SYNE1 mutation is associated with increased tumor mutation burden and immune cell infiltration in ovarian cancer (1263)

Laura Harbin; Jill Kolesar; Frederick Ueland; Nan Lin

doi:10.1016/j.ygyno.2023.06.172

Objectives Genomic hallmarks of ovarian cancer include frequent mutations in TP53, PIK3CA, KRAS, and ARID1A. A less frequently mutated gene, SYNE1, demonstrates alterations in 10% of gynecologic malignancies and 5% of epithelial ovarian cancers. Previous studies identified an association between SYNE1 mutation, elevated tumor mutation burden (TMB), and improved response to immunotherapy (IO) in other malignancies. This study evaluated the SYNE1 mutation frequency, association with tumor mutation burden, and downstream effects of SYNE1 mutations in ovarian cancer. Methods Eligible ovarian cancer patients at a large academic medical center were enrolled in the Total Cancer Care (TCC) clinical trial between February 2018 and August 2019. TCC utilized a standardized protocol to collect each patient's genetic information, including whole-exome sequencing, RNA analysis, germline testing, and somatic tumor testing. The data were obtained in collaboration with the Oncology Research Information Exchange Network (ORIEN). We abstracted clinical information from a statewide cancer registry. We compared mutation frequencies between our institutional ovarian cancer cohort and The Cancer Genome Atlas (TCGA) PanCancer Atlas dataset. Bioinformatic analysis was performed to compare gene expression. We compared continuous and categorical variables using the Student t-test, χ2 test, and Fisher's exact test, respectively. Tumor mutation burden was calculated with the Wilcoxon rank sum test. Raw whole exome sequencing reads were processed through the bioinformatics pipeline developed by M2Gen. Results Of the 50 patients in our cohort, 16 had an SYNE1 mutation. Most patients had high-grade serous histology (66%) and advanced-stage disease (64%). Overall, 15 of the 50 patients experienced disease recurrence. In the SYNE1 wild-type (WT) group, 12 of the 34 patients (35%) recurred compared to 3 of the 12 (19%) SYNE1 mutant patients (P = 0.3). When TMB was treated as a continuous variable, SYNE1 mutated patients had a median TMB of 25 (SD: 13.5) compared to a median TMB of 7 (SD: 14.7) for SYNE1 WT patients (P < 0.0001). Compared to the TCGA cohort, our cohort had significantly higher SYNE1 mutation rates (32% vs 6%, P < 0.001). Given the role of SYNE1 in gene stability and gene expression, we used RNA sequencing analysis to compare gene expression between SYNE1 mutated and WT patients. SYNE1 mutated patients had significantly increased gene expression related to immune cell trafficking, inflammatory response, and humoral immune response (z > 2.0). Conclusions SYNE1 mutation is associated with an increased tumor mutation burden in our institutional ovarian cancer cohort. The cause of increased mutational load in this population is unclear but is likely multifactorial. Increased immune cell infiltration and elevated TMB in SYNE1 mutated tumors suggest they may respond better to immunotherapy.

SYNE1 mutation is associated with increased tumor mutation burden and immune cell infiltration in ovarian cancer (1263)

View Online

Abstract

Details

Metrics