Introduction
Incidence-wise, breast cancer is the utmost prevalent type of cancer, while it ranks second in terms of overall cancer-related deaths [1]. The disease is multifactorial, meaning that it is influenced by various factors such as genetics, environment, reproductive factors, and lifestyle choices [2]. Although the precise mechanism responsible for the onset of breast cancer remains incompletely understood, various risk factors for the disease have been identified. These include exposure to DNA-damaging agents from internal and external sources [3]. The inability to effectively repair DNA chemical structure damage is pivotal in cancer advancement [4]. The recognition and correction of DNA damage through repair mechanisms are critical in averting carcinogenesis, preserving genome stability, and safeguarding against mutations [5]. Genetic dissimilarities in DNA repair genes can contribute to differences in DNA repair activity among individuals, potentially influencing the risk of breast cancer [6]. Double-strand breaks (DSBs) in human cells are repaired through mechanisms such as homologous recombination (HR) and non-homologous end-joining (NHEJ). These pathways are essential for maintaining genomic stability and ensuring the integrity of DNA after damage occurs [7]. While multiple genes participate in these pathways, our focus here is on X-ray repair cross complementing (XRCC3), located on chromosome 14q32.3. The XRCC3 protein plays a pivotal role in HR by interacting with Rad51, facilitating the assembly of Rad51 multimers at sites of DNA damage [8]. This interaction is crucial for the effective repair of DNA double-strand breaks, thereby contributing to the conservation of genomic stability [9]. This study seeks to investigate whether there is an association between the XRCC3 Thr241Met genotype variants and the susceptibility to breast cancer.
This study is considered the first study in Iraq that sheds light on studying the effect of the XRCC3 Thr241Met genetic variants and their relationship with increased risk of breast cancer.
Material and methods
Study group
This case-control study was conducted at the Molecular Biology Laboratory, Department of Biology, Faculty of Science, University of Kufa, Iraq, from September 2023 to May 2024. The study involved 75 Iraqi women diagnosed with breast cancer, whose blood samples were obtained from the National Hospital for Oncology and Haematology in Al-Najaf, Iraq.
The diagnosis of breast cancer was confirmed through histological examination under the supervision of a hospital pathologist. Demographic details were collected using a questionnaire, which included patient age and family history of cancer. Data on clinicopathological features were extracted from hospital records. This included the TNM stage, which involves tumour, node, and metastasis staging; the histological grade, which classifies the cancer based on cellular differentiation; and the type of breast cancer, specifying the subtype diagnosed. Additionally, lymph node metastases, indicating whether cancer had spread to the lymph nodes, were recorded. This comprehensive approach ensured accurate diagnosis and detailed profiling of the breast cancer cases.
In this study, the control group comprised 50 apparently healthy Iraqi women. These participants were selected based on stringent criteria to ensure they were free from any inflammatory disorders, clinical manifestations of disease, or family history of cancer. Specifically, all control subjects reported no personal history of cancer and had no first-degree relatives with a history of any type of cancer. This careful selection process was designed to minimise the impact of genetic and environmental factors that could potentially confound the study results.
To further ensure the validity of our control group, participants were screened through a detailed health questionnaire and medical history review. This approach aimed to confirm that the control group did not possess any characteristics that might introduce bias or distort the findings related to the study’s primary focus.
Characteristics of the control group:
• Health Status: All participants were verified to be in good health, with no evidence of chronic illnesses or acute conditions.
• Family History: None of the control group members reported a family history of cancer, reducing the potential genetic burden that could affect the study outcomes.
• Demographics: The control group was demographically matched to the study group in terms of age and socioeconomic status to control for these variables.
By adhering to these criteria, we aimed to ensure that the control group was appropriately matched to the study group and to mitigate potential biases related to genetic and environmental factors.
