Department of Human Evolutionary Biology, Institute of Anthropology, Adam Mickiewicz University, Umultowska 89, 61-614 Poznan, Poland. Abnormalities in ...
Gene-gene association in cervical squamous cell carcinoma (CSCC) Polish population - preliminary studies 11
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Edyta Pawlak-Adamska , Magdalena Bartosiñska , Lidia Karabon , Iwona Wlodarska-Polinska , Barbara Izmaj³owicz , Oskar 44 33 33 33 33 11 Nowak , Agnieszka Ignatowicz-Pacyna , Jan Kornafel , Marcin Stepieñ , Rafa³ Matkowski , Irena Frydecka 1
Laboratory of Immunopathology, Department of Experimental Therapy, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigl 12, 53-114 Wroclaw, Poland 2 Euromedic Oncotherapy Walbrzych Poland, Sokolowskiego 4, 58-309 Walbrzych, Poland 3 Department of Oncology and Gynecological Oncology Clinic, Medical University, Wroclaw, Poland 4 Department of Human Evolutionary Biology, Institute of Anthropology, Adam Mickiewicz University, Umultowska 89, 61-614 Poznan, Poland
Introduction: Abnormalities in DNA repair system and regulation of tumorigenesis, inflammation, adipocyte differentiation and glucose homeostasis are one of the crucial factors implicated in carcinogenesis. Studies on the polymorphic variability within genes encoding molecule critical in those pathways may indicate whether a specific genetic variants are linked to cancer susceptibility and/or clinical outcome by affecting the function of their protein products.
Table 1. Combined effects of all studied genetic marker on the development of CSCC.
Purpose: The main aim of our research was to assessed the gene-gene interaction between selected 13 SNPs located within two DNA repair genes: ERCC4 (chromosome 16p13.12) and XRCC3 (chromosome 14q32.33), and a member of nuclear hormone receptor superfamily - peroxisome proliferator-activated receptor-ã (PPARã) (chromosome 3p25.2) (Fig. 1.) In cervical squamous cell carcinoma (CSCC). Fig. 1. Cytogenetic localisation of ERCC4, XRCC3 and PPARã gene in human.
Odds Ratio
95% C.I.
Coefficient
S. E.
Z-Statistic
p
ERCC4rs3136176[TT]
3.0729
1.0420 - 9.0621
1.1226
0.5518
2.0346
0.0419
ERCC4rs1799798[GA+AA]
1.6167
0.8813 - 2.9659
0.4804
0.3096
1.5517
0.1207
XRCC3rs3212079[AA+GA]
5.3323
2.1465 - 13.2465
1.6738
0.4643
3.6052
0.0003
XRCC3rs3212102[CC]
1.5688
0.6058 - 4.0625
0.4503
0.4855
0.9276
0.3536
XRCC3rs861534[TT]
0.8160
0.4109 - 1.6207
-0.2033
0.3501
-0.5808
0.5614
XRCC3rs861537[CC+CT]
0.7608
0.3220 - 1.7975
-0.2734
0.4387
-0.6233
0.5331
XRCC3rs709399[GG]
3.1766
1.1232 - 8.9844
1.1558
0.5305
2.1789
0.0293
XRCC3rs12432907[TT+CT]
1.3854
0.6009 - 3.1942
0.3260
0.4262
0.7649
0.4444
XRCC3rs1799796[TT]
1.1069
0.5843 2.0967 -
0.1016
0.3259
0.3116
0.7553
PPARã2Pro12Ala[GG+CG]
2.3056
1.1287 - 4.7096
0.8353
0.3644
2.2923
0.0219
PPARãVal290Met[AA+GA]
3.5744
0.1126 - 113.4709 -
1.2738
1.7642
0.7220
0.4703
PPARãPhe380Leu[TT+CT]
0.1078
0.0053 - 2.2105
-2.2271
1.5410
-1.4452
0.1484
PPARãHis449His[AA+TA]
0.5456
0.2835 - 1.0498
-0.6059
0.3339
-1.8145
0.0696
-0.9034
0.5102
-1.7705
0.0767
Test
Statistic
df
p
Score
34.7546
13
0.0009
Likelihood Ratio
38.4656
13
0.0002
CONSTANT Convergence Iterations
ERCC4 gene
Final -2*Log-Likelihood
XRCC3 gene
PPARã gene
4 348.2783 Odds Ratio
95% C.I.
Coefficient
S. E.
Z-Statistic
p
ERCC4rs3136176[TT]
2.8906
1.0362 - 8.0640
1.0615
0.5234
2.0279
0.0426
XRCC3rs3212079[AA+GA]
4.1331
1.7902 - 9.5423
1.4190
0.4269
0.0009
XRCC3rs709399[GG]
2.7987
1.0980 - 7.1338
1.0291
0.4774
3.3241 2.1557
PPARã2Pro12Ala[GG+CG]
2.1518
1.0680 - 4.3354
0.7663
0.3574
2.1439
0.0320
PPARãHis449His[AA+TA]
0.5067
0.2671 - 0.9612
-0.6799
0.3267
-2.0811
0.0374
-0.3212
0.1647
-1.9503
0.0511
Test
Statistic
df
p
Score
29.7712
5
0.0000
Likelihood Ratio
32.2242
5
0.0000
CONSTANT Convergence Iterations
Materials and methods:
Converged
Final -2*Log-Likelihood Cases included
Converged 4 355.9239
0.0311
280
In population-based/case-control association study in 280 Polish Caucasian women, including 139 CSCC patients, two ERCC4tagSNPs (rs3136176, rs1799798), seven XRCC3tagSNPs (rs3212079, rs3212102, rs861534, rs861537, rs709399, rs12432907, rs1799796) and four functional PPARã SNPs: Val290Met (rs72551362), His449His (rs3856806), Phe380Leu (rs72551363) and Pro12Ala (rs1801282) were studied. Combined effects of all studied genetic marker on the development of CSCC as well as on remission achievement were TM analyzed by multivariate logistic regression analysis employing a quasi-Newton estimation method (Epi Info 7.1.1.14).
Results: The combined gene-gene association analysis pointed that four of studies polymorphism were independent CSCC risk factors (Table 1). The most pronounced association was observed for XRCC3rs3212079 marker, which 4.13-fold increased risk of CSCC (p= 0.0009) (Table 1). Weaker association were observed for PPARã2Pro12Ala (rs1801282) and ERCC4rs3136176 markers (p= 0.03, OR= 2.15, and p= 0.04, OR= 2.89, respectively) (Table 1). Contrary, PPARãHis449His (rs3856806) polymorphism was the independent CSCC-protection factor (p= 0.04, OR= 0.51) (Table 1).
Conclusions:
Altogether, this indicate a significant role of polymorphic variation of selected genes: ERCC4, XRCC3 and PPAR PPARãã in the pathogenesis CSCC.
