This study was a case-control study conducted between October 2019 and October 2021 in the city of Ouagadougou, capital of Burkina Faso (West Africa). The study population consisted of 144 participants, including 65 patients with breast cancer histologically confirmed by a pathologist and 79 healthy controls without breast cancer who came for medical consultations at the University Hospitals: Yalgado Ouédraogo (CHU-YO) and Bogodogo (CHU-B); and at the Medical Centers with Surgical Branch (Paul VI and Schiphra). Biomolecular analyses were performed at the Laboratory of Molecular Biology and Genetics (LABIOGENE), and at the Pietro Annigoni Biomolecular Research Center (CERBA).

We are included in this study the cases related to all female patients with sporadic breast tumor or family history of breast cancer (hereditary) living in Burkina and whose the diagnosis is confirmed histologically by anatomo-pathologist. The cases were recruited during medical consultations (chemotherapy or chemotherapy interval check-up).

The controls included were all female living in Burkina, without any breast anomaly (as confirmed by mammography). Controls were selected from patients admitted to the same hospital for illnesses other than breast cancer.

We are excluded all men, any patient without histological confirmation of breast cancer ; any patient who voluntarily refuses to participate in the study.

Patients were classified as “sporadic breast cancer cases” if no one in their family had or currently has breast cancer. Patients were considered as with “family history of breast cancer” if at least one member of their family (niece, sister, mother, cousin, etc.) had or currently has breast cancer.

We are included all ages were in the study and all patients included in the study freely consented to their participation. We scrupulously respected confidentiality and anonymity. Written informed consents were obtained from each patient and control.

Our study was conducted according the Helsinki Declaration guidelines on ethics in medical research and obtained approval from the Health Research Ethics Committee (CERS) of Burkina Faso (Deliberation No. 2019-5-067 of 15 May 2019).

The socio-demographic, anthropometric and residence data of the participants were obtained via questionnaires. The questionnaires were administered by trained interviewers or working in the field of breast cancer. According to patient’s residence, we used the classification of INSD [24]: urban if the women lived in town (province capital or urban municipality status) with a population greater than 10,000 inhabitants and rural if the community size was smaller. The age at diagnostic was determined by verification of identification card of each participant. Then, 5mLof venous blood from each consenting woman was collected on EDTA (Ethylene-Diamine-Tetra-Acetic) impregnated tubes, centrifuged at 13000 rpm for 15 min, plasma and pellet were stored at -20°C with individual codes. DNA was obtained from the blood pellets by the “Salting Out” technique as described by Miller et al. [25]. Then, using the Biodrop, the DNA extracts were quantified and the purity verified.

The genotyping of the p.R72P and PIN3 Ins16bp polymorphisms of the TP53 gene was performed respectively by ASO-PCR and conventional PCR [26,7]. PCR-RFLP was used for the I157T mutation of the CHEK2 gene [27].

The reaction mix had a volume of 15μl for each polymorphism consisting 3μl of DNA, 2.8μl 5X FIREPol® Master Mix (Solis Biodyne), 8.2μl of sterile water, and 0.5μl of the R and F primers (0.5μM). The sequences of the primer pairs [7] are recorded in Table 1.

The reaction mix had a total volume of 15μl for each polumorphism consisting of 3μl of DNA (10ng/μl), 2.8μl 5X FIREPol ®Master Mix (Solis Biodyne), 8.2μl of sterile water; 0.5μl of each primer pair of the R allele or P allele (0.5μM) and 0.5ul of the Reverse (R) and Forward (F) primers; (0.5μM) of the primers for β-globin gene have been used as internal control. The sequences of the primer pairs [28] are recorded in Table 1. The amplification was performed in a Gene Amp®PCR System 9700 (Applied Biosystems™) thermal cycler. The amplification program for the p.R72P polymorphism (R and P allele) was : an initial denaturation at 95°C, 15 minutes, followed by 35 cycles of amplification (denaturation at 95°C for 30 sec, hybridization at 60°C for 30 sec and elongation at 72°C for 30 sec) and a final extension at 72°C for 5 minutes. We have amplified the P allele and the R allele in separate reactions mix. For the internal control β-globin, the program was : an initial denaturation at 95°C, 15 minutes, followed by 10 cycles (β-globine) of amplification (denaturation at 95°C for 30 sec, hybridization at 60°C for 30 sec, and elongation at 72°C for 30 sec and a final extension at 72°C for 5 minutes.

