Breast cancer is one of the most common malignancies in women, with over 1 million new cases diagnosed annually. Recent research indicates a growing prevalence of breast cancer among Iranian women, particularly at a younger age, which raises concerns [37, 38]. Although our knowledge of breast cancer is still evolving, we have identified various genetic risk factors associated with the disease [10].

Our current study's results reveal that CYP1A2 SNPs (rs17861162) in breast cancer patients are associated with a 21.7% decrease in the frequency of the CC genotype and a 21.6% and 77.8% increase in the frequency of CG and GG genotypes, respectively. Furthermore, this SNP leads to an 11% decrease in the frequency of the C allele and an 11% increase in the frequency of the G allele within the breast cancer group compared to healthy controls (P-value = 0.00). Altogether, the CYP1A2 SNP (rs17861162) results in an alteration of the allelic balance observed in women without breast cancer. Notably, there is a limited body of research on the impact of the rs17861162 locus polymorphism on the CYP1A2 gene, and as far as our knowledge extends, no previous study has explored this aspect in Iran.

The known and possible functional roles of this SNP in breast cancer have not yet been revealed precisely, however, CYP1A2 plays a prominent role in the activation of pre-carcinogens through metabolic processes [39] and SNPs can alter the activity of the corresponding proteins [19]. Given the prominent role of human Cytochrome P450 enzymes in the metabolism of medications, toxins, and chemical compounds, any alteration to the genomic sequence encoding these enzymes may subsequently elevate the risk of cancer [18, 42]. It is noteworthy that the link between clinicopathological characteristics and the prognosis of breast cancer with the CYP1A2-rs17861162 SNP was first identified by Bai et al. They reported a significant correlation between the CYP1A2-rs17861162 SNP and factors such as age, menstrual status, and the presence of the P53 marker in women diagnosed with breast cancer. In comparison to individuals with the CC genotype, those carrying this SNP, particularly the combined genotype (GG + CG), were more likely to be younger and pre-menopausal, as well as to test negative for the P53 tumor marker [10]. CYP1A2 acts as an agent for metabolizing endogenous compounds such as steroid hormones, retinoic acid, and bile acids [39]. Estrogen levels significantly influence breast cancer risk in postmenopausal women, a factor intricately linked to both menstrual status and age [40]. However, Bai et al. did not observe any connection between this SNP and the patient's genotype in relation to breast cancer prognosis. Additionally, the interplay between coffee consumption and the CYP1A2*1F genotype has been shown to impact the age at which breast cancer is diagnosed and the status of estrogen receptors [41].

Khvostova et al. investigated the polymorphism of estrogen-metabolizing enzymes (cytochromeP450s: CYP1A1, CYP1A2, and CYP19) in breast cancer patients within a cohort of Siberian women. They reported several polymorphisms associated with an increased risk of cancer development and progression. Furthermore, they observed that the CYP1A2 polymorphism increases the risk of developing estrogen receptor-positive tumors [43]. Liu et al. observed that SNPs occurring in CYP1A2-rs17861162 and –rs-11636419 influence the efficacy of epidural ropivacaine in women with breast cancer [44]. Ghotbi et al. reported differences in CYP1A2 polymorphism frequencies between the Swedish and Korean populations [45], while Lim et al. observed significant inter-ethnic differences among the Chinese, Malay, and Indian populations [22]. Perera et al. observed a significant difference in CYP1A2 activity between South Asian and European ethnicities [23]

CYP1A2 plays a pivotal role in the metabolism of 10–13% of all carcinogens and medications, including clozapine, olanzapine, theophylline, and heterocyclic aromatic amines [22, 23, 46]. It is also involved in metabolizing substances like coffee and estrogen [47], while inactivating exogenous compounds such as environmental pro-carcinogens [10]. CYP1A2 significantly contributes to the 2-hydroxylation of the primary estrone and estradiol [47, 48]. Notably, through the activation of various carcinogenic heterocyclic amines, CYP1A2 may contribute to the progression of specific malignancies [22]. The literature underscores that genetic polymorphisms substantially influence the expression and activity of CYP1A2 [10, 24]. To date, over 30 SNPs have been identified in the CYP1A2 upstream sequence and its intron-1 region [23], contributing to its role in cancer development and progression [10, 49].

The link between CYP1A2 polymorphisms and an increased susceptibility to developing lung, colorectal, breast, and biliary cancers has been established [43, 50]. In general, the role of CYP1A2 polymorphisms in cancer development remains a subject of debate. While numerous studies have investigated the role of CYP1A2 polymorphisms in breast cancer development among different ethnicities, findings have not consistently aligned [10, 47]. Some studies report a negative association between CYP1A2*1F and breast cancer incidence [25] or that the presence of the C allele is protective against the disease [25, 51]. However, others have failed to observe the same trends [25, 48] or establish their precise role in disease development [48]. Additional investigations have reported associations between CYP1A2 SNPs and breast cancer [10]. Increased CYP1A2 gene activity has also been linked to a heightened risk of breast cancer development [52]. These discrepancies may arise from various individual, genetic, and ethnic determinants, alongside exposure to environmental risk factors and differences in healthcare approaches or a complex interplay between these factors [22].

