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Year : 2020  |  Volume : 16  |  Issue : 6  |  Page : 1279-1286

Breast cancer-related single-nucleotide polymorphism and their risk contribution in Mexican women

1 Pharmacogenetics Laboratory, UMIEZ, FES-Zaragoza, UNAM, Mexico City, Mexico
2 Pharmacological Biochemistry Laboratory, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
3 Laboratory of Genomic Medicine, Department of Genomics, National Institute of Rehabilitation Luis Guillermo Ibarra Ibarra, Mexico City, Mexico
4 Department of Pharmacy, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City, Mexico
5 Faculty of Medicine, University of Veracruz, Mendoza City, Veracruz, Mexico
6 Dean of Health Sciences, Autonomous University of Guadalajara, Jalisco, Mexico
7 Genomics Laboratory, National Cancer Institute, Mexico City, Mexico
8 College of Sciences and Humanities, Autonomous University of Mexico City, Cuautepec Campus, Mexico City, Mexico
9 Division of Genomic Medicine, National Medical Center '20 de Noviembre' ISSSTE, Mexico City, Mexico
10 Molecular Biology Laboratory, Hipocrates University, Acapulco de Juarez, Guerrero, Mexico
11 Bicentennial Mexican University, Tultitlán Higher Studies Unit, Mexico, Mexico
12 Molecular Cancer Biology Laboratory, UMIEZ, FES-Zaragoza, UNAM, Mexico City, Mexico

Date of Submission04-Jan-2020
Date of Decision07-Apr-2020
Date of Acceptance18-Jun-2020
Date of Web Publication18-Dec-2020

Correspondence Address:
Octavio Daniel Reyes-Hernández
Unidad Multidisciplinaria de Investigación Experimental Zaragoza, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México, 09230
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_14_20

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 > Abstract 

Context: Four single-nucleotide polymorphisms (SNPs) in Mexican patients and their association with the development of breast cancer (BC).
Aims: This work is focused on determining the association of fibroblast growth factor receptor (rs12196489), TOX3 (rs3803662), human telomerase reverse transcriptase (h TERT, rs10069690), and FTO (rs17817449) polymorphisms and BC in a cohort of Mexican women.
Settings and Design: The study included 56 patients with a confirmed diagnosis of BC and 83 controls. Clinical characteristics were obtained from medical records.
Subjects and Methods: Genomic DNA from the samples was obtained from lymphocytes, and the genotyping of rs12196489, rs3803662, rs10069690, and rs17817449 polymorphisms was performed by real-time polymerase chain reaction using specific TaqMan probes. Statistical analysis was assessed to evaluate the distribution of genotype frequencies between cases and controls.
Statistical Analysis: We used the STATA Statistical Package (version 10.1; STATA Corp., College Station, TX, USA). Student's t-test, χ2 test, or Fisher's exact test was used to evaluate the distribution of genotype frequencies.
Results: No statistical differences in allelic and genotypic frequencies were found between patients with BC and controls for SNPs: rs1219648, rs3803662, and rs17817449. Interestingly, according to the χ2 test, a significant difference was exhibited for rs10069690 (odds ratio = 0.095; 95% confidence interval = 0.038–0.214; P < 0.001).
Conclusions: The h TERT (rs10069690) polymorphism might be associated with BC in Mexican women. Nevertheless, additional studies in a larger cohort are required to confirm this association and to possibly use this polymorphism as a potential biomarker in the early diagnosis of BC.

Keywords: Breast cancer, cancer risk factors, genetic polymorphisms, human telomerase reverse transcriptase, Mexican population

How to cite this article:
Figueroa-Gonzalez G, Arellano-Gutiérrez CV, Cortés H, Leyva-Gómez G, Carmen MG, Bustamante-Montes LP, Rodríguez-Morales M, López-Reyes I, Alcaraz-Estrada SL, Sandoval-Basilio J, Quintas-Granados LI, Reyes-Hernández OD. Breast cancer-related single-nucleotide polymorphism and their risk contribution in Mexican women. J Can Res Ther 2020;16:1279-86

How to cite this URL:
Figueroa-Gonzalez G, Arellano-Gutiérrez CV, Cortés H, Leyva-Gómez G, Carmen MG, Bustamante-Montes LP, Rodríguez-Morales M, López-Reyes I, Alcaraz-Estrada SL, Sandoval-Basilio J, Quintas-Granados LI, Reyes-Hernández OD. Breast cancer-related single-nucleotide polymorphism and their risk contribution in Mexican women. J Can Res Ther [serial online] 2020 [cited 2021 Dec 4];16:1279-86. Available from: https://www.cancerjournal.net/text.asp?2020/16/6/1279/303890

 > Introduction Top

Breast cancer (BC) is the most frequent neoplasm in women worldwide; data from the World Health Organization (WHO)[1] suggest that BC comprises 16% of total cancer cases. Besides, each year, 138 million new cases are detected, and approximately 458,000 deaths occur due to this pathology.

