Rare<i>BRCA1</i>haplotypes including 3’UTR SNPs associated with breast cancer risk

Pelletier, Cory; Speed, William C.; Paranjape, Trupti; Keane, K; Blitzblau, Rachel; Hollestelle, Antoinette; Safavi, Kyan; Ouweland, Ans van den; Zelterman, Daniel; Slack, Frank J.; Kídd, Kenneth K.; Weidhaas, Joanne B.

doi:10.4161/cc.10.1.14359

Cited by 25 publications

(26 citation statements)

References 34 publications

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“…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.…”

Section: Discussionmentioning

confidence: 84%

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

et al. 2016

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Although a wide number of breast cancer susceptibility alleles associated with various levels of risk have been identified to date, about 50% of the heritability is still missing. Although the major BRCA1 and BRCA2 genes are being extensively screened for truncating and missense variants in breast and/or ovarian cancer families, potential regulatory variants affecting their expression remain largely unexplored. In an attempt to identify such variants, we focused our attention on gene regulation mediated by microRNAs (miRs). We screened two genes, MIR146A and MIR146B, producing miR-146a and miR-146b-5p, respectively, that regulate BRCA1, and the 3ʹ-untranslated regions (3ʹ-UTRs) of BRCA1 and BRCA2 in the GENESIS French national case/control study (BRCA1-and BRCA2-negative breast cancer cases with at least one sister with breast cancer and matched controls). We identified one rare variant in MIR146A, four in MIR146B, five in BRCA1 3ʹ-UTR and one in BRCA2 3ʹ-UTR in 716 index cases and 619 controls. Among these 11 rare variants, 7 were identified each in 1 index case. None of the three relevant MIR146A/MIR146B variants affected the pre-miR sequences. The potential causality of the four relevant BRCA1/BRCA2 3ʹ-UTRs variants was evaluated with luciferase reporter assays and co-segregation studies, as well as with bioinformatics analyses to predict miRs-binding sites, RNA secondary structures and RNA accessibility. This is the first study to report the screening of miR genes and of BRCA2 3ʹ-UTR in a large series of familial breast cancer cases. None of the variant identified in this study gave convincing evidence of potential pathogenicity.

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Section: Discussionmentioning

confidence: 84%

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

et al. 2016

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“…The ability of miRNAs to bind to the 3'UTR of mRNA is critical for regulating mRNA levels and protein expression, and this binding can be affected by single-nucleotide polymorphisms. Data from our group and others indicate that BRCA1/2 3'UTR variants may be potential genetic markers of breast cancer risk (Pongsavee et al, 2009;Pelletier et al, 2011). It is possible that the c.*1287C>T (rs12516) SNP in the 3'UTR region of the BRCA1 gene reported here could decrease the affinity of binding or create or eliminate new binding sites for some miRNAs.…”

Section: Discussionmentioning

confidence: 97%

“…Most notably, rs16888927, rs16888997, and rs16889040 in introns of RAD21, rs12516 in introns of BRCA1 and rs15869 in introns of BRCA2 were reported, suggesting that SNPs in other genes in the DSBR pathway may affect breast cancer risk. In another study, Pelletier et al, (2011) reported numerous known BRCA1 3'UTR SNPs. To identify the frequency of these known polymorphisms and/or to identify novel SNPs (Betel et al, 1994) of this binding site, Effect: The impact of different alleles, Allele: The considered allele; Score: The predicted score of miRNA-mRNA binding by miRanda software.…”

Section: Clinical Associationmentioning

confidence: 99%

“…However, although no variation was determined via BRCA1/2 screening in some patients, they did not respond to the available therapy (Ford et al, 1998). To date, the genetic screening of the BRCA1 and BRCA2 genes has been performed only for coding regions; nonetheless, the importance of miRNAs in the regulation of BRCA genes was recently identified (Sehl et al, 2009;Pelletier et al, 2011). As the majority of these miRNAs binds to the 3'UTR region of the genes (Sehl et al, 2009), variations in the 3'UTR regions of BRCA1/2 may also affect the regulation of related proteins and thus response to the applied therapy (Nilsen, 2007).…”

Section: Introductionmentioning

confidence: 99%

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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

Ertürk¹,

Çeçener²,

Polatkan³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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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.

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“…As previously reported, the derived alleles at rs12516 and rs8176318 in the BRCA1 3'UTR demonstrated a positive association with familial ovarian and breast cancer in Thai women, and the 2 SNPs were in strong linkage disequilibrium in populations and varied by ethnicity (8). In the present study, in order to better evaluate the global genotypes of rs12516 and rs8176318 in BRCA1, the frequency distribution data of these variants across 11 worldwide populations were summarized (Tables III and IV).…”

Section: Brca1 3'utr Selected Variants and Their Putative Mirna Bindimentioning

confidence: 99%

Identification and frequency of the rs12516 and rs8176318 BRCA1 gene polymorphisms among different populations

Yang

Chen

et al. 2016

Oncology Letters

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Abstract. Genetic mutation of breast cancer 1 (BRCA1) is one of the most notable factors responsible for a proportion of breast cancer cases. BRCA1 encodes a 1,863-amino acid protein and functions as a negative regulator of tumor growth. Thus, investigation of the underlying mechanisms that regulate BRCA1 gene expression provide further insight into possible targets for breast cancer therapy. Previous studies have demonstrated that the genetic variants in the BRCA1 3' untranslated region (3'UTR), in addition to the cytosine-phosphate-guanine (CpG) islands in the promoter region, are significantly associated with breast cancer risk; however, the role of single nucleotide polymorphisms (SNPs) in the BRCA1 3'UTR remains unclear. The present study aimed to investigate the association between SNPs and BRCA1 mRNA expression levels. Bioinformatics analysis demonstrated that 2 SNPs in the BRCA1 3'UTR (rs12516 and rs8176318 with putative microRNA binding sites) were significantly correlated with mRNA expression in lymphoblastoid cell lines (P=2.55x10 , respectively). Furthermore, the genotype frequency distribution varied between populations worldwide. In addition, 3 CpG islands and several transcription factor binding sites in the BRCA1 promoter region were established. The identification of such polymorphisms and CpG islands may aid in designing improved therapeutic strategies to treat patients with BRCA1-associated breast cancer.

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RareBRCA1haplotypes including 3’UTR SNPs associated with breast cancer risk

Abstract: . Weidhaas (2011) Rare BRCA1 haplotypes including 3'UTR SNPs associated with breast cancer risk, Cell Cycle, 10:1, 90-99,

Cited by 25 publications

References 34 publications

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

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

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

Identification and frequency of the rs12516 and rs8176318 BRCA1 gene polymorphisms among different populations

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