Dataset Information

Tumor suppressor genes and allele-specific expression: mechanisms and significance.

ABSTRACT: Recent findings indicate that allele-specific expression (ASE) at specific cancer driver gene loci may be of importance in onset/progression of the disease. Of particular interest are loss-of-function (LOF) of tumor suppressor gene (TSGs) alleles. While LOF tumor suppressor mutations are typically considered to be recessive, if these mutant alleles can be significantly differentially expressed relative to wild-type alleles in heterozygotes, the clinical consequences could be significant. LOF TSG alleles are shown to be segregating at high frequencies in world-wide populations of normal/healthy individuals. Matched sets of normal and tumor tissues isolated from 233 cancer patients representing four diverse tumor types demonstrate functionally important changes in patterns of ASE in individuals heterozygous for LOF TSG alleles associated with cancer onset/progression. While a variety of molecular mechanisms were identified as potentially contributing to changes in ASE patterns in cancer, changes in DNA copy number and allele-specific alternative splicing possibly mediated by antisense RNA emerged as predominant factors. In conclusion, LOF TSGs are segregating in human populations at significant frequencies indicating that many otherwise healthy individuals are at elevated risk of developing cancer. Changes in ASE between normal and cancer tissues indicates that LOF TSG alleles may contribute to cancer onset/progression even when heterozygous with wild-type functional alleles.

SUBMITTER: Clayton EA

PROVIDER: S-EPMC6996918 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tumor suppressor genes and allele-specific expression: mechanisms and significance.

Clayton Evan A EA Khalid Shareef S Ban Dongjo D Wang Lu L Jordan I King IK McDonald John F JF

Oncotarget 20200128 4

Recent findings indicate that allele-specific expression (ASE) at specific cancer driver gene loci may be of importance in onset/progression of the disease. Of particular interest are loss-of-function (LOF) of tumor suppressor gene (TSGs) alleles. While LOF tumor suppressor mutations are typically considered to be recessive, if these mutant alleles can be significantly differentially expressed relative to wild-type alleles in heterozygotes, the clinical consequences could be significant. LOF TSG ...[more]

PMID: 32064050

Similar Datasets

Project description:BackgroundThe expression of genes involved in regulating adipogenesis and lipid metabolism may affect economically important fatness traits in pigs. Allele-specific expression (ASE) reflects imbalance between allelic transcript levels and can be used to identify underlying cis-regulatory elements. ASE has not yet been intensively studied in pigs. The aim of this investigation was to analyze the differential allelic expression of four genes, PPARA, PPARG, SREBF1, and PPARGC1A, which are involved in the regulation of fat deposition in porcine subcutaneous and visceral fat and longissimus dorsi muscle.ResultsQuantification of allelic proportions by pyrosequencing revealed that both alleles of PPARG and SREBF1 are expressed at similar levels. PPARGC1A showed the greatest ASE imbalance in fat deposits in Polish Large White (PLW), Polish Landrace and Pietrain pigs; and PPARA in PLW pigs. Significant deviations of mean PPARGC1A allelic transcript ratio between cDNA and genomic DNA were detected in all tissues, with the most pronounced difference (p < 0.001) in visceral fat of PLW pigs. To search for potential cis-regulatory elements affecting ASE in the PPARGC1A gene we analyzed the effects of four SNPs (rs337351686, rs340650517, rs336405906 and rs345224049) in the promoter region, but none were associated with ASE in the breeds studied. DNA methylation analysis revealed significant CpG methylation differences between samples showing balanced (allelic transcript ratio ≈1) and imbalanced allelic expression for CpG site at the genomic position in chromosome 8 (SSC8): 18527678 in visceral fat (p = 0.017) and two CpG sites (SSC8:18525215, p = 0.030; SSC8:18525237, p = 0.031) in subcutaneous fat.ConclusionsOur analysis of differential allelic expression suggests that PPARGC1A is subjected to cis-regulation in porcine fat tissues. Further studies are necessary to identify other regulatory elements localized outside the PPARGC1A proximal promoter region.

Project description:BackgroundTargeted therapies in oncology are promising but variants of uncertain significance (VUS) limit their use for clinical management and necessitate functional testing in vitro. Using BRCA1 and BRCA2 variants, which have consequences on PARP inhibitor sensitivity, and POLE variants, potential biomarkers of immunotherapy response, we developed a rapid functional assay based on CRISPR-Cas9 genome editing to determine the functional consequences of these variants having potentially direct implications on patients' access to targeted therapies.MethodsWe first evaluated the functional impact of 26 BRCA1 and 7 BRCA2 variants by editing and comparing NGS results between the variant of interest and a silent control variant. Ten of these variants had already been classified as benign or pathogenic and were used as controls. Finally, we extended this method to the characterization of POLE VUS.ResultsFor the 23 variants that were unclassified or for which conflicting interpretations had been reported, 15 were classified as functionally normal and 6 as functionally abnormal. Another two variants were found to have intermediate consequences, both with potential impacts on splicing. We then compared these scores to the patients' responses to PARP inhibitors when possible. Finally, to prove the application of our method to the classification of variants from other tumor suppressor genes, we exemplified with three POLE VUS. Among them, two were classified with an intermediate functional impact and one was functionally abnormal. Eventually, four POLE variants previously classified in databases were also evaluated. However, we found evidence of a discordance with the classification, variant p.Leu424Val being found here functionally normal.ConclusionsOur new rapid functional assay can be used to characterize the functional implication of BRCA1 and BRCA2 variants, giving patients whose variants were evaluated as functionally abnormal access to PARP inhibitor treatment. Retrospective analysis of patients' responses to PARP inhibitors, where accessible, was consistent with our functional score evaluation and confirmed the accuracy of our protocol. This method could potentially be extended to the classification of VUS from all essential tumor suppressor genes and can be performed within a timeframe compatible with clinical applications, thereby having a direct theranostic impact.

Dataset Information

Tumor suppressor genes and allele-specific expression: mechanisms and significance.

Publications

Tumor suppressor genes and allele-specific expression: mechanisms and significance.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets