Intronic alterations in<i>BRCA1</i>and<i>BRCA2</i>: effect on mRNA splicing fidelity and expression

Chen, Xiaowei; Truong, Tuyet-Trinh; Weaver, JoEllen; Bove, Betsy; Cattie, Kimberly; Armstrong, Brock; Daly, Mary B.; Godwin, Andrew K.

doi:10.1002/humu.20319

Cited by 68 publications

(56 citation statements)

References 36 publications

(33 reference statements)

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“…Although sequencing might not identify minor populations of normal transcript from the variant allele, the absence of the A-allele at position c.4837 suggests that the wild-type transcript is almost certainly derived from only one of the two alleles. The BRCA1 c.498616T4G variant has been reported previously [Chen et al, 2006] and this variant leads to the activation of the same cryptic splice-site and the same aberrant RNA transcript as described here for the c.498615G4T variant. Six splice prediction programs were used to predict variation in splicing efficiency in the normal sequence vs. the variant sequence (see Materials and Methods): BDGP, NG2, SSF, ASSA, MES, and SSqF.…”

Section: Splice-site Prediction Of Intronic Variants In Brca1 and Brca2supporting

confidence: 75%

“…Exon skipping or the activation of a cryptic splice-site leading to deletion of exon sequences or retention of intronic sequences provide strong evidence that the variant is pathogenic. Alternatively, normal mRNA processing indicates that the variants can be considered as neutral variations [Petrij-Bosch et al, 1997;Scholl et al, 1999;Fetzer et al, 1999;Pyne et al, 2000;Laskie et al, 2001;Hofmann et al, 2003;Claes et al, 2003;Campos et al, 2003;Keaton et al, 2003;Brose et al, 2004;Tesoriero et al, 2005;Chen et al, 2006;Bonatti et al, 2006]. Based on the highly conserved sequences, splice-site prediction programs (SSPPs) have been developed to predict the possible effect of a variant on RNA splicing.…”

Section: Introductionmentioning

confidence: 99%

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Intronic variants inBRCA1andBRCA2that affect RNA splicing can be reliably selected by splice-site prediction programs

et al. 2009

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A large number of sequence variants identified in BRCA1 and BRCA2 cannot be distinguished as either disease-causing mutations or neutral variants. These so-called unclassified variants (UVs) include variants that are located in the intronic sequences of BRCA1 and BRCA2. The purpose of this study was to assess the use of splice-site prediction programs (SSPPs) to select intronic variants in BRCA1 and BRCA2 that are likely to affect RNA splicing. We performed in vitro molecular characterization of RNA of six intronic variants in BRCA1 and BRCA2. In four cases (BRCA1, c.81-6T4A and c.498615G4T; BRCA2, c.76171 2T4G and c.875415G4A) a deleterious effect on RNA splicing was seen, whereas the c.135-15_-12del variant in BRCA1 showed no effect on RNA splicing. In the case of the BRCA2 c.68-7T4A variant, RNA analysis was not sufficient to establish the clinical significance. Six SSPPs were used to predict whether an effect on RNA splicing was expected for these six variants as well as for 23 intronic variants in BRCA1 for which the effect on RNA splicing has been published. Out of a total of 174 predictions, 161 (93%) were informative (i.e., the wild-type splice-site was recognized). No falsenegative predictions were observed; an effect on RNA splicing was always predicted by these programs. In four cases (2.5%) a false-positive prediction was observed. For DNA diagnostic laboratories, these programs are therefore very useful to select intronic variants that are likely to affect RNA splicing for further analysis.

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Section: Splice-site Prediction Of Intronic Variants In Brca1 and Brca2supporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Intronic variants inBRCA1andBRCA2that affect RNA splicing can be reliably selected by splice-site prediction programs

et al. 2009

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“…There is growing evidences for involvement of genetic polymorphisms in complex disorders as they can affect the functions of genes by altering characteristics such as the expression level, altering DNA binding sites, mRNA stabilization, splicing and folding (Jin et al, 1996;Duan et al, 2003;Chen et al, 2006). For the rs10,046 polymorphism of CYP19gene, the exact functional activity is not clearly understood, and it seems not to have an autonomous function, but it has been claimed that in conjunction with other polymorphisms, the rs10,046 polymorphism may influence the levels of mRNA and its stability (Bampali et al, 2015), so it can be associated with altered levels of the aromatase enzyme and affected estrogen metabolism.…”

