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Hindawi Journal of Oncology Volume 2019, Article ID 2976373, 8 pages https://doi.org/10.1155/2019/2976373 Research Article RAD51 and XRCC3 Polymorphisms Are Associated with Increased Risk of Prostate Cancer 1 1 1 1 Maria Nowacka-Zawisza , Agata Raszkiewicz, Tomasz Kwasiborski, Ewa Forma, 1 2 1 Magdalena BryV, Waldemar RóhaNski, and Wanda M. Krajewska Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland Department of Urology 2, Faculty of Biomedical Sciences and Postgraduate Training, Medical University of Lodz, Lodz, Poland Correspondence should be addressed to Maria Nowacka-Zawisza; email@example.com Received 21 January 2019; Revised 14 March 2019; Accepted 31 March 2019; Published 2 May 2019 Guest Editor: Zhihua Kang Copyright © 2019 Maria Nowacka-Zawisza et al. is Th is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Genetic polymorphisms in DNA repair genes may aeff ct DNA repair efficiency and may contribute to the risk of developing cancer. The aim of our study was to investigate single nucleotide polymorphisms (SNPs) in RAD51 (rs2619679, rs2928140, and rs5030789) and XRCC3 (rs1799796) involved in DNA double-strand break repair and their relationship to prostate cancer. eTh study group included 99 men diagnosed with prostate cancer and 205 cancer-free controls. SNP genotyping was performed using the PCR-RFLP method. A significant association was detected between RAD51 rs5030789 polymorphism and XRCC3 rs1799796 polymorphism and an increased risk of prostate cancer. Our results indicate that RAD51 and XRCC3 polymorphism may contribute to prostate cancer. 1. Introduction benign conditions such as inflammation and benign prostatic hypertrophy and procedures such as bladder catheteriza- Prostate cancer is the second most commonly occurring tion, transrectal ultrasound, gland biopsy, cystoscopy, and cancer and the fifth leading cause of cancer death in men with transurethral endoscopy. The search for markers other than an estimated 1.3 million new cases and 359.000 associated PSA, allowing for early diagnosis and prognosis of prostate deaths worldwide in 2018. It is the most frequently diagnosed cancer, seems to be justified [3, 4]. The factors associated with cancer among men in over one-half of the countries of the an increased risk of prostate cancer include family burden, world [1, 2]. Prostate cancer is characterized by the highest race, ethnicity, obesity, high fat diet, smoking, and exposure dynamic of increase in the last decade, and in 2016, for to androgens . Germline and somatic mutations appeared the rs fi t time, it became the most common cancer among to be well-established risk factors for primary and metastaic men in Poland . This cancer is very rarely manifested prostate cancer. In addition, genome-wide association studies before the age of 50, and more than half of patients at the (GWAS) have identified approximately 170 SNPs associated time of diagnosis are at least 70 years old. Age-adjusted with the development of prostate cancer. Pathogenic variants incidence rates of prostate cancer increased dramatically of high and moderate penetrance genes, such as BRCA1 and this is largely because of the increased availability of and BRCA2, mismatch repair genes, and HOXB13 confer screening for specific prostate antigen (PSA) in men without modest to high lifetime risk of prostate cancer. Some, such symptoms of the desease. PSA screening offers a potential as BRCA2, have emerging clinical relevance in the treatment benefit of reducing the chance of death from prostate cancer. and screening for prostate cancer [5–8]. However, the value of PSA screening is moderate. An increase The process of tumorigenesis occurs in the absence of in PSA over 4 ng/ml suggests cancer, but nearly 25% of efficient DNA repair systems and this may, among others, men with elevated levels of PSA do not have cancer, and result from genetic variations in the genes involved in nearly 20% of patients with prostate cancer have normal them. The most deleterious form of DNA damage is the serum PSA. Elevated PSA levels may be also associated with double-strand break (DSB). In order to maintain