Abstract
DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden in a nationwide cohort
Journal of clinical oncology, Vol.40(16_suppl), pp.e17634-e17634
06/01/2022
DOI: 10.1200/JCO.2022.40.16_suppl.e17634
Abstract
e17634
Background: DACH1 is a novel transcriptional repressor and tumor suppressor gene. DACH1 mutations are associated with poor prognostic features and reduced overall survival in endometrial cancer, with an increased prevalence in the Appalachian region of Kentucky. Preliminary studies have suggested an association with an increase in tumor mutation burden. In this follow up study, we utilized the nationwide Oncology Research Information Exchange Network (ORIEN) to determine the frequency of DACH1 mutations in patients with endometrial cancer through a multi-institution analysis and evaluate its impact on RNA expression, clinical correlates, and outcomes. Methods: We obtained clinical and genomic data for 691 patients with endometrial cancer from nine U.S. institutions within the ORIEN collaborative. We examined the clinical attributes of the cancers with DACH1 status by comparing whole-exome sequencing (WES), RNA Sequencing (RNASeq), microsatellite instability (MSI), and tumor mutational burden (TMB). Results: Appalachian women with endometrial cancer had an increased frequency of DACH1 mutations (6/41 patients, 15%) compared to the non-Appalachian endometrial cancer population (24/581 patients, 4.1%) with p-value = 0.010, with the non-Appalachian DACH1 mutation frequency mirroring the rate of DACH1 gene mutation seen in TCGA at 3.8%. DACH1 mutated patients have a higher tumor mutation burden compared to DACH1 wild-type (32.2 vs. 4.62, p-value = 0.001) though no differences in microsatellite instability between DACH1 mutated and wild-type were present (p-value = 0.350). DACH1 mutations showed significant gene co-occurrence patterns with POLE, MLH1, MSH2, MSH6 and PMS2. Conclusions: DACH1 mutations are prevalent in Kentucky patients with endometrial cancer, particularly those from the Appalachian region. These results were again reflected in the TCGA PanCancer Atlas as well as the ORIEN multi-institution cohort. These mutations are associated with high tumor mutational burden and co-occur with genome destabilizing gene mutations. These findings suggest DACH1 as a candidate biomarker for future trials with immunotherapy, particularly in endometrial cancers.
Details
- Title: Subtitle
- DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden in a nationwide cohort
- Creators
- McKayla J Riggs - University of KentuckyNan Lin - University of KentuckyRachel W. Miller - University of KentuckyDava West Piecoro - University of KentuckyBryan P. Schneider - Indiana University HealthHye Sook Chon - Moffitt Cancer CenterJohn D. Carpten - Translational Genomics Research InstituteMichelle L. Churchman - M2Gen, Tampa, FLBradley Corr - University of Colorado DenverChristina Washington - Oklahoma State University Oklahoma CityRobert Dood - The University of Texas MD Anderson Cancer CenterStephen B. Edge - Roswell Park Comprehensive Cancer CenterAliza L. Leiser - Rutgers, The State University of New JerseyErin M. Siegel - Moffitt Cancer CenterFrederick West Ueland - University of KentuckyJill Kolesar - University of Kentucky
- Resource Type
- Abstract
- Publication Details
- Journal of clinical oncology, Vol.40(16_suppl), pp.e17634-e17634
- DOI
- 10.1200/JCO.2022.40.16_suppl.e17634
- ISSN
- 0732-183X
- eISSN
- 1527-7755
- Language
- English
- Date published
- 06/01/2022
- Academic Unit
- Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984695791702771
Metrics
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