PCR products were migrated on 2% gel for p.R72P and PIN3 Ins16bp of TP53 gene, 4% for I157T polymorphism of CHEK2 gene subjected to 100Volts and 80 mA voltage

Finally, DNA visualization was done with the Gene Flash Revelation (Synengege Bio Imaging, USA) instruments.

The validity of the PCR amplification of a sample for p.R72P polymorphism were conditioned by amplification of the β-globin gene (260bp) and it is invalid if no bands for β-globin were visible. The P allele is at 177bp and the R allele is at 141bp (Figure 1).

The study population consisted of 144 women, 65 of whom were cases (breast cancer patients) and 79 controls (non-breast cancer patients). The mean age of the cases was 44.51 ± 8.90 years and that of the controls 37.76 ± 11.01 years. Of all cases, 70.77% were older than 40 years. In addition, our results showed a significant difference between subjects over 40 years old and those under 40 years old (p < 0,001). This confirms previous studies that revealed that more than 40 years older have a higher risk than those with less than 40 years.

Also, among the patients, housewives were most represented (39.06%) followed by officials (35.94%) (Table 2).

In this study, parity and nulliparity didn’t show statistically significant difference (p>0.05) between cases and controls. Abortion, age at menarche, regularity of the menstrual cycle, age at first child were not also associated with a risk of breast cancer (Table 3). In the first hand, postmenopausal women are more exposed to breast cancer than those who are not yet (Table 3).

The P allele of the p.R72P polymorphism was the most prevalent in 50.77% of cases in our study population. The R allele was present in only 49.23% of the study participants. But, no association between the occurrence of breast cancer and the alleles R and P (OR=0.96; 95%IC (0.59-1.56); p=0.471) were found. The most present genotype of the p.R72P polymorphism was RP (heterozygous) with a proportion of 73.85% for cases and 73.42% for controls. The homozygous (RR) and (PP) genotypes were respectively 12.30% and 13.85% in the cases and 11.39% and 15.18% in the controls. Furthermore, no genotype was statistically associated (RR: OR=0.93; 95% IC (0.29-3.01); p=0.548 and PP: OR=0.84; 95%IC (0.19-3.68); p=0.527) with a risk of breast cancer (Table 4).

We wanted to know if combined genotypes would increase the risk of developing breast cancer. Then, we paired the polymorphisms p.R72P and PIN3 Ins16bp of TP53. None of the combined polymorphism genotypes were associated with development (p>0.05) (Table 5).

The average number for parity in this study is 2.3 ± 1.8 children and the mean age at first birth was about 24 years (24.03 ± 0.61 years). In the past, African women were characterized by an advanced age at menarche (after 15 years); the birth of the first child at a relatively early age (around 19 years old) and by a relatively high multiparity (5 to 9 children per woman), which would protect them from breast cancer [32]. But the adoption of Western lifestyles nowadays contributes to the regression of these protective factors among African women [33]. This last observation is a reality in our study population.

In our study, associations between nulliparity and multiparity were not associated with the disease occurrence (p=0.067). On the other hand, multiparity is often associated with protection and nulliparity with a risk of breast cancer. Full-term pregnancy and breastfeeding have been shown to contribute to a decrease in estrogen levels and increases this protection against the development of breast cancer [34].

Our results do not indicate a significant difference (p=0.174) between the age at menarche, the irregularity of the menstrual cycle and the development of breast cancer. Our results confirms that of a nigerian study [35] who found no association between age at menarche; parity and risk of developing breast cancer in a study of a cohort of 2000 Nigerian participants. But other studies have reported that an early menarche before the age of 12 increases the risk of developing breast cancer [36].

