0.5918  0.63 (0.22–1.66)  0.3646  0.5411 
ERCC5_rs2094258
CC  164, 284      117, 157     
  1 (–)      1.32 (0.95–1.84)  0.1021  0.2732 
CT  84, 131      55, 73     
  1.15 (0.8–1.64)  0.4523  0.594  1.32 (0.86–2.03)  0.2034  0.3979 
TT  20, 25      6, 7     
  1.18 (0.6–2.28)  0.6264  0.6695  1.16 (0.34–3.9)  0.8081  0.7233 
XPC_rs2228001
GT  135, 217      79, 115     
  1 (–)      1.15 (0.78–1.69)  0.4692  0.6028 
TT  99, 154      63, 80     
  1.04 (0.73–1.49)  0.8162  0.7253  1.31 (0.86–2)  0.2132  0.4081 
GG  34, 70      36, 41     
  0.72 (0.43–1.18)  0.1989  0.3936  1.25 (0.73–2.13)  0.4123  0.5715 
OGG1_rs2472037
AG  114, 211      88, 106     
  1 (–)      1.5 (1.01–2.22)  0.0438  0.1606 
AA  109, 165      66, 97     
  1.14 (0.8–1.62)  0.483  0.6097  1.15 (0.76–1.74)  0.5008  0.6183 
GG  44, 56      23, 33     
  1.44 (0.88–2.34)  0.1471  0.3368  1.64 (0.86–3.07)  0.126  0.3089 
XRCC1_Gln399Arg_rs25487
GG  165, 276      120, 140     
  1 (–)      1.36 (0.98–1.88)  0.0622  0.2023 
AG  151, 272      109, 146     
  0.91 (0.68–1.21)  0.5177  0.6261  1.31 (0.95–1.82)  0.1041  0.2761 
AA  51, 80      35, 33     
  1.07 (0.7–1.61)  0.7657  0.7124  1.7 (1–2.91)  0.0499  0.1756 
APEX1_rs3136817
TT  139, 232      99, 115     
  1 (–)      1.35 (0.94–1.95)  0.1062  0.2792 
CT  107, 158      65, 103     
  0.97 (0.68–1.33)  0.8541  0.7342  1 (0.66–1.49)  0.9874  0.7616 
CC  22, 51      14, 19     
  0.69 (0.38–1.21)  0.2077  0.4018  1.27 (0.57–2.78)  0.5455  0.6383 
ERCC1_rs3212986
GG  208, 373      152, 181     
  1 (–)      1.5 (1.12–1.99)  0.0057  0.0359 
GT  139, 219      98, 123     
  1.15 (0.86–1.52)  0.3395  0.5234  1.47 (1.06–2.04)  0.0214  0.098 
TT  20, 36      14, 15     
  1.08 (0.59–1.94)  0.7928  0.7194  1.77 (0.8–3.88)  0.1503  0.3408 
MUTYH_rs3219489
CC  141, 230      102, 121     
  1 (–)      1.37 (0.95–1.98)  0.0873  0.2496 
GC  100, 176      63, 105     
  0.91 (0.64–1.28)  0.5925  0.6571  1.08 (0.72–1.61)  0.7206  0.6998 
GG  26, 35      12, 10     
  1.49 (0.82–2.67)  0.1873  0.3822  1.68 (0.65–4.39)  0.2838  0.4786 
ERCC3_rs3738948
AA  160, 262      108, 144     
  1 (–)      1.19 (0.84–1.67)  0.3193  0.5081 
GA  92, 159      58, 83     
  0.97 (0.69–1.37)  0.872  0.7383  1.29 (0.84–1.96)  0.2395  0.4365 
GG  16, 20      12, 10     
  1.28 (0.61–2.62)  0.5096  0.6224  2 (0.79–5.18)  0.1441  0.3331 
ERCC3_XPB_rs4150459
CC  244, 399      162, 205     
  1 (–)      1.29 (0.97–1.71)  0.0762  0.2296 
CT  24, 38      15, 31     
  0.92 (0.51–1.61)  0.7645  0.712  0.83 (0.41–1.59)  0.5796  0.6521 
TT  0, 2      1, 1     
  --      1.69 (0.07–43.58)  0.714  0.6978 
KLH4_rs5922437
GG  170, 287      115, 135     
  1 (–)      1.5 (1.07–2.1)  0.019  0.0903 
AA  47, 96      36, 59     
  0.96 (0.62–1.46)  0.8355  0.7299  1.14 (0.69–1.88)  0.5947  0.658 
GA  51, 57      27, 43     
  1.16 (0.72–1.89)  0.5392  0.6356  0.82 (0.46–1.45)  0.4993  0.6176 
XRCC3_Thr241Met_rs861539
CC  132, 238      106, 136     
  1 (–)      1.41 (1–1.99)  0.052  0.1804 
TG  181, 283      125, 137     
  1.21 (0.9–1.63)  0.1983  0.3931  1.79 (1.28–2.51)  0.0008  0.0063 
TT  54, 107      32, 45     
  0.92 (0.61–1.37)  0.6708  0.6845  1.2 (0.71–2.02)  0.4967  0.6164 
*

