Aim of this article is to investigate the association between the genotypes of the XRCC1-Arg399Gln (rs25487) and ERCC4-Arg415Gln (rs1800067) polymorphisms and smoking- and drinking-related larynx cancer in a Polish population

Blasiak, J.

Gajecka, M.

Kaczmarczyk, D.

Kasznicki, J.

Kiwerska, K.

Krupa, R.

Morawiec-Sztandera, A.

Olszewski, J.

Rydzanicz, M.

Szyfter, K.

Experimental Oncology

Наукова електронна бібліотека періодичних видань НАН України (Vernadsky National Library of Ukraine)

Experimental Oncology ��� ������ ���� ��arc�� ��POLYMORPHISMS OF THE DNA REPAIR GENES XRCC1 AND ERCC4 ARE NOT ASSOCIATED WITH SMOKING- AND DRINKING-DEPENDENT LARYNX CANCER IN A POLISH POPULATIONR. Krupa1, J. Kasznicki2, M. Gajęcka3, M. Rydzanicz3, K. Kiwerska3, D. Kaczmarczyk4, J. Olszewski5, K. Szyfter3,6, J. Blasiak1,*, A. Morawiec-Sztandera41Department of Molecular Genetics, University of Lodz, Lodz 90-236, Poland2Department of Internal Medicine, Diabetology and Clinical Pharmacology, Medical University of Lodz, Lodz 90-419, Poland3Institute of Human Genetics, Polish Academy of Sciences, Poznan 60-479, Poland4Department of Head and Neck Cancer, Medical University of Lodz, Lodz 90-419, Poland5Department of Otolaryngology, Medical University of Lodz, Lodz 90-419, Poland6Department of Otolaryngology, Medical University of Poznan, Poznan 61-701, PolandBackground: Tobacco smoking and alcohol drinking generate oxidative DNA damage and may contribute to larynx carcinogenesis. The X-ray repair cross complementing 1 (XRCC1) and excision repair cross-complementing rodent repair deficiency, complementa-tion group 4 (ERCC4(XPF)) genes are important components of DNA excision repair systems, which repair DNA damage induced by various factors, including tobacco smoking and alcohol. Aim: To investigate the association between the genotypes of the XRCC1-Arg399Gln (rs25487) and ERCC4-Arg415Gln (rs1800067) polymorphisms and smoking- and drinking-related larynx cancer in a Polish population. Methods: The polymorphisms were determined by PCR-RFLP method in 253 patients with squamous cell carcinoma of the larynx and 253 sex- and age-matched controls. Results: We did not find any association between the investigated polymorphisms and larynx carcinoma, dependent on either smoking or drinking status. No association was found between these polymorphisms and larynx cancer grade, stage or age at diagnosis. Conclusions: The results indicated that Arg399Gln polymorphism of XRCC1 gene and Arg-415Gln polymorphism of ERCC4 gene may not be associated with smoking- and drinking-related larynx cancer in Polish population.Key Words: smoking, alcohol consumption, XRCC1, ERCC4, larynx cancer, gene polymorphism.Tobacco smoking and alco�ol exposure are well known risk factors in t�e development of squamous cell carcinoma of t�e larynx. It was suggested t�at single nucleotide polymorp�isms �SNPs� in t�e DNA repair genes may alter t�e ability of cells to repair damaged DNA� and initiate malignant transformation. X-ray repair cross-complementing � �XRCC1� gene coding for t�e XRCC�� one of a key protein of base excision repair �BER� pat�way. Excision repair cross-complementing rodent repair deficiency� complementation group 4 �ERCC4/XPF) gene coding for t�e ERCC4/XPF protein one of es-sential parts of nucleotide excision repair �NER� pat�way. A G → A substitution at �8��� of t�e XRCC1 gene� exon ��� producing an Arg to Gln c�ange in codon �99 �t�e Arg�99Gln polymorp�ism� �as been linked to slig�tly �marginally statistically significant� increased risk of la-ryngeal carcinoma among Caucasians [�]. T�e ERCC4/XPF G��44A polymorp�ism is a G-to-A c�ange in t�e exon 8 �Arg4��Gln� rs�8����7� t�at results in a c�ange from arginine to glutamine at 4�� codon. T�is polymor-p�ism �as been reported to be associated wit� an in-creased risk for breast cancer [�].In t�is paper� we �ave used a �ospital-based case-control study in Poland to assess t�e potential association of t�e XRCC1-Arg�99Gln and ERCC4-Arg4��Gln SNPs wit� t�e development and