genomic 2 Journal of Oncology stability, double-strand breaks must be repaired by homol- Table 1: Clinicopathological characteristics of studied material. ogous recombination (HR) or nonhomologous end join- Parameter ing (NHEJ). Germline and somatic mutations in genes Control group (n=205) that promote homology-directed repair, especially BRCA1 Age and BRCA2, are frequently observed in several cancers, in particular, breast and ovary, but also prostate and other Range 43 - 84 cancers. The critical biochemical function of BRCA2 in Mean± SD 63.33± 9.28 homology-directed repair is to promote RAD51 la fi ment Median 64 assembly onto ssDNA that arises from end resection. BRCA2 PSAT (ng/ml) directly interacts with RAD51 at multiple sites to facilitate Range 0.004 – 3.94 RAD51 lfi ament assembly. BRCA2 is shown to regulate both Mean± SD 1.09± 0.88 the intracellular localization and DNA-binding ability of Median 0.95 RAD51. Loss of these controls may be a key event leading Patients with prostate cancer (n=99) to genomic instability and tumorigenesis [9, 10]. The human Age RAD51, located on chromosome 15q15.1, plays a crucial Range 49 - 85 role in DNA double-strand break repair . The protein encoded by this gene is a member of RAD51 protein family. Mean± SD 70.38± 8.63 RAD51 family members are highly similar to bacterial RecA Median 71 and Saccharomyces cerevisiae Rad51 and are known to be PSAT (ng/ml) involved in the homologous recombination and repair of Range 4.01 – 1489.00 DNA. RAD51 binds to single- and double-stranded DNA and Mean± SD 59.17± 184.59 exhibits DNA-dependent ATPase activity. RAD51 catalyzes Median 9.22 the recognition of homology and strand exchange between Free/total PSA (F/T PSA) homologous DNA partners to form a joint molecule between Range 0.04-0.79 a processed DNA break and the repair template. RAD51 Mean± SD 0.19±0.15 binds to single-stranded DNA in an ATP-dependent manner to form nucleoprotein la fi ments which are essential for Median 0.16 the homology search and strand exchange. RAD51 plays a < 0.16 48 role in regulating mitochondrial DNA copy number under ≥ 0.16 51 conditions of oxidative stress in the presence of RAD51C and PSA Density (PSAD, ng/ml) XRCC3 and is also involved in interstrand cross-link repair. Range 0.07-56.4 At the site of DNA damage nuclear foci containing BRCA1, Mean± SD 2.57±8.44 BRCA2, and RAD51, together with other proteins engaged Median 0.28 in homologous recombination, are forming. The protein that < 0.28 49 binds to RAD51 is XRCC3. This combination facilitates for- ≥ 0.28 50 mation of the nucleoprotein lfi ament that represents primary Prostate volume (ml) vector for both homologous and heterologous recombination [12–16]. Range 20.7-191 As we have previously shown the rs1801320 polymor- Mean± SD 59.5±39.0 phism in RAD51 may contribute to prostate cancer suscepti- Median 48.2 bility in Poland . The purpose of the presented work was to < 48 46 investigate further selected single nucleotide polymorphisms ≥ 48 53 (SNPs), i.e., rs2619679, rs2928140, and rs5030789 in RAD51 Gleason score and rs1799796 in RAD51 paralog XRCC3 and their relation- <728 ship to prostate cancer. ≥771 Cancer stage 2. Material and Methods T1-T2 58 2.1. Patients. The study group included 99 men with prostate T3-T4 41 adenocarcinoma and 205 sex- and age-matched cancer-free subjects with low (<4 ng/ml) levels of PSA as a control group. Peripheral blood samples from the patients with prostate 2.2. DNA Isolation. DNA from peripheral blood was isolated adenocarcinoma were obtained from the Department of by phenol extraction  or using AxyPrep Blood Genomic Urology 2, Medical University of Lodz, Poland. Peripheral DNA Miniprep Kit (Axygen Biosciences) and stored in - blood samples from the control group were obtained from 70 C. DNA preparations were subjected to spectrophotomet- the Urological Department of the Provincial M. Sklodowska- ric analysis (Biophotometer Eppendorf AG, Germany) by Curie Hospital in Zgierz, Poland. Table 1 presents clini- measuring absorbance at 260 nm and 280 nm to determine copathological characteristics of patients and the control the quantity and quality of the isolated nucleic acid. The group. A260/A280 ratio was in the range 1.8-2.1. Journal of Oncology 3 Table 2: Polymorphic sites in RAD51 and XRCC3 (according to NCBI). Gene SNP Other names Chromosome SNP position g.3879T>A rs2619679 15: 40694039 Promoter c.