The reference category for each gene analyzed is having the wild type and being exposed to a radon concentration <200Bq/m3.

a

Adjusted by age, sex and tobacco consumption.

b

p-Values.

c

Corrected p-values.

Discussion

We found that the association with lung cancer may be modulated by different genetic polymorphisms in the BER and NER pathways. These polymorphisms appear to have the most prominent effect when they are homozygous in heavy smokers. Some polymorphisms could also increase NSCLC association in those individuals exposed to high radon concentrations. To our knowledge, this is the study with the largest number of DNA repair genes analyzed involved in lung cancer related to radon exposure. It also provides potentially valuable data for further understanding of the carcinogenic pathway of tobacco consumption. The sample size of our study is large, with 2027 participants including smokers, never smokers and indoor radon exposure, and expands a previous study performed exclusively in never smokers.7

We have observed that participants considered heavy smokers, globally, had an increased association with lung cancer compared with the wild type in never smokers. The polymorphism most associated with NSCLC was rs125701 (OGG1) in its homozygous variant form. Attending to the study of Hualong Qin et al. this polymorphism is frequently methylated in NSCLC, but in that study no significant result was obtained. This could be due to the absence of homozygous participants for this gene. In contrast with our study, it was performed only in Chinese population.21 A relevant association was also observed for rs2472037 and rs3212986, both in the OGG1 gene, for its homozygous genotypes, increasing the association of lung cancer in heavy smokers. Regarding rs3212986, this polymorphism is considered an important contributor to lung cancer development in smokers.22,23 In addition, no relation with never smokers was detected by Tau Yu et al.23

The NBN gene variant (rs1805794), located in MMR pathway, was also associated with an increased association with lung cancer in heavy smokers in accordance with Chuang et al.,24 though they only found association in male smokers. The homozygous mutation of this gene in heavy smokers shows a higher lung cancer association compared to never smokers. These results are similar to the obtained by Charlotta et al.25 who found an increased lung cancer association in never smoking women and smoking women with low tobacco consumption. The increased lung cancer association shown in our study is similar to that reported by the Wang et al. meta-analyses.26 In contrast, He et al. did not find any similar association.27 This gene is known to take part in other carcinogenic procedures such as ovarian, breast and colorectal cancer. In addition, it has been studied for clinical purposes in the testing of hereditary cancers.28

In general, our results note that a number of genetic polymorphisms are associated with increased lung cancer association when these polymorphisms are homozygous. This was apparent for a number of the analyzed genes, especially those in the NER pathway. This could be attributable to the importance of this pathway in the repair of bulky DNA lesions generated by environmental mutagens.12 The gene which showed a clear increase in NSCLC, compared to the wild type in heavy smokers, belonging to this pathway is ERRC1 (rs3212986). OGG1 polymorphisms rs125701 and rs2472037 showed the same effect but they are located in the BER pathway, which is specialized in repairing adducts originated by oxidation.13 This is one of the main routes through which tobacco smoke produces DNA adducts.8,29 This is interesting because there seems to be no association when we analyze these polymorphisms in the overall sample. Nevertheless, when we stratify the sample by smoking categories, we observe that for heavy smokers an association is present for some homozygous polymorphisms, suggesting a saturation effect on the anticarcinogenic pathways compared to wild type genes.