BC incidence, mortality, and prevalence have increased considerably in developing countries in recent years. In this regard, BC is the leading cause of incidence (39.5/100) and death (10/100) associated with cancer in Mexico.[2] BC is a multifactorial disease, and the identified risk factors include familial BC history, late menopause, increasing age, early menarche, nulliparity, alcohol consumption, and estrogen, as well as gene mutations and unhealthy lifestyle.

Concerning genetic factors, growing evidence suggests that single-nucleotide polymorphisms (SNPs) in cancer-related genes may be associated with the susceptibility for developing BC. In line with this, genome-wide association studies have proposed several candidate SNPs in genes considered to have high (such as BRCA1, BRCA2, PETEN, and TP53) and moderate penetrance (such as ATM, BRIP1, CHEK2, and PALB2).[3] However, these genes represent only ≈28% of genetic susceptibility to develop BC,[4] frequently exhibiting incomplete penetrance, and conferring moderate lifetime risks of BC. Therefore, there is an increasing need to identify other SNPs that may participate in the susceptibility to BC.

In this regard, some studies have suggested that fibroblast growth factor receptor 2 (FGFR2), TOX3, human telomerase reverse transcriptase (h TERT), and FTO genes could be associated with the risk for BC.[5] It is noteworthy that these genes possess functions that could be related to carcinogenic processes.

The FGFR2 gene encodes for FGFR2, which participates in the cell proliferation, endothelial cell differentiation, and drug resistance, as well as survival and death.[6] Moreover, it has been suggested that FGFR2 exerts an influence on mitogenesis, cell invasion, and epithelial-to-mesenchymal transition, depending on the cell type and microenvironment.[7] To date, it has been reported that eight SNPs within intron 2 of the FGFR2 gene are associated with susceptibility to BC (rs35054928, rs2981578, rs2912778, rs2912781, rs35393331, rs10736303, rs7895676, and rs33971856).[8]

Likewise, the TOX3 gene encodes TOX high mobility group (HMG) box family member 3. The TOX3 protein possesses an HMG box, suggesting that it could bend and unwind DNA and alter the chromatin structure and some other DNA-dependent cellular processes.[9] Remarkably, the expression of this protein is low in the normal mammary cells. However, it is highly expressed in mammary tumors, mainly in histologically defined luminal B (LumB) and LumBHer2+ BC. Furthermore, in vitro and in vivo studies have shown that increases of TOX3 protein promote the proliferation and survival of BC cells. Furthermore, it appears to increase the risk of developing metastasis and bone invasion in BC. In this regard, there are some reports on the association of TOX3 SNP with an increased risk for BC, such as rs3803662, rs3803662, rs12443621, and rs8051542.[10]

On the other hand, the h TERT gene encodes for a rate-limiting catalytic subunit. Telomerase is involved in the cellular senescence in somatic cells, and it is repressed postnatally, which progressively leads to telomere shortening. However, it has been suggested that the deregulation of telomerase expression could cause telomeric instability and contribute to oncogenesis.[11] In this respect, numerous studies have previously reported the association between BC risk and h TERT SNP in some populations, including Asian, European, and African, but not in American populations.[11] In 2017, Häberle et al. performed a study to identify SNP for the risk of BC, capable of predicting triple negativity. These authors found that rs10069690 (h TERT, CLPTM1L) was the only significant SNP.[12] However, other reports have suggested that rs2736109, rs2853669, rs2736098, and rs2736100 are also significantly associated with the risk for BC.[13]

Finally, the FTO gene encodes alpha-ketoglutarate-dependent dioxygenase, a nuclear protein that appears to play a role in the oxidative demethylation of alkylated DNA and RNA.[14],[15] Previous studies have linked FTO with obesity and the risk for diabetes.[16],[17] It is well known that adipose tissue represents the main source of estrogens after menopause, and a positive correlation between obesity and estrogen production and an increase in the risk for BC have been demonstrated.[18] Therefore, it is feasible to speculate on an association between FTO and BC. In this regard, some reports have shown evidence that FTO SNP may increase susceptibility to BC.

