Clinical Implications of Genomic Loss of Heterozygosity in Endometrial Carcinoma.

Abstract

Homologous recombination deficiency, identified by homologous recombination deficiency gene alterations or high percentage of genome-wide loss of heterozygosity (gLOH), is associated with improved prognosis, platinum sensitivity (PS), and poly (ADP-ribose) polymerase inhibitor response in high-grade ovarian cancer. Since the copy number-high (CN-H) endometrial cancer molecular subtype (EC-MS) shares molecular features with high-grade ovarian cancer, our aim was to assign EC-MS on the basis of comprehensive genomic profiling (CGP) results and evaluate the gLOH status with clinical behavior of EC. Eighty-two epithelial EC tumor tissues were sequenced by hybrid capture-based CGP, and results were used to assign EC-MS (ultramutated, microsatellite instability-high, CN-low; CN-high). Retrospective chart review established clinical characteristics, including PS. Relationships of PS, EC-MS, gene alterations, and gLOH were assessed statistically. PS and EC-MS of CN-H showed statistically significant difference in overall survival (OS). Most notably, when the CN-H EC-MS was subcategorized by gLOH status, there was a significant difference in OS with gLOH-H being associated with longer survival. Cox semi-proportional hazard modeling showed that gLOH, stage, and race were significant in modeling OS. The method of assigning EC-MS by CGP demonstrates similar clinical features to previous reports of EC-MS assigned by other methods. CGP can also assess gLOH status with gLOH-H most commonly seen in CN-H tumors. CN-H, gLOH-H patients showed significantly improved OS (hazard ratio, 0.100 [0.02-0.51 95% CI]). Thus, gLOH status may be a meaningful prognostic biomarker within the CN-H tumors and possibly across EC-MS.