Analysis of MUTYH alternative transcript expression, promoter function, and the effect of human genetic variants

2019 ◽  
Vol 40 (4) ◽  
pp. 472-482 ◽  
Author(s):  
Nicole Köger ◽  
Angela Brieger ◽  
Inga M. Hinrichsen ◽  
Stefan Zeuzem ◽  
Guido Plotz
Keyword(s):  
Genetic Variants ◽  
Alternative Transcript ◽  
Transcript Expression ◽  
Promoter Function

scholarly journals Breast Cancer Patient Prognosis Is Determined by the Interplay between TP53 Mutation and Alternative Transcript Expression: Insights from TP53 Long Amplicon Digital PCR Assays

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1531
Author(s):  
Annette Lasham ◽  
Nicholas Knowlton ◽  
Sunali Y. Mehta ◽  
Antony W. Braithwaite ◽  
Cristin G. Print
Keyword(s):  
Breast Cancer ◽  
Gene Locus ◽  
Tp53 Mutation ◽  
P53 Protein ◽  
Tp53 Gene ◽  
Digital Pcr ◽  
Protein Isoforms ◽  
Alternative Transcript ◽  
Transcript Expression ◽  
Splice Sites

The TP53 gene locus is capable of producing multiple RNA transcripts encoding the different p53 protein isoforms. We recently described multiplex long amplicon droplet digital PCR (ddPCR) assays to quantify seven of eight TP53 reference transcripts in human tumors. Here, we describe a new long amplicon ddPCR assay to quantify expression of the eighth TP53 reference transcript encoding ∆40p53α. We then applied these assays, alongside DNA sequencing of the TP53 gene locus, to tumors from a cohort of New Zealand (NZ) breast cancer patients. We found a high prevalence of mutations at TP53 splice sites in the NZ breast cancer cohort. Mutations at TP53 intron 4 splice sites were associated with overexpression of ∆133TP53 transcripts. Cox proportional hazards survival analysis showed that interplay between TP53 mutation status and expression of TP53 transcript variants was significantly associated with patient outcome, over and above standard clinical and pathological information. In particular, patients with no TP53 mutation and a low ratio of TP53 transcripts t2 to t1, which derive from alternative intron 1 acceptor splice sites, had a remarkably good outcome. We suggest that this type of analysis, integrating mutation and transcript expression, provides a step-change in our understanding of TP53 in cancer.

scholarly journals Impact of regulatory variation from RNA to protein

Science ◽  
2014 ◽  
Vol 347 (6222) ◽  
pp. 664-667 ◽  
Author(s):  
Alexis Battle ◽  
Zia Khan ◽  
Sidney H. Wang ◽  
Amy Mitrano ◽  
Michael J. Ford ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Messenger Rna ◽  
Effect Sizes ◽  
Posttranslational Regulation ◽  
Transcript Expression ◽  
Protein Abundance ◽  
Expression Levels ◽  
Protein Levels ◽  
Potential Impact ◽  
The Impact

The phenotypic consequences of expression quantitative trait loci (eQTLs) are presumably due to their effects on protein expression levels. Yet the impact of genetic variation, including eQTLs, on protein levels remains poorly understood. To address this, we mapped genetic variants that are associated with eQTLs, ribosome occupancy (rQTLs), or protein abundance (pQTLs). We found that most QTLs are associated with transcript expression levels, with consequent effects on ribosome and protein levels. However, eQTLs tend to have significantly reduced effect sizes on protein levels, which suggests that their potential impact on downstream phenotypes is often attenuated or buffered. Additionally, we identified a class of cis QTLs that affect protein abundance with little or no effect on messenger RNA or ribosome levels, which suggests that they may arise from differences in posttranslational regulation.

scholarly journals Canonical and alternative transcript expression of PAX6 and CXCR4 in pancreatic cancer

2017 ◽  
Vol 13 (6) ◽  
pp. 4027-4034 ◽  
Author(s):  
Elizabeth C. Little ◽  
Jennifer D. Kubic ◽  
Ravi Salgia ◽  
Paul J. Grippo ◽  
Deborah Lang
Keyword(s):  
Pancreatic Cancer ◽  
Alternative Transcript ◽  
Transcript Expression

Genetic Variation: Impact on Folate (and Choline) Bioefficacy

2010 ◽  
Vol 80 (45) ◽  
pp. 319-329 ◽  
Author(s):  
Allyson A. West ◽  
Marie A. Caudill
Keyword(s):  
Carbon Metabolism ◽  
Genetic Variants ◽  
Plasma Homocysteine ◽  
Water Soluble ◽  
Gene Interactions ◽  
Dietary Folate ◽  
Methyl Donors ◽  
Common Genetic Variants ◽  
One Carbon Metabolism ◽  
The Impact

Folate and choline are water-soluble micronutrients that serve as methyl donors in the conversion of homocysteine to methionine. Inadequacy of these nutrients can disturb one-carbon metabolism as evidenced by alterations in circulating folate and/or plasma homocysteine. Among common genetic variants that reside in genes regulating folate absorptive and metabolic processes, homozygosity for the MTHFR 677C > T variant has consistently been shown to have robust effects on status markers. This paper will review the impact of genetic variants in folate-metabolizing genes on folate and choline bioefficacy. Nutrient-gene and gene-gene interactions will be considered along with the need to account for these genetic variants when updating dietary folate and choline recommendations.

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