da Cunha et al. demonstrated that the interaction between two SNPs from different obesity-related genes (FTO, rs9939609/MC4R rs17782313) plays an important role in the risk for and the development of BC.[19] The rs11075995 (16q12.2/FTO) polymorphism was also directly associated with basal-like BC susceptibility in a cohort of 2901 BC samples.[20] The relevance of the pre- and post-menopausal state takes place within the context of the increased production of estrogens in the adipose tissue, as well as weight gain. In the postmenopausal women who never used hormones, this increment is considered one of the most critical mechanisms that contribute to BC susceptibility.[21]

The increased production of estrogens in the adipose tissue is one of the most crucial mechanisms potentially contributing to the risk of developing BC, as well as to poor prognosis in patients with obesity.

Although several studies have shown that SNPs rs1219648 (FGFR), rs3803662 (TOX3), rs10069690 (h TERT), and rs17817449 (FTO) are highly associated with BC susceptibility in several populations, the role of these SNPs in Mexican patients and their possible association with the menopausal status are as yet unknown. Therefore, in this work, we studied the possible association of the FGFR (rs12196489), TOX3 (rs3803662), h TERT (rs10069690), and FTO (rs17817449) polymorphisms with the susceptibility to develop BC in a group of Mexican female patients, according to pre- and post-menopausal state. The objective of our research was to find a possible biomarker for determining the potential of BC risk in Mexican patients.

 > Subjects and Methods Top

Study participants

Approval for this study was obtained from the Ethics and Research Committee of the Hospital Juárez de México. The case group consisted of patients with a histologically confirmed diagnosis of BC by the Oncology and Pathology Services. The control group consisted of healthy women. Participants were included in this study after obtaining their written informed consent. Clinical characteristics, such as menopausal state, tumor lymph node metastasis (TNM), and age at the time of diagnosis, were obtained from medical records. TNM status was only obtained for the case group. All procedures performed in this study were carried out according to the Code of Ethics of the Helsinki Declaration.

DNA extraction

Genomic DNA was isolated from 5 mL of the whole blood using a sodium perchlorate/chloroform extraction method. Briefly, DNA was prepared by combining each blood sample with 35 mL of lysis buffer (320 mM sucrose, 5 mM MgCl2, 1% [v/v] Triton X-100, 10 mM Tris-HCl, pH 8). The nuclear pellet was collected by centrifugation at 20,006 g for 10 min and then resuspended in 2 mL of solution B (150 mM NaCl, 60 mM EDTA, 1% [w/v] sodium dodecyl sulfate, 400 mM Tris-HCl, pH 8). The suspension was mixed with 0.5 mL of 5 M sodium perchlorate and then incubated at 65°C for 30 min. Following the incubation, 2 mL of chloroform was added, and the mixture was centrifuged at 14,006 g for 10 min. The aqueous DNA-containing upper phase was precipitated by the addition of 2 volumes of 100% ethanol and washed with 70% ethanol. The DNA was then resuspended in 200 μL of 10 mM Tris-HCl, 1 mM EDTA, pH 7.4 and quantified by measuring absorbance at a wavelength of 260 nm.


Genotyping of the FGFR (rs1219648), TOX3 (rs3803662), h TERT (rs10069690), and FTO (rs17817449) polymorphisms was conducted by the TaqMan probe-based real-time polymerase chain reaction (PCR) assays (Applied Biosystems, Foster City, CA, USA) using an ABI Prism 7000 Sequence Detection System with TaqMan Universal PCR Master Mix (Applied Biosystems, Foster City, CA, USA). Forty PCR cycles of the following parameters were utilized: initial denaturalization at 95°C for 10 min; 92°C for 15 s, and then 60°C for 1 min. The fluorescent signals from VIC/FAM-labeled probes of each cycle were detected, and after amplification, allelic discrimination was performed to determine the genotype of each subject. The genotypes were obtained through StepOne v2.1 software (Applied Biosystems, Foster City, CA, USA).

Statistical analysis

Statistical analysis was conducted using the STATA Statistical Package (version 10.1; STATA Corp., College Station, TX, USA). Student's t-test, χ2 test, or Fisher's exact test was used to evaluate whether the distribution of genotype frequencies of FGFR, TOX3, h TERT, and FTO varied between cases and controls. The χ2 test was used to compare the observed and reported genotype frequencies. The χ2 test was also used to assess the deviations of allelic frequencies from the Hardy–Weinberg equilibrium. In all cases, P < 0.05 was considered statistically significant.