-1285T>A g.7995G>C, RAD51 rs2928140 15: 40698155 Intron 1 c.-2-602G>C g.3997A>G, rs5030789 15: 40694157 Promoter c.-1167A>G g.20897A>G XRCC3 rs1799796 14: 103699590 Intron 7 c.562A>G 2.3. Genotyping. Single nucleotide polymorphism (SNP) ratio (OR) together with a 95% confidence interval. All was determined by PCR-RFLP (polymerase chain reaction- results were considered statistically significant at p values restriction fragment length polymorphism). Tested SNPs are <0.05. Statistical calculations were made using spreadsheets shown in the Table 2. available on the websites: quantpsy.org/chisq/chisq.htm and The primers for studied SNPs were as follows: (F) 5 - vassarstats.net/odds2x2.html. CCGTGCAGGCCTTATATGAT-3 and (R) 5 -AGATAA- ACCTGGCCAACGTG-3 for rs2619679; (F) 5 -GCTTCT- 3. Results GGCTATTTTCAAGT-3 and (R) 5 -TGAGGCAGGTAA- Table 3 presents results of studied polymorphisms in RAD51 ATGGCTTC-3 for rs2928140; (F) 5 -CCGTGCAGGCCT- and XRCC3 using the PCR-RFLP method. The distribution TATATGAT-3 and (R) 5 -AGATAAACCTGGCCAACG- TG-3 for rs5030789; (F) 5 -CCGCATCCTGGCTAAAAA- of genotypes and alleles in the control group and in patients with prostate cancer was consistent with Hardy-Weinberg law TA-3 and (R) 5 -CAGAGTATGGGCACTGTGAGC-3 for (p>0.05). Statistically signica fi nt differences were found in rs1799796. The primers were synthesized at Sigma-Aldrich . The polymerase chain reaction (PCR) was performed in an the distribution of genotypes and alleles for rs5030789 and rs1799796 polymorphism in RAD51 and XRCC3, respectively, Applied Biosystems 2720 thermocycler in total volume of 10 𝜇 l. The reaction mixture contained 10 ng of genomic DNA; between control group and prostate cancer patients. The odds ratio (OR) analysis showed that rs5030789 poly- 0.2𝜇 moles of primers (F) and (R); 3 HOT FIREPol units of morphism in RAD51 and rs1799796 polymorphism in XRCC3 DNA polymerase (5 U/ml); 1 mM GeneAmp dNTPmix (10 mM); 2.5 mM magnesium chloride (25 mM); and 1 x Solis are associated with susceptibility to prostate cancer (Table 4). The presence of the GG genotype in both polymorphic sites of BioDyne buffer B1 (10x concentrated). The components of the RAD51 and XRCC3 increases the risk of prostate cancer (OR PCR reaction mixture were from Solis BioDyne (Estonia) and Applied Biosystem (USA). =2.782, p = 0.038 for rs5030789; OR = 1.986, p = 0.041 for rs1799796). Also, the presence of the G allele increases the risk The temperature-time prole fi of PCR was as follows: Pre- ∘ ∘ ∘ of developing prostate cancer in both above polymorphisms PCR: 95 Cfor 12 min; PCR(30 cycles): 95 C for 0.5 min, 63 C ∘ ∘ (OR = 1.571 for rs5030789 and OR = 1.441 for rs1799796, (rs2928140) or 64 C (for rs2619679 and rs1799796) or 65 C ∘ ∘ p<0.05). (rs5030789) for 0.5 min, 72 Cfor 1min;Post-PCR at 72 Cfor 5min. Because the polymorphism rs5030789 in RAD51 and polymorphism rs1799796 in XRCC3 increase the risk of The amplification products were digested with restric- prostate cancer, the correlation of these polymorphisms with tion enzymes: Hinf I (rs2619679), EarI (rs2928140), NlaIII (rs5030789), or AluI (rs1799796)at 37 Cfor 16hours. Enzyme age and clinicopathological characteristcs of prostate cancer ∘ ∘ patients was examined (Table 5). It was revealed that there is inactivation lasted 20 minutes at 65 Cfor EarIand at 80 C a relationship between rs1799796 polymorphism in XRCC3 for Hinf I, NlaIII, and AluI. The enzymes came from New England BioLabs Inc. DNA fragments were separated in a and the age of patients over 71 years (OR = 1.916, p = 0.033) and Gleason score of cancer equal to or higher than 7 (OR = 3% agarose gel with ethidium bromide for UV visualization. Electrophoresis was performed in 1x TBE bueff r (10x TBE: 89 2.373, p = 0.012). No association was found with the level of PSAT, nor with rs5030789 in RAD51 nor rs1799796 in XRCC3. mM Tris, 89 mM boric acid, 2 M EDTA pH 8.0) and 100V. Examples of the obtained restriction patterns are shown in Figure 1. 