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

McKayla J Riggs; Nan Lin; Chi Wang; Dava W Piecoro; Rachel W Miller; Oliver A Hampton; Mahadev Rao; Frederick R Ueland; Jill M Kolesar

doi:10.1371/journal.pone.0244558

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

Journal article

Open access

Peer reviewed

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

McKayla J Riggs, Nan Lin, Chi Wang, Dava W Piecoro, Rachel W Miller, Oliver A Hampton, Mahadev Rao, Frederick R Ueland and Jill M Kolesar

PloS one, Vol.15(12), e0244558

12/30/2020

DOI: 10.1371/journal.pone.0244558

PMCID: PMC7773279

PMID: 33378353

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Abstract

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.

Registries

Aged

Databases, Genetic

DNA Polymerase II - genetics

Endometrial Neoplasms - genetics

Endometrial Neoplasms - pathology

Eye Proteins - genetics

Female

Humans

Kentucky

Microsatellite Instability

Middle Aged

Mismatch Repair Endonuclease PMS2 - genetics

Mutation Rate

MutL Protein Homolog 1 - genetics

Neoplasm Grading

Poly-ADP-Ribose Binding Proteins - genetics

Prevalence

Prognosis

Sequence Analysis, RNA

Transcription Factors - genetics

Whole Exome Sequencing

Details

Title: Subtitle: DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden
Creators: McKayla J Riggs - University of Kentucky
Nan Lin - University of Kentucky
Chi Wang - University of Kentucky
Dava W Piecoro - University of Kentucky
Rachel W Miller - University of Kentucky
Oliver A Hampton - Department of Bioinformatics and Biostatistics, M2Gen, Tampa, Florida, United States of America
Mahadev Rao - Manipal Academy of Higher Education
Frederick R Ueland - University of Kentucky
Jill M Kolesar - University of Kentucky
Resource Type: Journal article
Publication Details: PloS one, Vol.15(12), e0244558
DOI: 10.1371/journal.pone.0244558
PMID: 33378353
PMCID: PMC7773279
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Grant note: P30 CA177558 / NCI NIH HHS
Language: English
Date published: 12/30/2020
Academic Unit: Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics
Record Identifier: 9984696543202771

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13 Times Cited - Web of Science