 > Results Top

We included 56 patients with a confirmed diagnosis of BC and 83 control subjects; all were eligible for analysis. Clinicopathological characteristics for the entire patient and control populations are depicted in [Table 1]. The studied population had similar demographic and clinical characteristics to those of the control subjects. The main difference between the studied groups was premenopausal status. The majority of volunteers of the control population were premenopause (52/83), whereas among patients with BC, 22/56 were in the premenopausal state [Table 1].
Table 1: Clinicopathological characteristics of the study subjects

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Allelic and genotypic frequencies of the analyzed SNP are presented in [Table 2] and [Table 3], respectively. According to the statistical analysis, there were no significant differences between cases and controls in terms of allelic and genotypic frequencies of rs1219648 (FGFR), rs3803662 (TOX3), and rs17817449 (FTO) [Table 2] and [Table 3]. On the other hand, for the variant rs10069690 (h TERT), the frequencies of alleles C and T in the cases were 93.6% and 6.4%, respectively; in contrast, in the controls, these were 55.4% and 44.6% for alleles C and T, respectively [Table 2]. Statistical analysis revealed a significant difference (P < 0.001) for this variant. Likewise, the genotypic frequencies of CC, CT, and TT genotypes in cases were 89.3%, 7.1%, and 3.6%, whereas these were 38.6%, 33.7%, and 27.7% in control subjects, respectively. These frequencies exhibited significant differences (P < 0.001) [Table 3].
Table 2: Allelic frequency distribution of variants fibroblast growth factor receptor 2, TOX3, FTO, and human telomerase reverse transcriptase in case and control populations

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Table 3: Genotypic frequency distribution of variants fibroblast growth factor receptor 2, TOX3, FTO, and human telomerase reverse transcriptase in case and control populations

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Moreover, we performed an analysis between the distribution of the allelic variant of h TERT in combination with FGFR, TOX3, and FTO variants [Table 4]. The combinatory analysis revealed no statistically significant differences between h TERT and the allelic variants of FGFR, TOX3, and FTO. Interestingly, 100% of the subjects of the case group demonstrated the allelic h TERT TT/FGFR GG, with a significant difference (P = 0.018). Moreover, the combination h TERT CC/TOX3 CA had frequencies of 64.0% and 40.6% in cases and controls, respectively, with a significant difference (P = 0.038) [Table 4].
Table 4: Distribution of allelic variant of human telomerase reverse transcriptase gene in combination with fibroblast growth factor receptor 2, TOX3, and FTO variants

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In addition, we evaluated the possible association between menopausal status and the genotypic frequency distribution of FGFR, TOX3, FTO, and h TERT variants. According to the statistical analysis, no significant difference was found in the genotypic distribution of allelic variants and menopausal status [Table 5].
Table 5: Associations between menopausal status with genotypic frequency of fibroblast growth factor receptor 2, TOX3, FTO, and human telomerase reverse transcriptase variants

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 > Discussion Top

In this study, we evaluated the potential association of SNP in FGFR2, TOX3, h TERT, and FTO genes with the susceptibility to develop BC in Mexican women. Allelic variants in FGFR2, TOX3, and FTO did not show an association with BC susceptibility [Table 2] and [Table 3]. This result is in discrepancy with other studies performed in Caucasian,[5],[22],[23],[24],[25],[26] Asian,[27],[28] African-American,[29],[30] and Latin-American[31] populations.

Interestingly, among the variants included in this study, only SNP rs10069690 of the h TERT gene exhibited a significant difference. Namely, according to our results, the C allele of this SNP revealed a higher frequency in the BC group in comparison with that in the control group [Table 2] and [Table 3]. In this regard, h TERT polymorphisms have been associated with a high risk of developing several types of cancer, such as BC.[32],[33],[34],[35],[36] However, rs10069690 was also associated with a reduced risk of developing a tumor in patients with hepatocellular carcinoma and prostate cancer.[37] In addition, recent research demonstrated that the T allele of rs10069690 might inhibit cancer development.[37] Moreover, a previous study showed that the SNP rs4246742 of h TERT is associated with a protector effect on the development of BC in Caucasian and Latin-American populations, possibly due to its inhibitory effect on the expression of telomerase.[38]

In agreement with that study, we found that h TERT rs10069690 is associated with a reduced risk for BC in the Mexican population. We found that the T allele of h TERT (rs10069690), which is associated with a higher risk of developing cancer in other populations, is present at a higher frequency in the control group than in the BC group. Thus, our results suggest that in the Mexican population, this specific allele might function as a putative protective genetic factor. Although our findings may be contradictory to those of other investigations, the high complexity of the associations of genetic variants and biological, clinical, and epigenetics issues might reflect that genetic heterogeneity among different populations contributes, in a particular way, to increasing or decreasing the risk of developing BC.

