DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden

• Published in: PloS one Vol. 15; no. 12; p. e0244558
• Main Authors: Riggs, McKayla J, Lin, Nan, Wang, Chi, Piecoro, Dava W, Miller, Rachel W, Hampton, Oliver A, Rao, Mahadev, Ueland, Frederick R, Kolesar, Jill M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.12.2020; Public Library of Science (PLoS)
• Subjects: Aged; Biology and Life Sciences; Biomarkers; Bladder; Breast cancer; Cancer; Cancer therapies; Clinical trials; Data exchange; Databases, Genetic; Development and progression; DNA Polymerase II - genetics; Endometrial cancer; Endometrial Neoplasms - genetics; Endometrial Neoplasms - pathology; Endometrium; Enrollments; Eye Proteins - genetics; Female; Gene mutations; Gene sequencing; Genes; Genetic aspects; Genomes; Genomics; Gynecology; Humans; Immunotherapy; Insects; Kentucky; Medical prognosis; Medical research; Medicine and Health Sciences; Melanoma; Metastasis; Microsatellite Instability; Middle Aged; Mismatch Repair Endonuclease PMS2 - genetics; MLH1 protein; Mutation; Mutation Rate; MutL Protein Homolog 1 - genetics; Neoplasm Grading; Obstetrics; Oncology; Oncology, Experimental; Patients; People and places; Pharmacy; Poly-ADP-Ribose Binding Proteins - genetics; Prevalence; Prognosis; Prostate cancer; Registries; Research and analysis methods; Ribonucleic acid; Risk factors; RNA; Sequence Analysis, RNA; Transcription; Transcription Factors - genetics; Tumor suppressor genes; Tumors; Uterine cancer; Whole Exome Sequencing; Kentucky; United States; United States > US; Lexington Kentucky
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0244558

DACH1 is a transcriptional repressor and tumor suppressor gene frequently mutated in melanoma, bladder, and prostate cancer. Loss of DACH1 expression is associated with poor prognostic features and reduced overall survival in uterine cancer. In this study, we utilized the Oncology Research Information Exchange Network (ORIEN) Avatar database to determine the frequency of DACH1 mutations in patients with endometrial cancer in our Kentucky population. We obtained clinical and genomic data for 65 patients with endometrial cancer from the Markey Cancer Center (MCC). We examined the clinical attributes of the cancers by DACH1 status by comparing whole-exome sequencing (WES), RNA Sequencing (RNASeq), microsatellite instability (MSI), and tumor mutational burden (TMB). Kentucky women with endometrial cancer had an increased frequency of DACH1 mutations (12/65 patients, 18.5%) compared to The Cancer Genome Atlas (TCGA) endometrial 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 our Kentucky population (490 vs. 2160, p-value = 6.0E-04). DACH1 mutated patients have a higher tumor mutation burden compared to DACH1 wild-type (24 vs. 6.02, p-value = 4.29E-05). DACH1 mutations showed significant gene co-occurrence patterns with POLE, MLH1, and PMS2. DACH1 mutations were not associated with an increase in microsatellite instability at MCC (MSI-H) (p-value = 0.1342). DACH1 mutations are prevalent in Kentucky patients with endometrial cancer. These mutations are associated with high tumor mutational burden and co-occur with genome destabilizing gene mutations. These findings suggest DACH1 may be a candidate biomarker for future trials with immunotherapy, particularly in endometrial cancers.