Evaluation of Genetic Variations in miRNA-Binding Sites of BRCA1 and BRCA2 Genes as Risk Factors for the Development of Early-Onset and/or Familial Breast Cancer

Abstract

Although genetic markers identifying women at an increased risk of developing breast cancer exist, the majority of inherited risk factors remain elusive. Mutations in the BRCA1/BRCA2 gene confer a substantial increase in breast cancer risk, yet routine clinical genetic screening is limited to the coding regions and intronexon boundaries, precluding the identification of mutations in noncoding and untranslated regions. Because 3' untranslated region (3'UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and can act as genetic markers of cancer risk, we aimed to determine genetic variation in the 3'UTR of BRCA1/BRCA2 in familial and early-onset breast cancer patients with and without mutations in the coding regions of BRCA1/ BRCA2 and to identify specific 3'UTR variants that may be risk factors for cancer development. The 3'UTRs of the BRCA1 and BRCA2 genes were screened by heteroduplex analysis and DNA sequencing in 100 patients from 46 BRCA1/2 families, 54 non-BRCA1/2 families, and 47 geographically matched controls. Two polymorphisms were identified. SNPs c.*1287C>T (rs12516) (BRCA1) and c.*105A>C (rs15869) (BRCA2) were identified in 27% and 24% of patients, respectively. These 2 variants were also identified in controls with no family history of cancer (23.4% and 23.4%, respectively). In comparison to variations in the 3'UTR region of the BRCA1/2 genes and the BRCA1/2 mutational status in patients, there was a statistically significant relationship between the BRCA1 gene polymorphism c.*1287C>T (rs12516) and BRCA1 mutations (p=0.035) by Fisher's Exact Test. SNP c.*1287C>T (rs12516) of the BRCA1 gene may have potential use as a genetic marker of an increased risk of developing breast cancer and likely represents a non-coding sequence variation in BRCA1 that impacts BRCA1 function and leads to increased early-onset and/or familial breast cancer risk in the Turkish population.

Genetic variants in microRNA‐binding sites of DNA repair genes as predictors of recurrence in patients with squamous cell carcinoma of the oropharynx

“…These results indicated that this polymorphism in BRCA1 may function in the development of breast cancer. 27 In contrast, in this study, SCCOP patients with the variant genotypes of BRCA1 rs12516 had a significantly reduced risk of disease recurrence. Our finding may support that this polymorphism in the 3'UTR of BRCA1 alters the ability of miRNA to bind to the BRCA1 3'UTR and leads to loss of certain functions of BRCA1.…”

Mutation screening of MIR146A/B and BRCA1/2 3′-UTRs in the GENESIS study

“…In conclusion, although several studies reported the association of BRCA1 3ʹ-UTR, miR gene or miR-related frequent variants with breast cancer risk, [26][27][28] the clear involvement of rare variants has not been evidenced so far.…”

“…21 Using luciferase reporter assays and bioinformatics predictions, they were able to show that c.*1340_1342delTGT introduces a functional miR-103 target site and might be therefore pathogenic. 21 Data are much scarcer concerning the 3ʹ-UTR of BRCA2, as we are aware of only one small study published so far in 10 Iranian high-risk breast cancer families, 23 and 1 study performed on 100 Turkish earlyonset or familial breast cancer, 26 which both did not lead to the identification of any rare variant. Our study is thus the first to report the screening of this region in a large series, which showed that 3ʹ-UTR variants are extremely rare in BRCA2 (only one variant found, c. *172G4A).…”

Tumor-suppressive microRNA-452 inhibits migration and invasion of breast cancer cells by directly targeting RAB11A

“…Thus, it is important to explore the prevention of metastasis in breast cancer. Studies have recently identified that miRNAs may inhibit (30,31) or enhance the metastasis of breast cancer cells (32) or prostate cancer cells (33). The pivotal role of miRNAs in metastasis via the modulation of various target genes has promoted intensive research into miRNAs as a novel perspective on the metastatic process.…”