Date of Graduation

8-2016

Document Type

Thesis (MS)

Program Affiliation

Biomedical Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Anil K. Sood

Committee Member

Keith Baggerly

Committee Member

Menashe Bar-Eli

Committee Member

Junjie Chen

Committee Member

Xiongbin Lu

Abstract

Objectives: Homologous recombination deficiency (HRD) score is related to chemotherapy response in breast and ovarian cancers. The role of HRD is unknown in endometrial cancer. We examined the relationship between HRD score and survival in a cohort of endometrial cancer patients and with tumor growth using murine orthotopic models.

Methods: TCGA was queried to determine frequency and clinical significance of alterations in the HR pathway in endometrial cancer. 137 formalin-fixed paraffin-embedded endometrioid adenocarcinoma patient samples were tested for HRD score, microsatellite instability (MSI) and high mutation load (HML) using a next generation sequencing assay targeting the coding regions of 43 genes and 54,091 genome wide single nucleotide polymorphisms (SNPs) developed by Myriad Genetics. The HRD score is the sum of three previously described scores (loss of heterozygosity, telomeric allelic imbalance, and large-scale state transition) that quantitate genome rearrangement. Clinical records were obtained. HRD scores were also generated on a panel of established endometrial cancer cell lines and their in vivo growth and response to olaparib and chemotherapy were assessed. Tumor growth and patterns of metastatic spread were assessed in orthotopic mouse models of endometrial cancer.

Results: Median age at diagnosis was 62 years. The majority of patients presented with early stage disease (54%, 11%, 27%, 8% stage I, II, III, IV respectively), and FIGO grade 2 histology (1%, 73%, 26% grade 1, 2, 3). HRD scores were generated for 112 patient samples, MSI status was determined for 126 samples, and HML status determined for 137 samples. The median HRD score was 3. Patients with HRD score ≥ 10 trended toward worse survival as compared to patients with HRD score <10 >(P=0.17). Hec1a cell line (HRD score = 19) was highly sensitive to olaparib and was selected for in vivo use. At the time of necropsy, mice injected with Hec1a and treated with PARP inhibitor had significantly decreased tumor growth and HR function as compared with untreated controls, regardless of BRCA1 function.

Conclusions: High HRD score was associated with worse survival in our patient cohort. Our findings support the use of HRD score in guiding the choice of adjuvant therapy for patients with advanced endometrial cancer.

Available for download on Saturday, June 24, 2017

Share

COinS