We also associated the menopausal situation with the disease. Menopause would increase the risk of developing the disease (p=0.002). Among postmenopausal women, patients were 65.12% versus 34.88% for controls and among women who had not yet reached menopausal age, patients were 36.63% versus 63.37 % for controls. This result confirms what Sun et al., reported in 2017 that the risk of breast cancer increases by 3% each year after menopause [37]. But other studies did not find a direct association between breast cancer and age at menopause [38].

Our results show that the P allele of the p.R72P polymorphism was the most frequent in both cases (50.77%) and controls (51.90%) and the R allele had a proportion of 49.34% and 48.10% in cases and controls respectively but no association were found between an allele of this polymorphism and breast cancer. In Tunisian population, a study [39] have not found also association between an allele of the R72P polymorphism and breast cancer but it have showed that the R allele was the frequent in both cases (75%) and controls (65.3%). Out of Africa, our frequencies are slightly different from those obtained by a study in an Indian population [7] where the R allele was most frequent in controls (53.8%) and the P allele most frequent in cases (56.9%). Here also, none allele were associated with brest cancer. In addition, the P allele has been associated with the risk of developing colorectal cancer in the Japanese [40], Korean [41], Chinese [42] and Malaysian [43] population while the R allele has been associated with the risk of developing breast cancer in Greece [44]. It is also reported that the R allele induces apoptosis more efficiently than the P allele [8,45,46]. On the other hand, the P variant is more effective in inducing cell cycle arrest in the G1 phase, allowing better repair of damaged DNA [8,47].

At the genotypic level, the heterozygous genotype (RP) was in the majority in both cases (73.85%) and controls (73.41%) but none genotype were associated with breast cancer. These results are different to those of Guleria et al (2012) [7] in India where heterozygotes were 58.8% in cases and 40% in controls; no association were also reported. Furthermore, the association of PP genotype and increased risk of breast [48], colorectal [49], bladder cancer in the North Indian population have been reported. However, no association was found between breast cancer and the p.R72P polymorphism in Tunisian [39] and Russian [50] patients.

As for the PIN3 Ins16bp polymorphism, the A1 (wild type) allele was the most frequent in both cases (76.15%) and controls (77.85%) and the A2 (mutant) allele had a proportion of 23.85% and 22.15% respectively in cases and controls. We have not found a study in Africa on this polymorphism but these frequencies are similar to those obtained in a study in an Indian population [7] where the A1 allele was the most frequent in both patients (72.5%) and controls (81.9%). The A2 allele had a proportion of 27.5% and 18.1% in cases and controls respectively. At the genotypic level, the wild type (A1A1) was the majority in both cases (53.85%) and controls (60.76%). These results are similar to those of Guleria et al. (2012) in India where wild-type genotypes were the most frequent (53.8% in cases and 66.3% in controls) [7]. The A2A2 genotype has been reported as a risk for the development of breast cancer [51] . Also a high risk of A1A2 genotype in the development of breast cancer has been reported in Iranian population [52]. It is reported that the PIN3 Ins16bp polymorphism is a duplication of 16 base pairs in intron 3 of TP53 gene. It affects mRNA splicing, altering coding regions [7]. The involvement of this polymorphism in cancers such as colon cancer [16] and breast [17] is a consequence of its association to the reduction of p53 mRNA level and decreased apoptotic indices as well as DNA repair capacity in lymphoblastoid cell lines [16].

