SS 02 - GYN 1: Integrating the Next Wave of Biomarkers for Future Gynecologic Clinical Trials
109 - Mutational Landscape of ER Receptor Negative Endometrial Cancer Patients Categorized as No Specific Molecular Profile (NSMP)
Sunday, October 1, 2023
8:40 AM – 8:47 AM PT
Location: Room 5
M. R. Waters1,2, M. Inkman2, L. Habimana-Griffin3, A. Cohen4, J. Zhang2, J. Contreras5, J. K. Schwarz6, and S. Markovina2; 1Siteman Cancer Center, Barnes-Jewish Hospital, St. Louis, MO, 2Washington University School of Medicine in St. Louis, Department of Radiation Oncology, St. Louis, MO, 3Barnes Jewish Hospital, St. Louis, MO, 4Washington University in St Louis, St Louis, MO, 5Washington University in St. Louis, St. Louis, MO, 6Washington University School of Medicine in St. Louis, St. Louis, MO
Purpose/Objective(s): The endometrial cancer (EC) molecular classification introduced by The Cancer Genome Atlas(TCGA) has initiated molecular-based classification with clear prognostic value. Four major tumor subtypes exist: 1)TP53 mutation (p53abn); 2)POLE mutation (POLEmut); 3)mismatch repair protein deficient (MMRd); and 4)no specific molecular profile (NSMP). Of these subtypes, p53abn patients exhibited the worst prognosis. Recently, a prognostic refinement of NSMP EC using estrogen receptor (ER) status, from PORTEC-III trial data, showed that (ER-) NSMP patients had a strikingly poor prognosis, similar to p53abn patients. Currently, drivers of NSMP (ER-) disease are unknown and require genomic characterization. In this study, we perform an integrated molecular analysis to characterize this aggressive and poorly understood cohort. Materials/
Methods: RNAseq and mutational data was downloaded from the TCGA, PanCancer Atlas, Uterine Endometrial Carcinoma dataset via the genomic data commons (GDC). All patients in this cohort demonstrated endometrioid histology. P53abn, and POLE mutated patients were filtered using mutational data. MMRd and NSMP ESR1 gene low expressors (ER Low) were filtered using Z-score cutoffs of RNAseq expression data. Survival analysis was performed using the Survival R-package. Gene expression testing was performed using the EdgeR R-package. Pathway Enrichment analysis was conducted using EnrichR software. Results: 42 patients out of 529 samples met our GDC NSMP (ER low) filtering criteria (7%), similar to the 5% of PORTEC-III patients classified as NSMP (ER -). Strikingly 83% percent of GDC NSMP (ER low) patients harbored a mutation in the PI3K-AKT-mTOR signaling pathway, with 48% of GDC NSMP (ER low) patients carrying a mutation in the p110 alpha (PIK3CA) gene. Interestingly, of the patients with PIK3CA mutant tumors, 2/20 patients died in 5 years (10%), compared to 9/22 patients whose tumors were PIK3CA WT(41%) (p=0.02). Among GDC NSMP (ER low) patients with PIK3CA WT tumors gene expression signatures were enriched for MYC target genes(p=1.1e-51), DNA replication (p=4.3e-30), cell cycle(p=9.32e-20), and cell cycle checkpoints (p=6.4e-20) pathways. Additionally, strongly in PIK3CA WT tumors are mitochondrial membrane proteins (p=1.63e-37) and ribosomal proteins (2.9e-24). Conclusion: In this analysis, we show that GDC NSMP (ER low) tumors nearly all harbor a mutation in the PI3K-AKT-mTOR signaling pathway. Further we demonstrate that the most common gene mutation in the cohort, PIK3CA, is counterintuitively a marker of improved survival. Additionally, we show that within that this subpopulation, PIK3CA WT patients exhibit robustly upregulated gene expression programs dedicated to energy production, cell cycling, and division.