4. Discussion 2.4. Statistical Analysis. The compatibility of the genotype Prostate specific antigen (PSA) is a blood-based biomarker distribution with the Hardy-Weinberg law in the con- used for the detection and surveillance of prostate cancer. trol group and in study group was checked by the 𝜒 However, PSA levels can also be aec ff ted by benign pro- test. Significance of differences between the distribution static hyperplasia (BPH), local inflammation or infection, of genotypes/alleles in the control and study group was prostate volume, age, and genetic factors. In this regard, assessed by the 𝜒 test. The risk of comorbidity of geno- PSA seems to be an organ but not cancer specific biomarker types/alleles with the disease was assessed based on odds . Seeking the molecular mechanisms underlying prostate 4 Journal of Oncology Marker AA AA TA TT Marker CC GC GG 286 bp 332 bp 114 and 116 (a) (b) Marker AG GG AG AA Marker AA AG AG GG 300 303 bp 203 bp 100 100 (c) (d) Figure 1: PCR-RFLP genotyping of (a) RAD51 rs2619679 polymorphism; (b) RAD51 rs2928140 polymorphism; (c) RAD51 rs5030789 polymorphism; (d) XRCC3 rs1799796 polymorphism. Table 3: Distribution of genotypes and allele frequency of studied SNPs in RAD51 and XRCC3 in prostate cancer patients and control group. Gene rs Genotype/allele Control group (n=205) Prostate cancer patients (n=99) TT 48 30 TA 101 51 AA 56 18 rs2619679 𝜒 =3.59, p =0.17 T 197 111 A213 87 𝜒 =3.43, p =0.06 GG 95 43 GC 63 36 CC 47 20 RAD51 rs2928140 𝜒 =1.00, p =0.61 G253 122 C157 76 𝜒 =0, p =1.00 AA 29 7 AG 106 45 GG 70 47 rs5030789 𝜒 =6.43, p = 0.04 A164 59 G246 139 𝜒 =5.98, p = 0.01 AA 77 28 AG 92 45 GG 36 26 XRCC3 rs1799796 𝜒 =4.15, p =0.13 A246 101 G164 97 𝜒 =4.40, p = 0.04 Journal of Oncology 5 Table 4: Prostate cancer risk and RAD51 and XRCC3 polymorphism. Gene rs Genotype/allele Control group (n=205) Prostate cancer patients (n=99) OR (95% Cl) p value TT 48 30 1 (Ref.) TA 101 51 0.808 (0.459-1.424) 0.554 rs2619679 AA 56 18 0.514 (0.255-1.036) 0.089 T 197 111 1 (Ref.) A 213 87 0.725 (0.515-1.020) 0.077 GG 95 43 1 (Ref.) GC 63 36 1.262 (0.732-2.178) 0.484 RAD51 rs2928140 CC 47 20 0.940 (0.498-1.775) 0.841 G253 122 1(Ref.) C 157 76 1.004 (0.708-1.423) 0.526 AA 29 7 1 (Ref.) AG 106 45 1.759 (0.718-4.309) 0.299 rs5030789 GG 70 47 2.782 (1.126-6.872) 0.038 A164 59 1(Ref.) G246 139 1.571 (1.093-2.228) 0.018 AA 77 28 1 (Ref.) AG 92 45 1.345 (0.768-2.356) 0.371 XRCC3 rs1799796 GG 36 26 1.986 (1.022-3.860) 0.041 A246 101 1(Ref.) G164 97 1.441 (1.024-2.027) 0.044 cancer, many mutations and polymorphisms of a single sporadic breast cancer (OR 1.598, 95% CI 0.5638-4.528, p nucleotide have been identified, especially in DNA repair > 0.05). However, both variants homozygous T172T and genes, which increase the risk of developing prostate cancer. heterozygous G135C together showed a significant associ- Polymorphic genes of DNA repair are in great part included ation with sporadic breast cancer susceptibility. Michalska et al.  found that the polymorphism of RAD51 may be in low penetrance genes, which means that single gene product most often slightly aeff cts the disease occurrence positively associated with the incidence of triple-negative risk, but accumulation of changed alleles can have essential breast carcinoma while Sekhar et al.  indicated that significance for its development. RAD51, which is a critical RAD51 135G> C substitution in the homozygous form (CC) protein involved in the homologous recombination repair increases the risk of breast cancer in an ethnic-specific pathway, interacts with XRCC2, XRCC3, and other proteins manner. Sod ¨ erlund et al.  suggest that RAD51 135G>C to form a complex that is crucial for repairing the double- polymorphism predicts cyclophosphamide/methotrexate/5- strand breaks and maintaining chromosome stability [12, 16, u fl orouracil chemotherapy effect in early breast cancer. 