The<i>BRCA1</i>3′-UTR: 5711+421T/T_5711+1286T/T Genotype Is a Possible Breast and Ovarian Cancer Risk Factor

Pongsavee, Malinee; Yamkamon, Vichanan; Dakeng, Sumana; O-charoenrat, Pornchai; Smith, Duncan R.; Saunders, Grady F.; Patmasiriwat, Pimpicha

doi:10.1089/gtmb.2008.0127

Cited by 29 publications

(35 citation statements)

References 51 publications

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“…Our observation in CRC patients correlates well with the results obtained in a several transformed colon cell lines, further suggesting that altered PIGK expression may be an early event in colon carcinogenesis. In a recent study, 3' UTR polymorphisms in the BRCA1 gene were shown to be associated with reduced gene activity and this alteration was proposed as a possible breast and ovarian cancer risk factor (17). Similar to the CRC patients, we observed altered alleles (C/G or G/G) and corresponding low PIGK protein expression in some HCC patients and cell lines.…”

Section: Discussionsupporting

confidence: 72%

A single nucleotide polymorphism in the human PIGK gene associates with low PIGK expression in colorectal cancer patients

Dasgupta

Pal

Mukhopadhyay

et al. 2012

International Journal of Oncology

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Abstract. Colorectal cancer (CRC) represents one of the highest incidences of cancers worldwide. Phosphatidylinositol glycan, class K (PIGK), is a crucial member of the glycosylphosphatidylinositol transamidase (GPIT) protein complex that attaches a diverse group of macromolecules to the plasma membrane of eukaryotes. However, the precise role of PIGK in tumorigenesis remains largely unknown. Recently, we reported low expression of PIGK protein in primary tumors compared to paired normal tissues of colorectal cancer (CRC) patients. To understand the mechanism underlying this phenomenon, we performed sequencing of all 10 exons of the PIGK gene in 45 CRC patients. Corresponding PIGK protein expression was also evaluated in these patients by immunohistochemistry. No mutation was detected in the coding regions, however, we found a single nucleotide polymorphism (C/C→C/G or G/G; rs1048575) in the 3'UTR of the PIGK gene in 67% (30/45) of the patients. Most of the patients (22/26, 85%) with the altered alleles were of Jewish origin. In comparison, 47% (8/17) of the Arabian patients exhibited the altered C/G alleles. We observed a significantly low (p<0.002) expression of PIGK protein in the patients with the altered alleles

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Section: Discussionsupporting

confidence: 72%

A single nucleotide polymorphism in the human PIGK gene associates with low PIGK expression in colorectal cancer patients

Dasgupta

Pal

Mukhopadhyay

et al. 2012

International Journal of Oncology

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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: 65%

“…However, based on fisher's exact test, although no significant association was determined In the present study in Turkish breast cancer patients, two SNPs were detected in the 3'UTR of BRCA1 and BRCA2 at positions c.*1287C>T (rs12516) (BRCA1) and c.*105A>C (rs15869) (BRCA2). In the literature, these polymorphisms are associated with an increased risk of breast/ovarian cancer among familial and early-onset cancer groups, particularly in patients without mutations in the coding sequences of BRCA1 and BRCA2 (Pongsavee et al, 2009;Nicoloso et al, 2010). One study (Sehl et al, 2009) reported that SNPs within or near several double-stranded break repair DNA repair pathway genes are associated with breast cancer in individuals from a high-risk population.…”

Section: Clinical Associationmentioning

confidence: 99%

“…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). In addition, the importance of miRNA-binding site single-nucleotide polymorphisms (SNPs) of the BRCA1/2 genes in breast and ovarian cancer has been emphasized in recent studies of certain individual populations (Barroso et al, 2009;Pongsavee et al, 2009;Sehl et al, 2009;Kontorovich et al, 2010;Nicoloso et al, 2010;Joseph et al, 2011). However, knowledge about the effect of 3'UTR site variations of BRCA1/2 remains elusive.…”

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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“…16,[21][22][23][24][25] The first published studies reported two variants: c.*36C4G, identified while screening 211 breast cancer cases, 22 and c.*372_387del16 while screening 78 breast cancer cases belonging to high-risk breast and ovarian cancer families. 25 Pietschmann et al screened BRCA1/BRCA2 coding sequences and 5ʹ-and 3ʹ-UTRs in 10 Iranian high-risk breast cancer families.…”

Section: Discussionmentioning

confidence: 99%

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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TheBRCA13′-UTR: 5711+421T/T_5711+1286T/T Genotype Is a Possible Breast and Ovarian Cancer Risk Factor

Abstract: These results suggest that the inheritance of specific 3'-UTR polymorphisms may predispose individuals to early-onset or familial breast or ovarian cancer.

Cited by 29 publications

References 51 publications

A single nucleotide polymorphism in the human PIGK gene associates with low PIGK expression in colorectal cancer patients

A single nucleotide polymorphism in the human PIGK gene associates with low PIGK expression in colorectal cancer patients

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

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

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