Genomic dissection and mutation-specific target discovery for breast cancer PIK3CA hotspot mutations.

BACKGROUND: Recent 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. RESULTS: In 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. CONCLUSIONS: Using 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.

Genomic dissection and mutation-specific target discovery for breast cancer PIK3CA hotspot mutations.

Background: Recent 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. Results: In 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. Conclusions: Using 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.

Vanderbilt Electronic Health Record Voice Assistant Supports Clinicians.

BACKGROUND: Electronic health records (EHRs) present navigation challenges due to time-consuming searches across segmented data. Voice assistants can improve clinical workflows by allowing natural language queries and contextually aware navigation of the EHR. OBJECTIVES: To develop a voice-mediated EHR assistant and interview providers to inform its future refinement. METHODS: The Vanderbilt EHR Voice Assistant (VEVA) was developed as a responsive web application and designed to accept voice inputs and execute the appropriate EHR commands. Fourteen providers from Vanderbilt Medical Center were recruited to participate in interactions with VEVA and to share their experience with the technology. The purpose was to evaluate VEVA's overall usability, gather qualitative feedback, and detail suggestions for enhancing its performance. RESULTS: VEVA's mean system usability scale score was 81 based on the 14 providers' evaluations, which was above the standard 50th percentile score of 68. For all five summaries evaluated (overview summary, A1C results, blood pressure, weight, and health maintenance), most providers offered a positive review of VEVA. Several providers suggested modifications to make the technology more useful in their practice, ranging from summarizing current medications to changing VEVA's speech rate. Eight of the providers (64%) reported they would be willing to use VEVA in its current form. CONCLUSION: Our EHR voice assistant technology was deemed usable by most providers. With further improvements, voice assistant tools such as VEVA have the potential to improve workflows and serve as a useful adjunct tool in health care.