Section: Discussionmentioning

confidence: 99%

Analysis of CYP17, CYP19 and CYP1A1 Gene Polymorphisms in Iranian Women with Breast Cancer

Farzaneh¹,

Noghabaei²,

Barouti³

et al. 2016

Asian Pacific Journal of Cancer Prevention

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Breast cancer (BC) is the most common cancer and the second cause of mortality in women all around the world. It is caused by several factors including genetic determinants, so that both genetic susceptibility factors and environmental factors are involved in the etiology. Significance of genes functioning in steroid hormone synthesis and metabolism are well established in breast cancer susceptibility. In this study, 134 women with BC and 135 normal controls were analyzed for their genotypes for the polymorphisms, rs743572, rs10046 and rs4646903, resided in CYP17, CYP19 and CYP1A1 genes, respectively. Significant differences in distributions of allele and genotype frequencies were found for the rs10046 polymorphism in CYP19 (p-value=0.01, OR (CI 95%) =1.59 (1.1-2.3), p-value=0.04, OR (CI 95%) =1.7 (1.1-2.5) respectively). For rs743,572 and rs 4646903 polymorphisms, no significant associations were observed. A significant association was observed between the rs10046 polymorphism of the CYP19gene and breast cancer in Iranian patients. Due to inconsistent previous results, more studies in different populations with larger sample sizes are indicated.

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“…The mutant BRCA1/2 were eliminated or destabilized by nonsense-mediated mRNA decay (NMD) and lead to a state of haploinsufficiency (8). Whether AI of BRCA1/2 exists in individuals without BRCA1/2 mutations is rarely studied.…”

Section: Introductionmentioning

confidence: 99%

Allelic Imbalance in BRCA1 and BRCA2 Gene Expression and Familial Ovarian Cancer

Shen

Medico

Zhao³

2011

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Family history is the strongest risk factor for ovarian cancer. Recent evidence suggests that unidentified BRCA1/2 variations or other genetic events may contribute to familial ovarian cancers. Allelic imbalance (AI) of BRCA1/2 expression, a result of a significant decrease in the ratios between the expression from one allele of BRCA1/2 and the other allele, has been observed in breast cancer. The AI of BRCA1/2 expression could decrease the level of transcripts and thus contribute to an increased susceptibility of developing familial ovarian cancer.Methods: To test this hypothesis, we applied a quantitative, allelic-specific, real-time PCR method to survey the levels of AI in BRCA1/2 in lymphoblastoid cell lines (LCL) from 126 familial ovarian cancer patients who are noncarriers of any known BRCA1/2 and MLH/MSH mutations and 118 cancer-free relative controls.Results: The AI ratios of BRCA1, but not BRCA2, in the LCLs from familial ovarian cancer patients were found to be significantly increased as compared with family controls (BRCA1: 0.463 AE 0.054 vs. 0.405 AE 0.111, P ¼ 0.0007; BRCA2: 0.325 AE 0.124 vs. 0.302 AE 0.118, P ¼ 0.328). Using the cutoff point of 0.458 identified from the receiver operating characteristic (ROC) analysis, higher levels of AI were associated with a 4.22-fold increased risk of familial ovarian cancer (95% CI: 1.60-11.16). In further analysis, we observed that levels of AI were negatively significantly correlated with the age of familial ovarian cancer diagnosis (r ¼ À0.469, P < 0.001).Conclusion: Taken together, our data suggest that AI affecting BRCA1 may contribute to familial ovarian cancer. Cancer Epidemiol Biomarkers Prev; 20(1); 50-6. Ó2011 AACR.

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Intronic alterations inBRCA1andBRCA2: effect on mRNA splicing fidelity and expression

Cited by 68 publications

References 36 publications

Intronic variants inBRCA1andBRCA2that affect RNA splicing can be reliably selected by splice-site prediction programs

Intronic variants inBRCA1andBRCA2that affect RNA splicing can be reliably selected by splice-site prediction programs

Analysis of CYP17, CYP19 and CYP1A1 Gene Polymorphisms in Iranian Women with Breast Cancer

Allelic Imbalance in BRCA1 and BRCA2 Gene Expression and Familial Ovarian Cancer

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