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

PLoS One. 2020 Dec 30;15(12):e0244558. doi: 10.1371/journal.pone.0244558. eCollection 2020.


Objective: 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.

Methods: 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).

Results: 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).

Conclusions: 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • DNA Polymerase II / genetics
  • Databases, Genetic
  • Endometrial Neoplasms / genetics
  • Endometrial Neoplasms / pathology*
  • Exome Sequencing
  • Eye Proteins / genetics*
  • Female
  • Humans
  • Kentucky
  • Microsatellite Instability
  • Middle Aged
  • Mismatch Repair Endonuclease PMS2 / genetics
  • MutL Protein Homolog 1 / genetics
  • Mutation Rate*
  • Neoplasm Grading
  • Poly-ADP-Ribose Binding Proteins / genetics
  • Prevalence
  • Prognosis
  • Registries
  • Sequence Analysis, RNA
  • Transcription Factors / genetics*


  • DACH1 protein, human
  • Eye Proteins
  • MLH1 protein, human
  • Poly-ADP-Ribose Binding Proteins
  • Transcription Factors
  • DNA Polymerase II
  • POLE protein, human
  • PMS2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • MutL Protein Homolog 1