Extraction of DNA and genotyping analysis
Two millilitres of venous blood were taken from the patients and the control group in tubes containing an anticoagulant (EDTA), to isolate genomic DNA using a genomic DNA kit protocol (Geneaid Biotech, Taiwan), which is specifically manufactured for extracting DNA from blood. Forward primer sequence for PCR was (5’→3’): GGT CGA GTG ACA GTC CAA AC-3’, while the reverse primer was (5’→3’): TGC AAC GGC TGA GGG GTC TT. AccuPower® TLA PCR PreMix tubes were filled with 5 µl of template DNA and 2 µl of each primer (2 µl forward and 2 µl reverse). The nuclease-free water (Promega, USA), which was certified free of DNase and RNase activity, was added to a total volume of 20 µl (the dried pellet in each PreMix tube was not calculated in accordance with the manufacturer’s instructions). The PCR was carried out by applying and following the temperatures and the time and number of each cycle as follows: an initial denaturation step at 95°C for 5 minutes, followed by 30 cycles, each consisting of denaturation at 94°C for 45 seconds, annealing at 62°C for 45 seconds, and extension at 72°C for 30 seconds; the amplification process concluded with a final extension step at 72°C for 5 minutes. After amplification, the isolated DNAs were genotyped using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. This method helps determine the presence or absence of specific single nucleotide polymorphisms (SNPs) based on the patterns of DNA fragments generated by restriction enzymes cutting at SNP sites. The PCR product (5 µl) was combined with 0.5 µl of NlaIII restriction endonuclease and 2.5 µl of NE Buffer (10X), and distilled water was added to make up the total volume to 25 µl. The reaction mixture was then incubated at 37°C for 15 minutes and subsequently heat-inactivated at 65°C for 20 minutes. The digested products were subsequently observed using electrophoresis on a 1% agarose gel. After completion of incubation and electrophoresis, a specific genotype was obtained from the pieces resulting from RFLP technique: The individuals with a homozygous Thr/Thr genotype exhibited the production of fragments measuring 140 and 316 bp. On the other hand, individuals with a Met/Met genotype produced fragments measuring 140, 211, and 105 bp. In contrast, individuals with a heterozygous Thr/Met genotype produced all 4 fragments.
Statistical analysis
Statistical analysis was performed on all the data using SPSS version 23. To compare the outcomes from the 2 groups, the χ2 test (with a p value ≤ 0.05) was employed. The results were displayed using percentages and numbers of cases.
Results
Demographic characteristics of patients
The participants’ epidemiological data showed that the age presentation of patients at diagnosis revealed 12 (16%) in the age group 41–27 years, 40 (53.3%) in the age group 56–42 years, 18 (24%) in the age group 57–71 years, and 5 (6.67%) in the age group 86–72 years (Table 1). Their ages ranged from 27 to 77 years, with a mean age of 51.59 years and with a significant difference (p < 0.0001). Pathological analysis of the 75 tumour cases, evaluated by a hospital pathologist according to the TNM staging system, indicated that 16% were classified as stage I, 38.6% as stage II, and 45.3% as stage III/IV (Table 1). Most patients had cancer in advanced stages of growth, with a significant difference (p = 0.0048) compared to the number of early-stage cancers (stage I).
Based on grading criteria, the breast carcinomas were categorieds as 17.33% grade I, 68% grade II, and 14.66% grade III. Most of the cancers seen in the cases studied were advanced, poorly differentiated, high-grade cancers with significant differences (p ≤ 0.00001) from well-differentiated, low-grade, or grade 1 tumours (Table 1). Lymph node metastases were observed in 49 cases (65.33%), compared to 26 cases (34.66%) without metastatic lymph nodes (p ≤ 0.0079). Among the patients, 22.6% had a family history of breast cancer, while most patients (77.33%) did not have a family history (p ≤ 0.000002) (Table 1).