One possible explanation for the putative protective effect of the h TERT variant (rs10069690) is due to telomerase activity. Some investigations have demonstrated the primary role of h TERT variants in BC development through the activation of telomerase activity.[39] Telomeres are highly conserved functional structures that generate a protective effect.[40] According to evidence, polymorphisms in the h TERT gene are strictly related to human cancer.[41] The hTERT protein, encoded by the h TERT gene, functions as a catalytic subunit in the telomerase complex and plays a significant role in the activity of human telomerase by preventing the erosion of DNA ends during the replication process, therefore maintaining chromosomal integrity and stability.[42],[43] Telomerase activation has been detected in several carcinomas and immortalized cell cultures, but its expression had not been detected in healthy human cells.[44],[45] In this regard, it is possible that the expression of h TERT in the Mexican population was lower than that of other populations, leading to a protective effect in the development of BC. However, future genotyping PCR assays, with BC patients from different ethnic origins included, need to be performed to demonstrate this hypothesis.

Since polymerase activity is regulated through mRNA alternative splicing, this biological event might be involved in the apparent protective effect of h TERT (rs10069690) T allele in the Mexican population. It is known that the h TERT gene has 16 exons and that its mRNA can produce more than 20 variants.[46] During the development of humans, the loss of telomerase activity in the somatic cells is related to a shift in the splicing pattern of h TERT, producing mRNA splicing variants that do not encode for an active hTERT protein.[47] Evidence suggests that the alternative splicing of h TERT might be involved in RNA–RNA pairing, which might be regulated by the cellular microenvironment. Furthermore, some mRNA h TERT splicing variants may encode proteins that bind to the telomerase enzyme complex, acting as dominant-negative inhibitors of telomerase activity.[48] Thus, if telomerase activity remains inhibited, the neoplastic cell mechanism might be also inhibited.

Finally, we performed a more in-depth analysis of our data to establish a possible association between cancer phenotype and genotypic frequency of all evaluated SNPs. Interestingly, we found a positive correlation between the HER2 phenotype and the genotypic profile [Table 6]. Namely, cancer patients carrying the T allele (heterozygous or recessive homozygous) in h TERT genotypes have a higher probability of expressing the HER2 receptor. Moreover, all patients presenting these genotypes also show Stage III of cancer, which might be correlated with a more rapid progression to invasive disease.[49] Thus, the h TERT variant's effect depends on the carry population group; while, in the control subjects, h TERT variants have shown a protective effect, similar to Caucasian and Latin-American populations (as mentioned above) [Table 2] and [Table 3], in the other small patient proportion, with both BC and T allele, will develop HER2 phenotype [Table 6], a more aggressive BC type. On the other hand, data presented in [Table 5] suggest that the presence of FGFR2, TOX3, h TERT, and FTO variants did not confer an association with the menopausal status in the Mexican population.
Table 6: Associations between cancer phenotype with genotypic frequency of fibroblast growth factor receptor 2, TOX3, FTO, and human Telomerase reverse transcriptase variants

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 > Conclusions Top

Genetic variants might contribute to the incidence of BC according to the ethnic origins. In a Mexican population, the SNPs in FGFR (rs1219648), TOX3 (rs3803662), and FTO (rs17817449) genes were neither associated with the development of BC nor with menopause. Interestingly, the h TERT (rs10069690) variant resulted in a protective effect against the development of BC for Mexican women.


This work was supported by Consejo Nacional de Ciencia y Tecnología research funds (CB-2015-258156). Thanks are due to Alfonso Jair Rangel-Becerril and Mónica Sierra-Martínez for genotyping and technical assistance with the biological samples collection, respectively, and to Elba Reyes-Maldonado for providing hydrolysis probes for SNP determinations. This research was financially supported by Juárez Hospital of México (Hospital Juárez de México). C. V. Arellano-Gutiérrez is grateful to CONACyT (307505) and A. J. Rangel-Becerril to COMECYT (14BTM0403) for graduate student scholarships.

Financial support and sponsorship

The support for this research was provided by the Hospital Juárez de México and Consejo Nacional de Ciencia y Tecnología research funds (CB-2015-258156).

Conflicts of interest

There are no conflicts of interest.

 > References Top

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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