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Published on: May 17, 2019
Comparative genomic analysis of PIK3R1-mutated and wild-type breast cancers
Melody A Cobleigh1, Kayla Viets Layng2, Elizabeth Mauer2
1Rush University Medical Center, 1620 W Harrison St, Chicago, IL, 60612, USA. melody_cobleigh@rush.edu.
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.
Insights
PIK3R1 mutations are more frequent in triple-negative breast cancer (TNBC) than other subtypes. This study highlights PIK3R1 as a potential therapeutic target in TNBC, alongside its known role in HER2-/HR+ breast cancer.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- The PIK3R1 gene encodes a key regulatory subunit of the PI3K signaling pathway.
- Prior research indicates PIK3R1 alterations are common in breast cancers, but a comprehensive genomic characterization is lacking.
Purpose of the Study:
- To investigate the genomic landscape of breast cancer patients with PIK3R1 mutations.
- To determine the frequency and patterns of PIK3R1 alterations across different breast cancer subtypes.
Main Methods:
- Retrospective analysis of 6,009 breast cancer patient records.
- Next-generation sequencing (NGS) data from the Tempus xT solid tumor assay.
- Classification based on PIK3R1 mutations (short variants, copy number alterations) and receptor status (HER2, HR).
Main Results:
- PIK3R1 mutations occurred in 6% of triple-negative breast cancer (TNBC), 2% of HER2-/HR+, and 2.3% of HER2+ cases.
- Enrichment of co-mutations in PTEN, TP53, and NF1; decreased PIK3CA co-mutation; and higher tumor mutational burden in PIK3R1-mutated HER2- samples.
- Elevated PIK3R1 RNA expression in PIK3R1-mutated HER2- tumors.
Conclusions:
- This study represents the largest analysis of the PIK3R1 mutational landscape in breast cancer.
- PIK3R1 mutations are significantly more prevalent in TNBC compared to HER2+ or HER2-/HR+ subtypes.
- PIK3R1 emerges as a potential therapeutic target not only in HER2-/HR+ breast cancer but also in TNBC.
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