Additionally, in our investigation of the ADSL gene's SNP rs3788579, we found a significantly higher prevalence of the T allele in individuals with breast cancer compared to the healthy group, exceeding by 28.5% (P-value = 0.00). This finding suggests a potential association between the increased frequency of the T allele and breast cancer incidence. Furthermore, carriers of the T allele exhibited a 3.235-fold higher risk of developing breast cancer, indicating that the presence of this allele may contribute to an elevated risk of breast cancer incidence. To the best of our knowledge, no previous investigation has been made into the impact of ADSL-rs3788579 SNP on breast cancer development.

The ADSL gene exhibits typical characteristics of a housekeeping gene [53]. Functioning as an essential homotetrameric enzyme, ADSL plays a pivotal role in two key reactions: 1) the conversion of succinylaminoimidazolecarboxamide (SAICA)-ribotide (SAICAR) into AICA-ribotide (AICAR) through the de novo purine synthesis pathway, and 2) the generation of AMP by converting adenylo-succinate into adenosine monophosphate as part of the purine nucleotide cycle [54]. Potential modifications to the purine nucleotide degradation pathway resulting from non-synonymous SNPs in the ADSL gene could lead to structural or functional alterations in its associated protein [55]. Available evidence suggests that point mutations within the ADSL gene can result in significant variations in IMP content [56, 57]. Chen et al. investigated the relationship between the 7 SNP genotypes and expression levels of the ADSL gene in CEU cell lines, finding significant correlations between ADSL-rs8135371 and -17001863 and the expression of the ADSL gene. Furthermore, the total copies of the C and G alleles were found to increase ADSL expression in rs8135371 and rs17001863 SNPs, respectively [58].

The ADSL gene plays a crucial role in maintaining the ATP/AMP ratio, a fundamental factor in regulating cell division and metabolism [53]. It contributes to this equilibrium by providing the necessary purine nucleotides required for DNA replication and cell division. In vertebrates, the purine nucleotide degradation pathway consists of ten enzymatic steps, with ADSL, AMPD1, and ATIC being among the most significant. As ADSL oversees two of these pathway steps, modifications to the enzyme at either of these stages can lead to subsequent alterations in IMP content [53].

Increased levels of ADSL have been observed in various conditions, including colorectal, breast, and prostate cancer. Furthermore, genomic variations have been associated with specific traits, such as drug responsiveness, along with changes in gene expression [58]. Despite the recognized disruption of ADSL activity in various malignancies, such as breast, colorectal, prostate cancer, tubulovillous and tubular adenoma, glioma, and more, the precise mechanisms governing the impact of ADSL on the initiation and progression of these disorders remain incompletely understood [34, 59, 60].

Zurlo et al. documented that depletion of ADSL leads to an increase in the expression of the long non-coding RNA MIR2HG by altering adenosine and adenine levels. MIR22HG, in turn, reduces the expression of the oncogene c-YMC at the protein level. Consequently, knocking out ADSL hampers the growth and invasion of triple-negative breast cancer (TNBC) cells, both in vitro and in vivo [34]. Park et al. proposed that the ADSL gene promotes oncogenesis in endometrial cancer by upregulating the expression of killer cell lectin-like receptor C3 (KLRC3) through fumarate production. Their findings indicated that ADSL enhances tumor cell proliferation, invasion, and migration by modulating KLRC3 expression. The application of external fumarate restored KLRC3 expression in ADSL knockout cells, indicating that ADSL regulates KLRC3 expression through fumarate production [59]. Evidence confirms that in human endometrioid carcinoma, ADSL expression was correlated with increased histological aggressiveness and the extent of primary tumor progression.

Breast cancer arises from the accumulation of genetic defects in epithelial cells, resulting in the presentation of malignant phenotypes [61]. Although novel therapeutic options have significantly improved breast cancer treatment, the inherent histological, molecular, and genomic heterogeneity of this malignancy complicates gene-based interventions [62]. Due to the limitations and disadvantages of conventional diagnostic modalities such as X-rays, Ultrasound, and Computed Tomography (CT) scans, less invasive and cost-effective alternatives are gaining popularity. In this context, screening for genetic markers, such as CYP1A2 and ADSL, is considered a potential alternative to conventional methods. Numerous genomic variants, also known as SNPs, including CYP1A2 (rs17861162) and ADSL (rs3788579), appear to be correlated with the risk of breast cancer development. Investigating these SNPs may contribute to improving diagnostic accuracy due to their significant interpersonal and genetic variations [63, 64]. Besides their diagnostic potential, these markers may be useful in the early detection of breast cancer and risk assessment for individuals with this malignancy.