Increased Incidence of DACH1 Mutation in Appalachian Women with Uterine Cancer and Altered Chemotherapy Sensitivity

Abstract Background: DACH1 is a tumor suppressor with increased mutation frequency in uterine cancers in Kentucky. We compared the frequency of DACH1mutations between women with uterine cancer in Appalachian versus non-Appalachian regions in the Oncology Research Information Exchange Network (ORIEN). The effect of DACH1 mutation on RNA expression, clinical outcomes, and the impact of DACH1 knock-outs on DNA repair and drug sensitivity. Methods: We obtained data for 691 patients with endometrial cancer from nine U.S. institutions within the ORIEN network. We evaluated the frequency of DACH1 mutations and their association with clinical and genomics factors. DACH1knock-outs were created and assessed for impact on DNA repair, drug sensitivity, and synergy. Results: Appalachian women with endometrial cancer had an increased frequency of DACH1 mutations (14.6%) verses non-Appalachian women (4.1%) p-value=0.010. DACH1 mutated patients have a higher tumor mutation burden (TMB) compared to DACH1 wild-type (32.2 vs. 4.62, p-value=2.17E-10) with no difference in microsatellite instability (p-value=0.35). DACH1 mutations showed significant co-occurrence with POLE, MLH1, MSH2, MSH6, and PMS2. DACH1knock-outs were deficient in non-homologous end joining and resistant to cisplatin, however, addition of ATR inhibitors reversed resistance. Conclusions: DACH1mutations are prevalent in Appalachain Kentucky women with endometrial cancer. DACH1mutations are associated with high TMB suggesting DACH1 as a candidate biomarker for immunotherapy. DACH1 knockouts are cisplatin resistant which may partialy explain the excess mortality in this population, which may be overcome with addition of an ATR inhibitor, supporting further development of the combination for women with DACH1 mutated gynecological cancers.