Endometrial cancer (EC) remains challenging to treat, particularly recurrent cases. Advances in genomic studies, enabled by exome sequencing (WES), reveal distinct molecular subtypes of EC. Despite its potential to improve precision oncology, WES is underutilized in standard clinical practice, partly due to challenges with formalin-fixed, paraffin-embedded (FFPE) samples. This study analyzed WES data from FFPE samples of 13 EC patients, identifying mutations relevant for targeted therapies or clinical trials.
Patient selection followed inclusion criteria, such as confirmed diagnosis and informed consent, while excluding poor-quality samples or incomplete data. DNA was extracted and processed under stringent quality control, ensuring high purity and integrity for sequencing on the Illumina NovaSeq 6000 platform. The Geneyx Analysis platform facilitated bioinformatics processing, variant annotation, and filtering using ACMG guidelines and tools like SIFT, PolyPhen-2, and CADD.
Geneyx Analysis CNV/SV tab now automatically calculates
ACMG guidelines for all deletion and duplication events. View here how this works.
The study identified 352 unique variants, including mutations in PIK3CA, TP53, and PTEN, with significant clinical implications. PIK3CA mutations were frequent and linked to activation of the PI3K/AKT/mTOR pathway, highlighting PI3K inhibitors as potential treatments. PTEN mutations disrupted tumor suppression, further implicating the PI3K pathway. ARID1A mutations, associated with chromatin remodeling defects, suggest sensitivity to ATR and EZH2 inhibitors. KRAS mutations activated the RAS/RAF/MEK/ERK pathway, offering opportunities for MEK inhibitors and emerging KRAS-targeted therapies.
In summary, this study highlights the potential of WES in EC management, identifying actionable mutations for precision medicine. Key findings include frequent mutations in PIK3CA, PTEN, and KRAS. Targeted therapies, such as PI3K inhibitors (alpelisib) and mTOR inhibitors (everolimus), show promise, while emerging treatments like EZH2 inhibitors for ARID1A mutations offer further therapeutic opportunities. Despite limitations like the study’s small sample size, WES demonstrates a transformative potential in advancing personalized treatment strategies in EC and beyond.
Abbreviations Summary:
- EC: Endometrial cancer
- WES: Whole exome sequencing
- FFPE: Formalin-fixed, paraffin-embedded
- ACMG: American College of Medical Genetics and Genomics
- SIFT: Sorting Intolerant From Tolerant
- PolyPhen-2: Polymorphism Phenotype version 2
- CADD: Combined Annotation Dependent Depletion
- CNV/SV: Copy Number Variation / Structural Variation
- PI3K: Phosphoinositide 3-kinase
- AKT: Protein kinase B (Akt)
- mTOR: Mechanistic target of rapamycin
- PTEN: Phosphatase and Tensin homolog
- ARID1A: AT-rich interactive domain-containing protein 1A
- ATR: Ataxia telangiectasia and Rad3-related protein
- EZH2: Enhancer of zeste homolog 2
- KRAS: Kirsten rat sarcoma viral oncogene homolog
- RAS/RAF/MEK/ERK: A signaling pathway involved in cell division and survival
Read on. A Pilot Study by Dr. Carika Weldon, Founder and CEO of CariGenetics.
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