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Comparative genomic analysis of PIK3R1-mutated and wild-type breast cancers

  • Original Laboratory Investigation
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Abstract

Purpose

The PIK3R1 gene encodes the regulatory subunit—p85a—of the PI3K signaling complex. Prior studies have found that pathogenic somatic alterations in PIK3R1 are enriched in human breast cancers but the genomic landscape of breast cancer patients harboring PIK3R1 mutations has not been extensively characterized.

Methods

We retrospectively analyzed 6,009 patient records that underwent next-generation sequencing (NGS) using the Tempus xT solid tumor assay. All patients had breast cancer with known HER2 (+/-) and hormone receptor (HR; +/-) status and were classified according to the presence of PIK3R1 mutations including short variants and copy number alterations.

Results

The frequency of PIK3R1 mutations varied according to subtype: 6% in triple negative (TNBC, 89/1,475), 2% in HER2-/HR+ (80/3,893) and 2.3% in HER2+ (15/641) (p < 0.001). Co-mutations in PTEN, TP53 and NF1 were significantly enriched, co-mutations in PIK3CA were significantly less prevalent, and tumor mutational burden was significantly higher in PIK3R1-mutated HER2- samples relative to PIK3R1 wild-type. At the transcriptional-level, PIK3R1 RNA expression in HER2- disease was significantly higher in PIK3R1-mutated (excluding copy number loss) samples, regardless of subtype.

Conclusion

This is the largest investigation of the PIK3R1 mutational landscape in breast cancer patients (n = 6,009). PIK3R1 mutations were more common in triple-negative breast cancer (~ 6%) than in HER2 + or HER2-/HR + disease (approximately 2%). While alterations in the PI3K/AKT pathway are often actionable in HER2-/HR + breast cancer, our study suggests that PIK3R1 could be an important target in TNBC as well.

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Data Availability

Raw data for this study were generated at Tempus Labs. When possible, derived data supporting the findings of this study have been made available within the paper and any Supplementary Figures/Tables.

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Acknowledgements

MC thanks the Brian Piccolo Cancer Research Fund, the Brinson Foundation and the Sherman Fairchild Foundation for their support.

Funding

This study was funded by Tempus Labs, Inc., a for-profit company.

Author information

Authors and Affiliations

  1. Rush University Medical Center, 1620 W Harrison St, Chicago, IL, 60612, USA

    Melody A. Cobleigh & Abde M. Abukhdeir

  2. Tempus Labs Inc, 600 W Chicago, Chicago, IL, 60654, USA

    Kayla Viets Layng, Elizabeth Mauer, Brett Mahon & Adam J. Hockenberry

Authors
  1. Melody A. Cobleigh
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  2. Kayla Viets Layng
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  3. Elizabeth Mauer
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  4. Brett Mahon
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  6. Abde M. Abukhdeir
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Corresponding author

Correspondence to Melody A. Cobleigh.

Ethics declarations

Ethics approval

This study was performed on de-identified data under IRB exemption Pro00042950 - granted from the Advarra, Inc Institutional Review Board (IRB) on April 15, 2020 based on the Department of Health and Human Services regulations found at “45 CFR 46.104(d)(4)”.

Competing interests

Individuals with Tempus Labs affiliation (KVL, EM, BM, AJH) receive/ed either direct salary and/or equity shares from Tempus Labs as part of their employment for work on this project.

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AMA contributed to this article in his personal capacity, while an employee of the U.S. Food and Drug Administration. The views expressed are his own and do not necessarily represent the views of the Food and Drug Administration or the United States Government. He is currently an employee of AstraZeneca.

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Cobleigh, M.A., Layng, K.V., Mauer, E. et al. Comparative genomic analysis of PIK3R1-mutated and wild-type breast cancers. Breast Cancer Res Treat 204, 407–414 (2024). https://doi.org/10.1007/s10549-023-07196-4

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  • DOI: https://doi.org/10.1007/s10549-023-07196-4

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