In relation with indoor radon exposure, we observed that participants exposed to more than 200Bq/m3 showed an increased lung cancer association for some of the polymorphisms studied. Only three of them showed an increased lung cancer association for their homozygous genotype: rs1452584, located in chromosome 18, showed the highest association; ERCC1 (rs11615), located in NER pathway, which also showed an increased association for its wild type and APEX1 (rs1130409), located in BER pathway. The results obtained for ERCC1 are in accordance to the obtained by Lorenzo-González et al.8 though this study is limited to a never smoking population while ours includes also ever-smokers. Other polymorphisms showed higher association for their heterozygous genotype; one of them, located in the NER pathway, ERCC1 (rs3212986) showed similar results to those found by Lorenzo-Gonzalez et al.7

Despite the fact that some studies established a relationship between lung cancer association and DNA repair genes,22,30 we are not aware of any study relating these polymorphisms with indoor radon exposure. These findings support our hypothesis that lung cancer association is increased by indoor radon exposure and that some variants might have a special importance favouring the development of this disease.

This research has some limitations. The most important limitation is that when we correct the p-value with the false discovery rate, we observed that some “suggestive” p-values in different genes become “non-suggestive”, but it is important to resemble that a “non-suggestive” association cannot be deduced only by a p-value because it could be easily modified. For example, if we have a small number of participants in one category, we might have a “non-suggestive” p-value and a suggestive confidence interval. If we increase the number of participants in the category we could have a significant p-value while the width of the confidence interval narrows. Secondly, we did not have enough participants in some polymorphisms, which makes difficult to establish a potential association with lung cancer. One example is ERCC3 (rs4150459) that for its homozygous genotype for never-smokers did not have enough participants to obtain any result. Other limitations reside in the limited number of polymorphisms we have assessed. Not all polymorphisms present in the studied genes have been analyzed, and the BER and NER pathways have some more genes that we do not have analyzed. A further limitation is the fact that there are other pathways and genes involved in carcinogenesis that we do not have included and might have a role, such as deletion of GSTM1 and GSTT1 genes.31 Finally, the most frequent histological type was adenocarcinoma. This is due to the fact that we included an important amount of never-smokers from the LCRINS study (Lung Cancer Association in Never Smokers), where this histological type is the most frequent. Nevertheless, this fact favoured that we had the same percentage of cases of each sex (50% each), allowing for a better interpretation of the results both for men and women.

This study has also a number of advantages. First, the sample size is relatively large, and we have been able to include information regarding the second association factor of lung cancer, which is indoor radon exposure. This is of particular importance because there is a lack of information on the mechanisms of radon causing lung cancer. It is important to note that Galicia is a radon prone-area32,33 and the median time that cases and controls have been living at the same residence is high enough to induce lung cancer. Finally, the high participation rate and the multicentric nature of this research increase the external validity of its results.

In conclusion, these findings support that polymorphisms located in BER and NER pathways do not have an association with lung cancer onset, with the exception of the gene NBN (rs1805794). Nevertheless, this study support the hypothesis of their role modulating the effect of tobacco consumption, where heavy smokers might have their lung cancer association modulated by polymorphisms located in the BER and NER pathways. This could also happen for those individuals having high indoor radon exposures though at a minor extent.

Financial support

This work was funded by a competitive research grant offered by the Xunta de Galicia [10CSA2080057PR] “Risk factors of lung cancer in never smokers: a multicenter case–control study in the Northwest of Spain”, partially supported by the Instituto de Salud Carlos III [PI13/01765]. “Molecular genetic profile of DNA repair markers (BER and NER) and biological risk of lung cancer from residential radon exposure: A case–control study”, partially supported by Instituto de Salud Carlos III, Ministry of Science and Innovation of Spain [PI15/01211]. (Year 2015) and another from the same institution [PI031248] (Year 2012). “Residential Radon Exposure, Histologic Types, and Lung Cancer Risk. A Case–Control Study in Galicia, Spain”.

Conflict of interests

Dr. Kelsey is a founder and scientific advisor for Cellintec, which had no role in this research.

The authors declare no conflict of interests.

Acknowledgments

The genotyping service was accomplished at CEGEN-PRB3-ISCIII; it is supported by grant PT17/0019, of the PE I+D+I 2013–2016, funded by ISCIII and ERDF.

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This article is part of José Ramón Enjo-Barreiro doctoral thesis.

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