20]. Polymorphism of the RAD51 also seems to play a role in To our knowledge, genetic abnormalities in RAD51 par- other types of cancer. In our previous study we found a signif- alogs, i.e., RAD51C and RAD51D, have been identified in icant relationship between RAD51 polymorphism rsl801320 and an increased risk of prostate cancer . It has been prostate cancer, but not in RAD51 [5–10]. Our study has shown the importance of RAD51 and its paralog XRCC3 shown that subjects carrying RAD51 rs1801320 GC genotype polymorphism in prostate cancer. Single nucleotide poly- also have an increased risk of glioblastoma (GC vs GG,𝜒 (2) morphism within these genes may affect DNA double-strand = 10.75; OR 3.0087; p = 0.0010). In addition, RAD51 rs1801320 break repair capacity, hence the increased susceptibility to C allele increased the risk of developing glioblastoma also in neoplastic transformation. There is growing body of evi- combination with the XRCC1 rs25487 G allele and XRCC3 dence which suggests that polymorphic variants of these rs861539 C allele (𝜒 (2) = 6.558; p = 0.0053) . Trang et genes have impact on developing different cancers. A meta- al.  showed that the combination of Helicobacter pylori infection and RAD51 G135C genotype of the host leads to analysis conducted by Zeng et al.  suggests that RAD51 rs1801320 (135G/C) polymorphism is a risk factor for three an increased score for intestinal metaplasia. This suggests common gynecological tumors, i.e., breast, endometrial, and that RAD51 G135C may be an important predictor for gastric ovarian cancers, and especially for endometrial cancer. Al- cancer of Helicobacter pylori-infected patients. Mucha et Zoubi et al.  in their studies demonstrated that the al.  study revealed a statistically significant association homozygous variant T172T (rs1803121) is signicfi antly asso- also between rs5030789 polymorphism in RAD51 and the ciated with breast cancer risk (OR 3.717, 95% CI 2.283- risk of colorectal cancer. In turn in the case of rs2619679 6.052, p < 0.0001), while the heterozygous variant G135C polymorphism in RAD51, itwas shownthat itdoesnot (rs1801320) has no significant relationship with the risk of correlate with the risk of head and neck cancer . 6 Journal of Oncology Table 5: Relationship between G allele for rs5030789 in RAD51 and rs1799796 in XRCC3 and clinicopathological characteristics of prostate cancer patients. rs5030789 rs1799796 Clinicopathological parameter AG A G Age ≤ 71 35 67 60 42 > 71 24 72 41 55 OR = 1.567 (0.846-2.902) OR = 1.916 (1.089-3.371) p =0.202 p= 0.033 PSAT (ng/ml) < 4-10 34 68 53 49 > 10 25 71 48 48 OR = 1.420 (0.768-2.624) OR = 1.082 (0.619-1.889) p =0.335 p = 0.887 Free/total PSA (F/T PSA) < 0.16 25 71 44 52 ≥ 0.16 34 68 57 45 OR = 0.704 (0.381-1.301) OR = 0.668 (0.381-1.170) p =0.335 p =0.203 PSA Density (PSAD, ng/ml) < 0.28 26 72 49 49 ≥ 0.28 33 67 52 48 OR = 0.733 (0.397-1.352) OR = 0.923 (0.529-1.612) p =0.399 p = 0.888 Prostate volume (ml) < 48 31 61 52 40 ≥ 48 28 78 49 57 OR = 1.416 (0.768-2.608) OR = 1.512 (0.862-2.652) p = 0.337 p =0.192 Gleason score <719 37 37 19 ≥740 102 64 78 OR = 1.309 (0.675-2.541) OR = 2.373 (1.246-4.521) p =0.532 p = 0.012 Cancer stage T1-T2 35 81 58 58 T3-T4 24 58 43 39 OR = 1.224 (0.664-2.256) OR = 0.907 (0.515-1.597) p =0.624 p =0.841 Avadanei et al.  findings suggest that XRCC3 poly- to heterozygote and homozygote (AG and GG) genotypes, morphism in hepatocellular carcinoma may affect the aggres- respectively. The results presented by Ali et al.  suggest siveness of the tumor expressed by tumor grade. Statistically that the polymorphism rs1799794 in XRCC3 is strongly asso- signicfi ant differences were shown for rs1799796 A >Gand ciated with the development of breast cancer in Saudi women tumor grade, between wild type (AA) and heterozygote while genotype and allele frequencies of rs861539 C>T (AG) genotypes, andwildtype (AA) andheterozygote and and rs1799796 A>G did not show a significant difference. homozygote (AG and GG) genotypes. The logistic regres- However, the frequency of rs1799796 differed significantly in sion analysis found an OR of rs1799796 polymorphism patients depending on the age of the diagnosis, tumor grade, occurrence in hepatocellular carcinoma related to tumor and ER and HER2 status. The wild type A allele occurred grade. In the case of rs861539 C>T polymorphism, statistical more frequently in the ER- and HER2- group. 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