Increased Dach1 Mutation Frequency In A Kentucky Hospital Uterine Cancer Population.

Purpose:DACH1 is a transcriptional repressor and tumor suppressor gene frequently mutated in breast, bladder, and prostate cancer. Most studied in breast carcinoma, DACH1 expression was reduced or lost in invasive breast cancer patients, and its expression was inversely related to tumor diameter, stage, and nodal metastasis, and directly associated with increased survival time. While less studied in uterine cancer, nearly all normal endometrial samples show nuclear expression of DACH1, with DACH1 expression lost in more than half of uterine cancers. Loss of DACH1 expression has been associated with higher surgical stage, positive peritoneal cytology, and lymph node positivity in uterine cancer. In this study, the Oncology Research Information Exchange Network (ORIEN) Avatar database was used to determine the frequency of DACH1 mutations in our Kentucky hospital population with uterine cancer. Experimental Design: Clinical and genomic data were collected for 65 patients with uterine cancer from Markey Cancer Center (MCC) through Total Cancer Care (TCC) ®. TCC is a prospective cohort study with whole-exome tumor sequencing, RNA sequencing, germline sequencing, and lifetime follow-up. The clinical attributes, whole-exome sequencing, RNA sequencing, microsatellite instability, and tumor mutational burden were compared by DACH1 status. EdgeR was used to perform normalization, expression modeling, and difference testing. The network analysis was performed using Qiagen’s Ingenuity Pathway Analysis (IPA) system for core analysis of the RNA sequencing data and overlaid with the Global Molecular Network Overlay in the IPA knowledge base. The Cancer Genome Atlas Project (TCGA) PanCancer Atlas dataset was used for comparison through cBioPortal.org, utilizing endometrial cancer and carcinosarcoma subgroups for analysis totaling 586 patients. Results: Uterine cancer patients at MCC had an increased frequency of DACH1 mutations (12/65 patients, 18.5%) compared to the TCGA uterine cancer population (25/586 patients, 3.8%) with p-value = 1.04E-05. DACH1 mutations were associated with increased tumor mutation count in both TCGA (median 65 vs. 8972, p-value =7.35e-09) and MCC population (490 vs. 2160, p-value = 6E-04). DACH1 mutated patients had a higher tumor mutation burden compared to DACH1 wild-type (24 vs. 6.02, p-value = 4.288E-05). DACH1 mutations showed significant gene co-occurrence patterns with POLE, MLH1, and PMS2. Conclusions:DACH1 mutations are prevalent in Kentucky patients with uterine cancer. These mutations are associated with high tumor mutational burden and co-occur with genome destabilizing gene mutations. These findings suggest DACH1 could be a candidate biomarker for future trials with immunotherapy, particularly in uterine cancers, and may help explain the differences seen in uterine cancer incidence and mortality in Kentucky. Citation Format: McKayla Riggs, Nan Lin, Chi Wang, Dava Piecoro, Rachel Miller, Oliver Hampton, Mahadev Rao, Frederick Ueland, Jill Kolesar. Increased DACH1 mutation frequency in a Kentucky hospital uterine cancer population [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO009.