Impact of XRCC3 Thr241Met SNPs on breast cancer risk
The genotyping frequencies of XRCC3 Thr241Met, as shown in Table 1, revealed significant differences between breast cancer cases and controls. More precisely, the prevalence rates of the Thr/Thr, Thr/Met, and Met/Met genotypes among the cases were 37.34%, 41.33%, and 21.33%, respectively. In comparison, among controls, the frequencies were 68%, 28%, and 4% for the same variants. There was a notable significantly increase in the occurrence of both the Thr/Met and combined Met/Met genotypes in breast cancer cases compared to Thr/Thr genotype (p = 0.01 and p = 0.004, respectively). Moreover, individuals carrying the Thr/Met genotype of the XRCC3 Thr241Met gene polymorphisms exhibited a higher susceptibility to breast cancer in comparison to those with the Thr/Thr genotype (OR = 2.69, 95% CI: 1.2–6.02). The individuals with the Met/Met genotype had a higher likelihood of developing breast cancer; this genotype showed a 9.71-fold (OR = 9.71, 95% CI: 2.06–45.89) increase in the risk of breast cancer.
Table 2 lists the allele frequency of XRCC3 Thr241Met, which was determined for cases and controls. In cases, the normal (Thr) allele frequency was 58% and the variant (Met) allele frequency was 42%. In controls, the normal allele frequency was 82% and the variant allele frequency was 18%. Based on the data, the variant (Met) allele showed a positive association as a risk factor with an increase in the susceptibility to breast cancer of 3.3-fold in comparison with the Thr allele (OR = 3.3, 95% CI: 1.8–6.04; p = 0.0001).
Association of XRCC3 Thr241Met genotype with age
The study examined the relationship between the XRCC3 Thr241Met genotype variants and age in women with breast cancer. Among the patients in the age group 27–41 years (Group 1), 85.71% (18 individuals) were identified as having a homozygous genotype (Thr/Thr), 25% (3 individuals) had a heterozygous genotype (Thr/Met), and 8.33% (one individual) had a homozygous genotype (Met/Met). Among the patients in the age group 42–56 years (Group 2), out of a total of 40 patients, 17 (42.5%) had a homozygous genotype (Thr/Thr), 13 (32.5%) had a heterozygous genotype (Thr/Met), and 10 (25%) had a homozygous genotype (Met/Met). Among the patients in the age group 57–71 years (Group 3), 3 (16.66%) had a homozygous genotype (Thr/Thr), 11 (61.11%) had a heterozygous genotype (Thr/Met), and 4 (22.22%) had a homozygous genotype (Met/Met). Among the patients in the age group 72–86 years (Group 4), no patients were found to have a homozygous genotype (Thr/Thr), 4 (80%) had a heterozygous genotype (Thr/Met), and one (20%) had a homozygous genotype (Met/Met) (Table 3). The results revealed that the XRCC3 Thr241Met genotype variants were more frequent with increasing patients’ ages, with a significant difference (p = 0.039) compared to the first age group.
Association between XRCC3 Thr241Met polymorphism and clinicopathological variables in breast cancer patients
Association of XRCC3 Thr241Met genotype with stage
The study examined the association between the TNM staging of breast cancer and the XRCC3 Thr241Met genotype variants. Among patients with stage I tumours, 10 (83.33%) were identified as homozygous (Thr/Thr), one (8.33%) had a heterozygous genotype (Thr/Met), and one (8.33%) had a homozygous genotype (Met/Met). Among patients with stage II tumours, 12 (41.38%) had a homozygous genotype (Thr/Thr), 14 (48.28%) had a heterozygous genotype (Thr/Met), and 3 (10.34%) had a homozygous genotype (Met/Met). Among patients with stage III/IV tumours, 6 (17.65%) had a homozygous (Thr/Thr), 16 (47.05%) had a heterozygous (Thr/Met), and 12 (35.3%) had a homozygous (Met/Met) genotype (Table 4). The results revealed that the XRCC3 Thr241Met genotype variants were more frequent with increasing cancer stage, with a significant difference (p = 0.0005) compared to the first-stage group.
Association of XRCC3 Thr241Met genotype with histological grade
The study revealed that among grade I breast cancer cases (n = 13), 7 (53.84%) were identified as homozygous (Thr/Thr), 5 (38.46%) had a heterozygous genotype (Thr/Met), and one (7.69%) had a homozygous genotype (Met/Met). Among the patients with grade II tumours (n = 51), 19 (37.25%) were identified as homozygous genotype (Thr/Thr), 20 (39.22%) were identified as heterozygous genotype (Thr/Met), and 12 (23.53%) had a homozygous genotype (Met/Met). Among patients with grade III tumours (n = 11), 2 (18.18%) were identified as homozygous (Thr/Thr), 6 (54.55%) were heterozygous (Thr/Met), and 3 (27.27%) were identified as homozygous (Met/Met) (Table 4). The results revealed that the XRCC3 Thr241Met genotype variants were more frequent with increasing grade of cancer, with no significant difference (p = 0.41) compared to the first-grade group.
