MicroRNA‑126 expression in the peripheral white blood cells of patients with breast and ovarian cancer is a potential biomarker for the early prediction of cancer risk in the carriers of methylated <i>BRCA1</i>

Al‐Showimi, Maram; Al‐Yousef, Nujoud; Alharbi, Wejdan; Alkhezayem, Sara; Almalik, Osama; Alhusaini, Hamed; Alghamdi, Amani K. Hamdan; Al‐Moghrabi, Nisreen

doi:10.3892/ol.2022.13396

Cited by 6 publications

(9 citation statements)

References 45 publications

(77 reference statements)

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“…Moreover, studying the molecular effects of BRCA1 epimutation in WBCs has shown that there are cancer-related molecular changes that can occur in adult carriers and, more importantly, in newborn carriers. These changes are similar to those seen in females who have been diagnosed with breast cancer and ovarian cancer [5,9,25]. Thirdly, in a recent study [5], we found that the WBCs of CF BRCA1 methylation carriers had less ILR2G (a T cell functional molecule), suggesting that these carriers have reduced antitumor immunity.…”

Section: Discussionsupporting

confidence: 86%

“…Based on our data, almost 19% of CF Saudi women are carriers of constitutional epimutations: 10% carry MGMT epimutations and 8.6% carry BRCA1 epimutations from early on in life. Mounting evidence substantiates the notion that such persons are at a heightened risk of developing breast and/or ovarian cancer [ 4 , 5 , 9 , 25 , 31 , 32 , 33 ]. We previously demonstrated that the levels and arrangements of CpG island methylation at the BRCA1 promoters in WBCs are comparable among cancer patients, newborns, and adult BRCA1 methylation carriers [ 4 ].…”

Section: Discussionmentioning

confidence: 84%

“…Those who have inherited BRCA1 mutations have an increased risk of developing breast and ovarian cancer during their youth. In a similar vein, constitutive BRCA1 methylation is a substantial risk factor for serous ovarian cancer and is associated with a 3.5-fold increased risk of early-onset breast cancer [ 3 , 9 , 10 , 11 ]. Notably, pathogenic germline BRCA 1 mutations and methylated BRCA1 promoter methylation have been shown to be mutually exclusive in breast and ovarian cancer [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Constitutional BRCA1 and MGMT Methylation Are Significant Risk Factors for Triple-Negative Breast Cancer and High-Grade Serous Ovarian Cancer in Saudi Women

Al-Moghrabi,

Al-Showimi,

Alqahtani

et al. 2024

IJMS

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Breast cancer (BC) and ovarian cancer (OC) are rapidly increasing in Saudi Arabia. BRCA1 and MGMT epimutations have been linked to a higher risk of these malignancies. The present research investigated the impact of these epimutations on the prevalence of BC and OC among Saudi women. DNA methylation was evaluated using methylation-specific PCR, whereas mRNA expression levels were assessed using qRT-PCR. We evaluated white blood cell (WBC)–BRCA1 methylation in 1958 Saudi women (908 BC patients, 223 OC patients, and 827 controls). MGMT methylation was determined in 1534 of the 1958 women (700 BC patients, 223 OC patients, and 611 controls). BRCA1 methylation was detected in 8.6% of the controls and 11% of the BC patients. This epimutation was linked to 13.8% of the early-onset BC patients (p = 0.003) and 20% of the triple-negative breast cancer (TNBC) patients (p = 0.0001). BRCA1 methylation was also detected in 14% of the OC patients (p = 0.011), 19.4% of patients aged <55 years (p = 0.0007), and 23.4% of high-grade serous ovarian cancer (HGSOC) patients. In contrast, the BRCA1 mutation was detected in 24% of the OC patients, 27.4% of patients aged ≥55 years, and 26.7% of the HGSOC patients. However, MGMT methylation was detected in 10% of the controls and 17.4% of the BC patients (p = 0.0003). This epimutation was linked to 26.4% of the late-onset BC patients (p = 0.0001) and 11% of the TNBC patients. MGMT methylation was also found in 15.2% of the OC patients (p = 0.034) and 19.1% of HGSOC patients (p = 0.054). Furthermore, 36% of the BRCA1-methylated patients and 34.5% of the MGMT-methylated patients had a family history of cancer, including breast and ovarian cancer. Notably, BRCA1 and MGMT mRNA levels were greater in the WBC RNA of the BC patients and cancer-free methylation carriers than in that of the OC patients. Our data indicate that BRCA1 and MGMT epimutations significantly contribute to the development of breast cancer and ovarian cancer in Saudi cancer patients. These blood-based biomarkers could help identify female patients at high risk of developing TNBC and HGSOC at an early age.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

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Constitutional BRCA1 and MGMT Methylation Are Significant Risk Factors for Triple-Negative Breast Cancer and High-Grade Serous Ovarian Cancer in Saudi Women

Al-Moghrabi,

Al-Showimi,

Alqahtani

et al. 2024

IJMS

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“…To evaluate the use of WBC miR-155-5p as a molecular biomarker for the assessment of cancer risk in CF-BRCA1 methylation-carrying females, we measured the level of WBC miR-155-5p in ten BRCA1-methylation carriers, as used in our previous study [39]. Notably, similar to the BRCA1-methylation-positive patients with breast and ovarian cancers, miR-155-5p was significantly higher in the BRCA1-methylated carriers compared to age-matched controls (p = 0.0418) (Figure 6A).…”