clinical pat�ological parameters of larynx cancer.Patients. Blood samples were obtained from ��� pa-tients: �94 men and �9 women wit� larynx cancer �squa-mous cell carcinoma� treated in t�e Department of Head and Neck Cancer� �edical University of Lodz� Lodz� Poland and Department of Otolaryngology� �edical University of Poznan� Poznan� Poland in ��������9 and ��� cancer-free age and sex matc�ed controls. T�e patients ranged in age from 48 to 8� years �median age �� years�. Grade of differentiation �G� was evaluated in all cases �according to World Healt� Organization criteria�. T�ere were ��8 cases of � grade� ��4 cases of  � grade and �� of � grade in total. According to TN� staging t�ere were �� cases of stage I� �� cases of stage II� ��� cases of stage III� 4� cases of stage IVA and � of stage IVB. T�e study was approved by Et�ic Committee of �edical University of Lodz and �edical University of Poznan� and eac� patient gave a written consent.DNA isolation. Perip�eral blood lymp�ocytes �PBLs� were isolated by centrifugation in a density gradient of Histopaque-��77 ��� min� �8�g�. T�e pellet containing PBLs was resuspended in Tris-EDTA buffer� pH 8� to give about ��� x��� cells/ml. Genomic DNA was extracted from PBLs by p�enol/c�loroform extrac-Received: January 11, 2011. *Correspondence: Fax: +48426354484  E-mail: jblasiak@biol.uni.lodz.pl Abbreviations used: BER – base excision repair;  ERCC4 (XPF)  – excision repair cross-complementing rodent repair deficiency, complementation group 4 gene; NER – nucleotide excision repair; OR – odds ratio; PBLs – peripheral blood lymphocytes; PCR – RFLP – polymerase chain reaction - restriction fragment length polymorphism; SNPs – single nucleotide polymorphisms; XRCC1 – the X-ray repair cross complementing 1 gene.Exp Oncol ������� �� ������� Experimental Oncology ��� ������ ���� ��arc��tion and proteinase K digestion. T�e final samples were kept in Tris-EDTA buffer� pH 8� at ���  °C until use.Genotype determination. T�e PCR — restriction fragment lengt� polymorp�ism met�od �PCR � RFLP� was used to detect t�e genotypes of t�e Arg�99Gln polymorp�ism of XRCC1 gene and t�e Arg4��Gln poly-morp�ism of ERCC4 gene as described previously [�� 4]. Data analysis. For eac� genotype� deviation of t�e frequencies in t�e controls from t�ose expected under Hardy — Weinberg equilibrium was assessed using t�e standard χ�-test. Genotype frequencies in cases and controls were compared by χ�  or Fis�er’s exact tests. T�e genotype-specific risks were estimated as odds ratios �ORs� by unconditional logistic regression. Wild type Arg/Arg genotype was used as t�e reference. Because of small number of Gln/Gln variant genotypes of bot� polymorp�isms odds ratios were calculated for Gln allele carriers �Arg/Gln + Gln/Gln genotypes� p-values < �.�� were considered to be significant.All statistical analyses were performed wit� Sigma-Stat� ver. 8.� �Systat Software Inc� San Jose� CA� USA�.We s�owed previously t�at �eavy alco�ol drinking and tobacco smoking increased significantly t�e risk of laryn-geal carcinoma independently of any genetic variation �OR = �8; p < �.���� for smoking and drinking �eavily� [�]. Tobacco smoke contains many kinds of carcinogens t�at can cause DNA lesions� and variations in repair of to-bacco carcinogen-induced DNA lesions may contribute to t�e variation in susceptibility to cancer [�]. It was suggested t�at SNP at codon �99 of t�e XRCC1 gene may alter t�e ability of XRCC1 to repair damaged DNA [7]. It was also s�own t�at t�e �99Gln �o-mozygote genotype was associated wit� increased levels of bulky-DNA adducts in leucocytes of non-smokers [8].From t�e PCR analysis� ��� larynx cancer patients and ��� controls were divided into t�ree genotypes: Arg/Arg� Arg/Gln and Gln/Gln for bot� gene polymor-p�isms. Distributions of genotypes did not differ sig-nificantly from t�ose predicted by t�e Hardy-Weinberg equilibrium. T�ere were no significant differences in t�e frequencies of bot� polymorp�isms genotypes between patients and controls �p > �.