Association of XRCC3 Thr241Met genotype with lymph node metastases
The results of the study on the frequency of lymph node metastases revealed that among patients with tumours that had metastatic lymph node involvement, 7 individuals (14.29%) were identified as homozygous Thr/Thr genotype, 28 individuals (57.14%) were heterozygous Thr/Met genotype, and 14 individuals (28.57%) were homozygous Met/Met genotype. In cases without metastatic lymph node involvement, 21 (80.77%) were homozygous Thr/Thr, 3 (11.54%) were heterozygous genotype Thr/Met, and 2 (7.69%) were homozygous genotype Met/Met (Table 4). The results revealed that the XRCC3 Thr241Met genotype variants were more frequent with increasing positive lymph node status in patients, with a significant difference (p ≤ 0.00001) compared to cancer cases that did not include lymph node metastases.
Discussion
Cancer is a cluster of molecular ailments that are closely related but differ in their causes and mechanisms, although they do share some commonalities [10]. Breast cancer is the most common type of cancer among Iraqi women, accounting for the highest percentage of malignant tumours in this population, with colorectal cancer being the next most prevalent [11, 12]. While the development of breast cancer is influenced by a combination of genetic and environmental factors, genetic factors have been identified as the primary driver of its pathogenesis [13]. Elevated expression of certain genes associated with polymorphisms can increase the risk of breast cancer [14]. The XRCC3 has been identified as a significant candidate among the DNA repair genes that have been recently studied [15]. The disruption of this gene has been demonstrated to be linked to the development of cancer [16]. The XRCC3 gene encodes a protein belonging to the RecA/Rad51-related protein family. This protein plays a role in the homologous recombination pathway, which is responsible for repairing double-strand breaks and ensuring the stability of chromosomes [17]. XRCC3, in conjunction with RAD51, is involved in the process of recombinational repair [18]. The results of XRCC3 Thr241Met SNP genotyping in this study revealed that the mutant homozygote (Met/Met) allele showed significant association (OR = 3.3, 95% CI: 1.8–6.04; p = 0.0001) with increased breast cancer as a menace factor among Iraqi females.
These findings confirm the results of 2 prior studies, which indicated that individuals with the Thr/Met and Met/Met genotypes have a greater susceptibility to breast cancer compared to individuals with the wild-type Thr/Thr genotype [19, 20]. A recent study has demonstrated that a Thr/Met transition at exon 7 (XRCC3 -18067C > T, rs861539) leads to a substitution of threonine with methionine at codon 241, which has an impact on the function of DNA repair [21]. The substitution of hydrophilic threonine with hydrophobic methionine in the 241Met variant can result in reduced DNA repair capacity, potentially increasing the vulnerability to carcinogenesis [22]. Nevertheless, several other studies have demonstrated the absence of a correlation between XRCC3 Thr241Met and susceptibility to breast cancer in various populations, including that of Cyprus [23], Caucasian women [24], the Saudi population [25], the Egyptian population [26], US women [27], and females from the North Eastern Region of India [28]. Conversely, another study showed that the presence of the Thr241Met-XRCC3/135G/C-RAD51 genotype reduced the likelihood of developing breast cancer [29].
The XRCC3 Thr241Met polymorphism was found to be associated with older age. Patients with older age were significantly more likely to possess a copy of the Met allele for the XRCC3 gene SNP than younger patients in the first age group among the studied population. As reported previously, older age is the main risk factor for cancer [30]. This primarily indicates the gradual accumulation of DNA damage in cells over a period of time [31]. Harm can arise from biological processes or from being exposed to risk factors [32]. Genetic mutations in genes responsible for repairing DNA result in higher levels of genomic instability and increased frequency of mutations. This leads to a decrease in the efficiency of DNA repair and an increase in errors, causing a progressive accumulation of DNA damage and mutations. These mutations further contribute to the decline in physiological functions associated with aging [33, 34].