Section: Mir-155-5p Is Elevated In Wbcs Of Brca1-methylation Female C...mentioning

confidence: 99%

MicroRNA-155-5p, Reduced by Curcumin-Re-Expressed Hypermethylated BRCA1, Is a Molecular Biomarker for Cancer Risk in BRCA1-methylation Carriers

Al-Moghrabi,

Al-Showimi,

Al-Yousef

et al. 2023

IJMS

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Constitutional BRCA1-methylation is a cancer risk factor for breast (BC) and ovarian (OC) cancer. MiR-155, regulated by BRCA1, is a multifunctional microRNA that plays a crucial role in the immune system. The present study assessed the modulation of miR-155-5p expression in peripheral white blood cells (WBCs) of BC and OC patients and cancer-free (CF) BRCA1-methylation female carriers. Additionally, we investigated the potential of curcumin to suppress miR-155-5p in BRCA1-deficient breast cancer cell lines. MiR-155-5p expression was measured using a stem-loop RT-qPCR method. Gene expression levels were determined using qRT-PCR and immunoblotting. MiR-155-5p was more highly expressed in the BRCA1-hypermethylated HCC-38 and UACC-3199 BC cell lines than in the BRCA1-mutated (HCC-1937) and WT BRCA1 (MDA-MB-321) cell lines. Curcumin suppressed miR-155-5p in the HCC-38 cells but not in the HCC-1937 cells via the re-expression of BRCA1. Elevated levels of miR-155-5p were detected in patients with non-aggressive and localized breast tumors and in patients with late-stage aggressive ovarian tumors, as well as in CF BRCA1-methylation carriers. Notably, IL2RG levels were reduced in the OC and CF groups but not in the BC group. Together, our findings suggest opposing effects of WBC miR-155-5p, according to the cell and cancer type. In addition, the results point to miR-155-5p as a candidate biomarker of cancer risk among CF-BRCA1-methylation carriers.

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“…Few reports on miRNAs and the regulation of candidate genes involving the risk of BC are still inadequate in the Saudi population [ 14 , 15 ]. In addition, research on candidate gene miRNA polymorphisms, miR-196a2 (MIM 609687), miR-146a (MIM 610566), and miR-499 (MIM 613614), and their implications on BC risk is still insufficient.…”

Section: Introductionmentioning

confidence: 99%

Prospective Functions of miRNA Variants May Predict Breast Cancer Among Saudi Females

Ekram,

Alghamdi,

Elhawary

et al. 2023

Cureus

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Background Growing knowledge supports the importance of microRNAs (miRNAs) in modulating the initiation and development of breast cancer (BC) and underlying mechanisms. BC is a significant public health in females worldwide, where it remains the leading cause of death among Saudi females. Here, we evaluate the susceptibility of the miRNA genetic variants to the risk of BC in Saudi females. Methods One hundred fifty-four females, including 76 females diagnosed with BC and 78 healthy controls, were analyzed using TaqMan™ (Thermo Fischer Scientific, Waltham, MA) genotyping assays for the miR-196a2 rs11614913 C>T, miR-146a rs2910164 C>G, and miR-499 rs3746444 A>G. We utilized the SNPStats software ( https://www.snpstats.net ) (Institut Català d'Oncologia, Barcelona, Spain) to choose the best interactive inheritance model for the examined miRNAs. Results The examined miRNA single-nucleotide polymorphisms (SNPs) showed no clear association with the risk of BC (P > 0.05). As for genotypic distributions, significant associations were found for the rs2910164 SNP in most interactive models of inheritance: 2.50 (95% confidence interval {CI}, 1.2-5.17; P = 0.0135) in the codominant model, 2.34 (95% CI, 1.11-4.8; P = 0.0197) in the dominant model, and 2.40 (95% CI, 1.22-4.73; P = 0.0113) in overdominant model. The rs2910164 C/G heterozygosity showed overexpression in cases compared to controls (73.7% versus 53.9%; chi-squared (χ 2 ) = 6.5; P = 0.0109), but the homozygous rs2910164 G/G showed a significant protective effect (21.1% versus 38.5%; χ 2 = 17.4; P = 0.019). The heterozygosity did not affect the risk to the BC in the two miRNAs (rs11614913 C>T and rs3746444 A>G). Conclusion Despite lacking associations with the examined miRNAs, the heterozygous genotype rs2910164 C/G can identify at-risk females. More studies should be replicated using a panel of miRNA genes to discover significant associations with the risk of BC.

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MicroRNA‑126 expression in the peripheral white blood cells of patients with breast and ovarian cancer is a potential biomarker for the early prediction of cancer risk in the carriers of methylated BRCA1

Cited by 6 publications

References 45 publications

Constitutional BRCA1 and MGMT Methylation Are Significant Risk Factors for Triple-Negative Breast Cancer and High-Grade Serous Ovarian Cancer in Saudi Women

Constitutional BRCA1 and MGMT Methylation Are Significant Risk Factors for Triple-Negative Breast Cancer and High-Grade Serous Ovarian Cancer in Saudi Women

MicroRNA-155-5p, Reduced by Curcumin-Re-Expressed Hypermethylated BRCA1, Is a Molecular Biomarker for Cancer Risk in BRCA1-methylation Carriers

Prospective Functions of miRNA Variants May Predict Breast Cancer Among Saudi Females

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