A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE247822 | GEO | 2023/12/01
REPOSITORIES: GEO
Similar Datasets
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.
2023-12-01 | GSE247819 | GEO
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.
2023-12-01 | GSE247821 | GEO
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.
2023-12-01 | GSE248041 | GEO
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
Project description:A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations
| PRJNA1040776 | ENA
Project description:A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations [ATAC-Seq]
| PRJNA1040785 | ENA
Project description:A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations [RNA-seq]
| PRJNA1040784 | ENA
Project description:A functional genomics process for systematic dissection and mutation-specific target discovery in breast cancer PIK3CA hotspot mutations [CRISPR KO Screen Data]
| PRJNA1041446 | ENA
Project description:IntroductionWhile mutations in PIK3CA are most frequently (45%) detected in luminal breast cancer, downstream PI3K/AKT/mTOR pathway activation is predominantly observed in the basal subtype. The aim was to identify proteins activated in PIK3CA mutated luminal breast cancer and the clinical relevance of such a protein in breast cancer patients.Materials and methodsExpression levels of 171 signaling pathway (phospho-)proteins established by The Cancer Genome Atlas (TCGA) using reverse phase protein arrays (RPPA) were in silico examined in 361 breast cancers for their relation with PIK3CA status. MAPK1/3 phosphorylation was evaluated with immunohistochemistry on tissue microarrays (TMA) containing 721 primary breast cancer core biopsies to explore the relationship with metastasis-free survival.ResultsIn silico analyses revealed increased phosphorylation of MAPK1/3, p38 and YAP, and decreased expression of p70S6K and 4E-BP1 in PIK3CA mutated compared to wild-type luminal breast cancer. Augmented MAPK1/3 phosphorylation was most significant, i.e. in luminal A for both PIK3CA exon 9 and 20 mutations and in luminal B for exon 9 mutations. In 290 adjuvant systemic therapy naïve lymph node negative (LNN) breast cancer patients with luminal cancer, high MAPK phosphorylation in nuclei (HR=0.49; 95% CI, 0.25-0.95; P=.036) and in tumor cells (HR=0.37; 95% CI, 0.18-0.79; P=.010) was related with favorable metastasis-free survival in multivariate analyses including traditional prognostic factors.ConclusionEnhanced MAPK1/3 phosphorylation in luminal breast cancer is related to PIK3CA exon-specific mutations and correlated with favorable prognosis especially when located in the nuclei of tumor cells.
| S-EPMC5591392 | biostudies-literature
Project description:BackgroundTheragnostic management, treatment according to precise pathological molecular targets, requests to unravel patients' genotypes. We used targeted next-generation sequencing (NGS) or digital droplet polymerase chain reaction (ddPCR) to screen for somatic PIK3CA mutations on DNA extracted from resected lesional tissue or lymphatic endothelial cells (LECs) isolated from lesions. Our cohort (n = 143) was composed of unrelated patients suffering from a common lymphatic malformation (LM), a combined lymphatic malformation [lymphatico-venous malformation (LVM), capillaro-lymphatic malformation (CLM), capillaro-lymphatico-venous malformation (CLVM)], or a syndrome [CLVM with hypertrophy (Klippel-Trenaunay-Weber syndrome, KTS), congenital lipomatous overgrowth-vascular malformations-epidermal nevi -syndrome (CLOVES), unclassified PIK3CA-related overgrowth syndrome (PROS) or unclassified vascular (lymphatic) anomaly syndrome (UVA)].ResultsWe identified a somatic PIK3CA mutation in resected lesions of 108 out of 143 patients (75.5%). The frequency of the variant allele ranged from 0.54 to 25.33% in tissues, and up to 47% in isolated endothelial cells. We detected a statistically significant difference in the distribution of mutations between patients with common and combined LM compared to the syndromes, but not with KTS. Moreover, the variant allele frequency was higher in the syndromes.ConclusionsMost patients with an common or combined lymphatic malformation with or without overgrowth harbour a somatic PIK3CA mutation. However, in about a quarter of patients, no such mutation was detected, suggesting the existence of (an)other cause(s). We detected a hotspot mutation more frequently in common and combined LMs compared to syndromic cases (CLOVES and PROS). Diagnostic genotyping should thus not be limited to PIK3CA hotspot mutations. Moreover, the higher mutant allele frequency in syndromes suggests a wider distribution in patients' tissues, facilitating detection. Clinical trials have demonstrated efficacy of Sirolimus and Alpelisib in treating patients with an LM or PROS. Genotyping might lead to an increase in efficacy, as treatments could be more targeted, and responses could vary depending on presence and type of PIK3CA-mutation.
| S-EPMC8194016 | biostudies-literature