In this study, relationships between XRCC3 Thr241Met polymorphism and the tumour criteria were analysed. The results recorded a significant association between XRCC3 Thr241Met polymorphism and tumour stage. Breast cancer patients with the Met mutant allele were more likely to present with advanced tumour stages (II and III/IV) compared with stage I tumour. The results obtained by Ozora et al. [35], who investigated the associated the XRCC3 Thr241Met polymorphism and clinical stage (p = 0.02). Patients carrying the Met/Met genotype showed that a 3.85-fold increased risk of being in advanced clinical stages III or IV (OR = 3.85, 95% CI: 1.20–12.7). These findings strongly support the current results. dos Santos Pereira et al. [36] which found that individuals with the Met/Met genotype exhibited a notably higher likelihood of developing oral cancer, especially at stage III or IV.
This study showed that higher rates of Thr/Met and Met/Met genotypes was recorded in grade II and III compared with grade I.
These findings were consistent with the results of Romanowicz-Makowska et al. [37], who investigated the association between histological grading and the XRCC3 Thr241Met polymorphism in Polish women. Histological grading was assessed in a total of 700 cases: 200 cases were classified as grade I, 450 as grade II, and 50 as grade III. Their study found that Met/Met homozygotes exhibited a significantly higher frequency in tumour grade II + III. Another study by Goričar et al. [38], conducted in Ljubljana, established a notable link between the XRCC3 Thr241Met polymorphism and the histological grade of breast cancer. Their findings revealed a higher prevalence of the Thr/Met and Met/Met genotypes (70.2%) in grades II/III compared to grade I (29.8%). These results imply that the Thr241Met polymorphism potentially influences the histological grading of breast cancer.
This study observed that higher rates of the Thr/Met and Met/Met genotypes of XRCC3 Thr241Met were recorded in metastatic lymph node-positive compared with metastatic lymph node-negative subjects.
A previous study found a correlation between the genotypes of DNA repair genes and the expression of hormone receptors, as well as lymph node metastasis, in breast cancer patients [39]. Krupa et al. [29] mentioned that the Thr241Met genotype of the XRCC3 polymorphism was found to increase the risk of local metastasis in breast cancer patients, with an OR of 2.56 and a 95% CI ranging from 1.27 to 5.17. Additionally, a significant difference in the distribution of genotypes and alleles of the Thr241Met polymorphism was observed between patients with positive and negative lymph nodes (χ² = 15.2; p < 0.005). More precisely, patients who were heterozygous for the Thr241Met variant had a higher likelihood of developing local metastasis, with high significant difference (p < 0.00001) in comparison with homozygous genotype. This suggested that the Thr241Met polymorphism may play a role in predisposing individuals to metastasis in breast cancer. The findings of this study were consistent with another study indicating significant associations between lymph node involvement (p = 0.035) and the Met allele of the XRCC3 [40].
Conclusions
This study identified a significant association between the XRCC3 Thr241Met polymorphism and the development of breast cancer, for the first time in Iraqi women. The presence of the mutant Met allele was more prevalent among women with high-grade, advanced-stage, and metastatic breast cancers.
Acknowledgements
The authors are grateful to the Faculty of Science and the University of Kufa for allowing them to perform this study in the Department of Biology’s molecular biology lab. Additionally, the authors would like to thank the patients and healthy controls for their participation in this study.
Disclosures
1. Institutional review board statement: The study was conducted following the ethical guidelines specified in the Declaration of Helsinki. Before collecting the sample, we obtained consent from each patient through both verbal and written means. The study protocol underwent a thorough review and received official approval from the Faculty of Science, University of Kufa, Iraq, as documented by No. 5449 dated 19/9/2023.
2. Assistance with the article: None.
3. Financial support and sponsorship: None.
4. Conflicts of interest: None.
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