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A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations

ABSTRACT: A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations

PROVIDER: PRJNA1040776 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26837757_1.fastq.gz	Fastqsanger.gz
	SRR26837757_2.fastq.gz	Fastqsanger.gz
	SRR26837758_1.fastq.gz	Fastqsanger.gz
	SRR26837758_2.fastq.gz	Fastqsanger.gz
	SRR26837759_1.fastq.gz	Fastqsanger.gz

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A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations [ATAC-Seq]

Project description:Despite the general understanding that different mutations impart different phenotypic changes within a cell, the majority of targeted therapies in cancer treatment are used to treat all mutations in the same gene regardless of location or phenotypic effects. There is a significant unmet need to distinguish distinct changes in cellular signaling which may provide opportunities for mutation-specific treatment with reduced toxicity to patients. Herein, we describe a series of functional genomic analysis with a unique isogenic cell line panel to accurately identify targetable differences between mutations within the same gene. Using an isogenic cell line model bearing two distinct hotspot PIK3CA mutations found in breast cancer, we were able to identify many gene expression and chromatin accessibility differences. These findings allowed us to identify mutation specific molecular targets, specifically AREG as well as a proximal gene regulatory region, that may provide clinically relevant targets. When disrupted, these targets induce a mutation-specific decrease in proliferation and survival in vivo. These findings suggest new mutation-specific modes of treatment for PIK3CA mutant breast cancer and provide a means with which to find mutation-specific targets for the treatment of other oncogenic mutations.

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A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations [RNA-seq]

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A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations [RNA-seq]

Project description:A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations [RNA-seq]

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A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations [ATAC-Seq]

Project description:A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations [ATAC-Seq]

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A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations [CRISPR KO Screen Data]

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A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations [CRISPR KO Screen Data]

Project description:A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations [CRISPR KO Screen Data]

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A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-12-01 | GSE247822 | GEO

Genomic dissection and mutation-specific target discovery for breast cancer <i>PIK3CA</i> hotspot mutations.

Project description:BackgroundRecent advancements in high-throughput genomics and targeted therapies have provided tremendous potential to identify and therapeutically target distinct mutations associated with cancers. However, to date the majority of targeted therapies are used to treat all functional mutations within the same gene, regardless of affected codon or phenotype.ResultsIn this study, we developed a functional genomic analysis workflow with a unique isogenic cell line panel bearing two distinct hotspot PIK3CA mutations, E545K and H1047R, to accurately identify targetable differences between mutations within the same gene. We performed RNA-seq and ATAC-seq and identified distinct transcriptomic and epigenomic differences associated with each PIK3CA hotspot mutation. We used this data to curate a select CRISPR knock out screen to identify mutation-specific gene pathway vulnerabilities. These data revealed AREG as a E545K-preferential target that was further validated through in vitro analysis and publicly available patient databases.ConclusionsUsing our multi-modal genomics framework, we discover distinct differences in genomic regulation between PIK3CA hotspot mutations, suggesting the PIK3CA mutations have different regulatory effects on the function and downstream signaling of the PI3K complex. Our results demonstrate the potential to rapidly uncover mutation specific molecular targets, specifically AREG and a proximal gene regulatory region, that may provide clinically relevant therapeutic targets. The methods outlined provide investigators with an integrative strategy to identify mutation-specific targets for the treatment of other oncogenic mutations in an isogenic system.

| S-EPMC10802285 | biostudies-literature

A systematic dissection of whole transcriptome profiling in the APP/PS1 mouse brain

Project description:This study is the first to provide a systematic dissection of whole transcriptome profiling in the APP/PS1 mouse brain. The identified ceRNA networks may provide insight into the diagnosis and therapy of AD in the future.

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High-depth RNA sequencing of isogenic wild-type, PIK3CA-WT/H1047R and PIK3CA-H1047R/H1047R human iPSCs

Project description:We used CRISPR/Cas9 to knock in the cancer "hotspot" mutation PIK3CA-H1047R into one or both alleles of a wild-type induced pluripotent stem cell (iPSC) line (WTC11; Coriell # GM25256; P37-P38). Four cultures from each genotype (3 wild-type clones, 3 heterozygous clones, 2 homozygous clones) were subjected to paired-end mRNA sequencing (mean read length = 150 bp). The aim of this experiment was to confirm and expand upon previous transcriptomic results suggesting a near-binary transcriptional effect in homozygous versus heterozygous PIK3CA-H1047R iPSCs (publication doi: 10.1073/pnas.1821093116). According to the high-depth transcriptomic dataset, PIK3CA-H1047R/H1047R iPSCs exhibited altered expression of 5644 genes, whereas heterozygous hPSCs showed 492 differentially-expressed genes, supporting a nearly deterministic phenotypic effect of homozygosity for PIK3CA-H1047R. The differential gene expression analyses were performed based on the limma/voom/eBayes framework (doi: 10.1093/nar/gkv007), using customised scripts with FDR < 0.05 and absolute log2(fold-change) cut-off >= 1.3.

2019-10-01 | GSE134076 | GEO

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