Clinical Implications of Genomic Loss of Heterozygosity in Endometrial Carcinoma.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

A Pan-Cancer Landscape Analysis Reveals a Subset of Endometrial Stromal and Pediatric Tumors Defined by Internal Tandem Duplications of BCOR.

BACKGROUND: The Polycomb Repressive Complex 1 (PRC1) regulates epigenetic silencing and is manifestly linked to rare cancer types. The X-linked BCOR gene (BCL-6 Corepressor) is a member of the PRC1 complex and potentiates transcriptional repression through BCL6 binding of PRC1. Accumulating evidence suggests that internal tandem duplications (ITD) of BCOR are oncogenic drivers in a subset of pediatric sarcomas and rare adult tumors. OBJECTIVE: We reviewed the genomic profiles of a large series of advanced cancer patients to determine the frequency and genomic spectrum of ITD of BCOR across cancer. METHODS: Tissues from 140,411 unique advanced cancers were sequenced by hybrid-capture-NGS-based comprehensive genomic profiling of 186-315 genes plus introns from 14 to 28 genes commonly rearranged in cancer, as well as RNA for 265 genes for a portion of these cases. RESULTS: BCOR-ITDs were present in 0.024% of all cases (33/140,411). Of this dataset, sarcoma cancer types were most frequent, 63.6% (21/33), either of uterine origin 52.4% (11/21), or pediatric (nonuterine) 42.8% (9/21). The identified BCOR-ITDs occurred most frequently in exon 15, near C-terminus, 69.7% (23/33), with a mean insertion length of 31.7 codons (range 30-38). Of uterine cases, an expert gynecologic pathology central review identified all these cases as having a similar high-grade morphology consistent with endometrial stromal sarcomas (ESS), and 90% of cases having a round cell component. Of the uterine sarcoma cases harboring exon 15 BCOR-ITDs, none simultaneously carried gene fusions typically associated with ESS. CONCLUSION: BCOR-ITDs define a rare subset of pediatric sarcomas and clinically aggressive endometrial stromal sarcoma cases, as defined by NGS for the first time. Our findings help delineate the pan-cancer landscape of this alteration and suggest the need for focused investigation to delineate the pro-oncogenic function of BCOR, along with any sensitivity to targeted therapies.