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DACH1 Mutation Frequency in Endometrial Cancer Is Associated with High Tumor Mutation Burden

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University of Kentucky UKnowledge Obstetrics and Gynecology Faculty Publications Obstetrics and Gynecology 12-30-2020 DACH1 Mutation Frequency in Endometrial Cancer Is Associated with High Tumor Mutation Burden McKayla J. Riggs University of Kentucky, [email protected] Nan Lin University of Kentucky, [email protected] Chi Wang University of Kentucky, [email protected] Dava W. Piecoro University of Kentucky, [email protected] Rachel W. Miller University of Kentucky, [email protected] Follow this and additional works at: https://uknowledge.uky.edu/obgyn_facpub See next page for additional authors Part of the Biostatistics Commons, Obstetrics and Gynecology Commons, Oncology Commons, and the Pathology Commons Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Repository Citation Riggs, McKayla J.; Lin, Nan; Wang, Chi; Piecoro, Dava W.; Miller, Rachel W.; Hampton, Oliver A.; Rao, Mahadev; Ueland, Frederick R.; and Kolesar, Jill M., "DACH1 Mutation Frequency in Endometrial Cancer Is Associated with High Tumor Mutation Burden" (2020). Obstetrics and Gynecology Faculty Publications. 28. https://uknowledge.uky.edu/obgyn_facpub/28 This Article is brought to you for free and open access by the Obstetrics and Gynecology at UKnowledge. It has been accepted for inclusion in Obstetrics and Gynecology Faculty Publications by an authorized administrator of UKnowledge. For more information, please contact [email protected]. DACH1 Mutation Frequency in Endometrial Cancer Is Associated with High Tumor Mutation Burden Digital Object Identifier (DOI) https://doi.org/10.1371/journal.pone.0244558 Notes/Citation Information Published in PLOS ONE, v. 15, issue 12, e0244558. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Authors 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 This article is available at UKnowledge: https://uknowledge.uky.edu/obgyn_facpub/28 PLOS ONE RESEARCH ARTICLE DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden 1☯ 2☯ 3,4³ 5³ 1,4³ McKayla J. RiggsID , Nan Lin , Chi Wang , Dava W. Piecoro , Rachel W. Miller , 6³ 7³ 1,4³ 1,2,4☯ Oliver A. HamptonID , Mahadev Rao , Frederick R. Ueland , Jill M. Kolesar * 1 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Kentucky, Lexington, Kentucky, United States of America, 2 College of Pharmacy, University of Kentucky, Lexington, Kentucky, United States of America, 3 Department of Biostatistics, College of Public Health, University of a1111111111 Kentucky, Lexington, Kentucky, United States of America, 4 Markey Cancer Center, University of Kentucky, a1111111111 Lexington, Kentucky, United States of America, 5 Division of Pathology, Department of Pathology and a1111111111 Laboratory Medicine, University of Kentucky, Lexington, Kentucky, United States of America, 6 Department a1111111111 of Bioinformatics and Biostatistics, M2Gen, Tampa, Florida, United States of America, 7 Department of a1111111111 Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India ☯ These authors contributed equally to this work. ³ These authors also contributed equally to this work. * [email protected] OPEN ACCESS Citation: Riggs MJ, Lin N, Wang C, Piecoro DW, Miller RW, Hampton OA, et al. (2020) DACH1 Abstract mutation frequency in endometrial cancer is associated with high tumor mutation burden. PLoS ONE 15(12): e0244558. https://doi.org/10.1371/ Objective journal.pone.0244558 DACH1 is a transcriptional repressor and tumor suppressor gene frequently mutated in mel- Editor: Sumitra Deb, Virginia Commonwealth University, UNITED STATES anoma, 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 Received: October 6, 2020 the Oncology Research Information Exchange Network (ORIEN) Avatar database to deter- Accepted: December 11, 2020 mine the frequency of DACH1 mutations in patients with endometrial cancer in our Kentucky Published: December 30, 2020 population. Peer Review History: PLOS recognizes the benefits of transparency in the peer review Methods process; therefore, we enable the publication of all of the content of peer review and author We obtained clinical and genomic data for 65 patients with endometrial cancer from the Mar- responses alongside final, published articles. The key Cancer Center (MCC). We examined the clinical attributes of the cancers by DACH1 editorial history of this article is available here: status by comparing whole-exome sequencing (WES), RNA Sequencing (RNASeq), micro- https://doi.org/10.1371/journal.pone.0244558 satellite instability (MSI), and tumor mutational burden (TMB). Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or Results otherwise used by anyone for any lawful purpose. Kentucky women with endometrial cancer had an increased frequency of DACH1 mutations The work is made available under the Creative (12/65 patients, 18.5%) compared to The Cancer Genome Atlas (TCGA) endometrial can- Commons CC0 public domain dedication. cer population (25/586 patients, 3.8%) with p-value = 1.04E-05. DACH1 mutations were Data Availability Statement: Authors received no associated with increased tumor mutation count in both TCGA (median 65 vs. 8972, p-value special privileges in accessing the data. Raw data cannot be shared because they are both potentially = 7.35E-09) and our Kentucky population (490 vs. 2160, p-value = 6.0E-04). DACH1 identifying and contain sensitive patient data, mutated patients have a higher tumor mutation burden compared to DACH1 wild-type (24 PLOS ONE | https://doi.org/10.1371/journal.pone.0244558 December 30, 2020 1 / 21 PLOS ONE DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden including geographic location, dates of diagnosis vs. 6.02, p-value = 4.29E-05). DACH1 mutations showed significant gene co-occurrence and dates of testing and receiving a medication. In patterns with POLE, MLH1, and PMS2. DACH1 mutations were not associated with an addition, there are contractual agreements between the University of Kentucky and the Kentucky increase in microsatellite instability at MCC (MSI-H) (p-value = 0.1342). Cancer Registry precluding data sharing. Any requests for data must be submitted to: Jacyln K. Conclusions McDowell, Epidemiologist, Kentucky Cancer DACH1 mutations are prevalent in Kentucky patients with endometrial cancer. These muta- Registry 2365 Harrodsburg Rd, Suite A230 Lexington, KY 40504 859-218-2228 Jaclyn. tions are associated with high tumor mutational burden and co-occur with genome destabi- [email protected]. lizing gene mutations. These findings suggest DACH1 may be a candidate biomarker for Funding: Funding for this project was received by future trials with immunotherapy, particularly in endometrial cancers. the NCI Cancer Center Support Grant (P30 CA177558). Dr. Piecoro's spouse's employment by Exelixis, Inc, is noted but completely unrelated to this project. His funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the Introduction manuscript in any way. Dr. Hampton is employed Uterine cancer is increasing in incidence and mortality in the United States. In 2020, an esti- by M2Gen and serves as the chief officer of mated 65,620 women will be diagnosed with endometrial cancer, making it the fourth most bioinformatics over the ORIEN pipeline. M2Gen did not play a role in the study design, data collection common female cancer, with an estimated 12,590 deaths [1]. Kentucky is an above-average and analysis, or decision to publish. He and his risk region, with 29 new cases per 100,000 women compared to 27.6 per 100,000 women department assisted in separating our patients into nationally [2]. The mean five-year survival rate for endometrial cancer is 81.2%, with more DACH1 mutated vs wild-type cohorts through the than 67% of patients diagnosed at an early stage. The survival rate decreases to 69% for locally ORIEN software and provided the information metastatic and 16% for widely metastatic disease [3]. The treatment paradigm for endometrial regarding the ORIEN genomic processing pipeline for this paper. Dr. Hampton was not involved in the cancer has been unchanged for some time. Current first-line therapy includes a combination subsequent bioinformatics analysis. He did provide of surgery, carboplatin and paclitaxel chemotherapy, and radiation depending on the stage final proofreading of the manuscript prior to and risk. submission. The specific roles of these authors are To molecularly categorize endometrial cancers, Kandoth and colleagues performed an inte- articulated in the `author contributions' section. grated genomic, transcriptomic, and proteomic analysis of 373 endometrial carcinomas. They Competing interests: The employment of Dr. were able to classify these cancers into POLE ultramutated, microsatellite instability hypermu- Oliver Hampton by M2GEN does not alter our tated (MSI-H), copy number low, and copy
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