���. Additionally� odds ratio analysis did not s�ow any relation between t�is polymorp�isms and larynx cancer �data not s�own�.All ��� larynx cancer cases were stratified by grade of differentiation and stage of disease. Grades � and � were grouped toget�er for t�e purposes of statistical analysis. T�ere were no significant differences between distributions of genotypes in subgroups assigned to �is-tological grades and TN� stages �data not s�own�.To c�eck w�et�er DNA repair gene polymorp�isms were associated wit� tobacco smoking� participants were categorized into groups according to smoking �abits �Table�. T�ere were no significant differences inside t�ese groups in t�e Arg�99Gln and Arg4��Gln polymorp�isms genotypes distribution �p > �.���. Ad-ditionally� we did not find any association of investigated polymorp�isms and drinking status �Table�. We did not find any association of drinking and smoking status and laryngeal cancer for carriers of bot� variant genotypes of XRCC1 and ERCC4 genes �data not s�own�.Our results indicated t�at Arg�99Gln polymor-p�ism of XRCC1 gene and Arg4��Gln polymorp�ism of ERCC4 gene may not be associated wit� smoking- and drinking-related larynx cancer in Polis� population.ACKNOWLEDGEMENTST�is work was supported by t�e grants N4�� �9�� �� from t�e �inistry of Science and Hig�er  Education and ���/�7� from t�e University of Lodz� Poland. REFERENCES1. Yang Y, Tian H, Zhang ZJ. Association of the XRCC1 and hOGG1 polymorphisms with the risk of laryngeal carci-noma. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2008; 25: 211–3 (In Chinese).2.  Smith TR, Levine EA, Perrier ND, et al. DNA-repair genetic polymorphisms and breast cancer risk. Cancer Epide-miol Biomarkers Prev 2003; 12: 1200–4.3. Romanowicz-Makowska H, Smolarz B, Kulig A. Poly-morphisms in XRCC1 and ERCC4/XPF DNA repair genes and associations with breast cancer risk in women. Pol Merkur Lekarski 2007; 22: 200–3 (In Polish).4. Krupa R, Blasiak J. An association of polymorphism of DNA repair genes XRCC1 and XRCC3 with colorectal cancer. J Exp Clin Cancer Res 2004; 23: 285–94.5. Pawlowska E, Janik-Papis K, Rydzanicz M, et al. The Cys326 allele of the 8-oxoguanine DNA N-glycosylase 1 gene as a risk factor in smoking- and drinking-associated larynx cancer. Tohoku J Exp Med 2009; 219: 269–75.6. Friedberg EC. DNA damage and repair. Nature 2003; 421: 436–40.7. Duell EJ, Wiencke JK, Cheng TJ, et al. Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood monounclear cells. Carci-nogenesis 2000; 21: 965–71. 8. Matullo G, Palli D, Peluso M, et al. XRCC1, XRCC3, XPD gene polymorphisms, smoking and 32P-DNA adducts in a sample of healthy subjects. Carcinogenesis 2001; 22: 1437–45.Copyright © Experimental Oncology, 2011Table. Genotype distribution and odds ratio (OR) for Arg399Gln polymorphism of XRCC1 gene and Arg415Gln polymorphism of ERCC4 gene for  laryngeal cancer patients and controlsArg399Gln - XRCC1, number of patients/controls Arg415Gln - ERCC4 number of patients/controlsArg/Arg Arg/Gln Gln/Gln ORa /p Arg/Arg Arg/Gln Gln/Gln ORa /psmokersnever 12/50 12/56 8/17 1.23/0.30 29/106 2/17 1/0 1.13/0.69ever 33/30 46/33 22/13 0.83/0.30 88/70 11/6 2/0 1.07/0.80moderate 17/12 17/15 7/4 0.81/0.30 37/28 4/3 0/0 1.06/0.85heavy 31/13 36/9 12/1 0.76/0.19 67/20 9/3 3/0 0.98/0.95drinkersnever 24/45 26/50 10/17 1.32/0.17 55/99 4/13 1/0 1.05/0.88moderate 54/51 62/55 34/15 0.83/0.30 130/108 16/13 4/0 1.03/0.77heavy 15/9 23/8 5/3 0.81/0.30 36/17 6/3 1/0 1.09/0.79Note: a — odds ratio adjusted with age and sex; odds ratio calculated for Arg/Gln + Gln/Gln genotype carriers, Arg/Arg genotype served as the reference (OR = 1.00).

Polymorphisms of the DNA repair genes XRCC1 and ERCC4 are not associated with smoking- and drinking-dependent larynx cancer in a polish population

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Polymorphisms of the DNA repair genes XRCC1 and ERCC4 are not associated with smoking- and drinking-dependent larynx cancer in a polish population

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