Finally, for the I157T mutation of the CHEK2 gene, it was found in only one patient in our population. Similarly, the I157T mutation has not been identified in different populations [27,53,54] . Moreover, this mutation has not been associated with an increased risk in the Moroccan population [55]. On the other hand, a large study [56] reported the c.1343T>G mutation of CHEK2 in African subjects. This mutation was associated with a risk of prostate cancer in African men. In this same study three (03) mutations of CHEK2 gene including c.349A> G; c.1036C>T; c.538C>T was associated with breast cancer risk in European women and the c.1312G>T mutation was associated with prostate cancer risk in European men [56]. We did not find an African study reporting the presence of this mutation in Africa. It is reported that following a break in the double-stranded DNA via the action of an ionizing agent or a genotoxic substance, CHEK2 will be activated by phosphorylation and homodimerization by ATM kinase. After the activation of CHEK2, this molecule will activate other molecules such as p53, BRCA1, Cdc25A and Cdc25C. Activation of p53 by activated CHEK2 occurs through phosphorylation of p53 which stabilizes the p53 molecule [19,20]. All this results in consequences such as cell arrest in G1, S and G2/M or activation of DNA repair or apoptosis in certain cases. Thus, the I157T mutation of the CHEK2 gene produces a protein that is stable but unable to recognize p53, Cdc25 and BRCA1. This mutation takes place at the level of exon 3 [57] and leads to the formation of tumors by a dominant negative effect rather than by dysfunction [20].

In this study, none of these polymorphisms have been directly associated with the risk of developing breast cancer. Thus, the p.R72P and PIN3 Ins16bp polymorphisms of the TP53 gene as well as the I157T mutation of the CHEK2 gene do not appear to be genetic factors involved in the development of breast cancer in our study population. But muticenter studies and on large samples are needed before extending this result at national level.

Generally, the effect of a single SNP is weak to implicate a pathology but the combined effects of aberrant SNPs may contribute additively or synergistically to a risk of developing a pathology. In our study, the polymorphisms p.R72P, PIN3 Ins16bp and I157T associated two by two in correlation with the development of breast cancer did not show significant differences (p>0.05). We have not found previous studies regarding the association between p.R72P, PIN3 Ins16bp and I157T polymorphisms in breast cancer. The no association between the combined genotypes and the deseases can be justified by the relatively small sample size that influences the statistical power.

Despite all the efforts made, this study had some limits as the reduced size of the sample. Also, some clinicopathological parameters were not found in the medical records of patients, which weakened the multivariate analysis. The ages between patients and controls were not matched. Also, the subjects of this studies came from hospitals in the only city of Ouagadougou. For future investigations, several cities must be included in the study.

We have in prospects to extend this study to several cities in Burkina Faso to clearly establish the involvement of these polymorphism in development of breast cancer at national level. In addition does not there be a way to restore the alterations of TP53 gene of sporadic cancers? This is a question that we will try to answer in our future studies.

In conclusion, this study showed that the allele P of the p.R72P polymorphism and the wild-type allele (A1) of the PIN3 Ins16bp polymorphism were in the majority. As for the I157T mutation, it was very rare in our study population. In short, in our study, none of these polymorphisms were associated with the risk of developing breast cancer, so they do not appear to be genetic factors involved in the development of breast cancer in our study population. However, given the small size of our population, other investigations of the TP53 and CHEK2 genes in a large population may help to provide definitive informations.

This manuscript has been published as a preprint according to the following link: https://www. researchsquare.com/article/rs-1693953/v1 ORCID link of the corresponding author: https://orcid. org/0000-0002-9423-024X.

Our study obtained approval from the Health Research Ethics Committee (CERS) of Burkina Faso (Deliberation No. 2019-5-067 of 15 May 2019). All participants gave their free and informed consent. We scrupulously respected confidentiality and anonymity. A written consent were obtained from every patient and control.

The data used in this study are available and will be provided by the corresponding author on a reasonable request.

The authors declare that they have no conflict of interest.

No funding announcement.

Conceptualization, JS, AAZ and SD; Methodology: SD, AAZ, TIK, LJA, HKS, MDWA, BSB, LT, TCO and RAO; Formal analysis and investigation: SD, AAZ, HKS, TIK, MDWA and LT; Writing-original draft preparation: AAZ and SD; Writing-review and editing: TIK, LJA,HKS, MDWA, BSB, LT, TCO, RAO, NZ, TMZ, ATY, AYS and FWD; patient enrolment: NZ, AYS, ITK and LJA. Supervision: ATY and JS.

All authors were the major contributors in writing the manuscript. All authors read and approved the final manuscript.

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