Dataset Information

Large-scale discovery of chromatin dysregulation induced by oncofusions and other protein-coding variants

ABSTRACT: Although population-scale databases have expanded to millions of genetic variants, mechanistic insight into variant function has not kept pace. We present PROD-ATAC, a high-throughput method for discovering the effects of protein-coding variants on chromatin regulation. A pooled library of variants is expressed in a disease-agnostic biosensor cell line, and single-cell ATAC resolves each variant’s effect on chromatin. Using PROD-ATAC, we characterized the impacts of >100 oncogenic fusions and controls. We showed that pioneer activity is a common feature of fusions spanning an enormous range of frequencies. Further, fusion-induced dysregulation can be context-agnostic as observed mechanisms overlapped with cancer and cell-type specific prior knowledge. We also showed that gain-of-function pioneering is a common feature among oncofusions. This work provides a global view of fusion-induced chromatin disruption across many fusion frequencies and cancer types. Systematically dissecting this landscape revealed convergent mechanisms among seemingly disparate oncofusions and shared modes of chromatin dysregulation across different cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243553 | GEO | 2024/07/24

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Interethnic variability in chemotherapy response is becoming increasingly evident, making approaches for customizing chemotherapy treatment to different ethnic populations desirable. At the same time, significant genetic variation has also been observed between ethnic groups, including many germline and somatic pharmacogenetic variants involved in chemotherapy pharmacology. Recently, based on meta-analyses of studies on germline pharmacogenetic variant frequencies and clinical trials, the investigators found that chemotherapy outcomes between Asians and Caucasians colorectal cancer (CRC) patients could potentially be inferred from the frequencies of variants between the ethnic groups and their respective biological functions. In this study, the investigators seek to further clarify the validity of using pharmacogenetic variants to customize chemotherapy between ethnicities through the following specific aims: (1) To verify the differences observed in the frequency of germline pharmacogenetic variants related to chemotherapy between Asian and Caucasian CRC patients, (2) To test whether variations in the frequency of somatic pharmacogenetic gene mutations between Asian and Caucasian CRC patients could be used to infer differences in clinical outcomes between the two ethnicities. (3) (4) For Aim 1, DNA samples from approximately 1000 Asian and Caucasian CRC patients each will be analyzed for the frequency of a panel of germline pharmacogenetic variants identified in our meta-analyses using high-throughput methodology. For Aim 2, meta-analyses will be performed on pharmacogenetic studies and clinical trials to establish the relative frequencies of somatic variants and clinical outcomes in Asian and Caucasian CRC patients. These frequencies will be verified on the same series of DNA samples used in Aim 1. The clinical outcomes inferred from the frequency differences and biological functions will then be compared to those summarized from clinical trials. This data could provide a basis for developing a rational approach to customizing chemotherapy in non-Caucasian populations and improve assessment of drug feasibility in different ethnic populations.If validated, this working hypothesis would be of high clinical interest, giving the opportunity to use this as a DNA prognosis biomarker in CRC. Pharmacogenetic frequencies could be a potentially useful approach for predicting likely chemotherapy outcomes in non-Caucasian populations

Dataset Information

Large-scale discovery of chromatin dysregulation induced by oncofusions and other protein-coding variants

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets