Drivers of genomic loss of heterozygosity in leiomyosarcoma are distinct from carcinomas

Abstract

Leiomyosarcoma (LMS) is a rare, aggressive, mesenchymal tumor. Subsets of LMS have been identified to harbor genomic alterations associated with homologous recombination deficiency (HRD); particularly alterations in BRCA2. Whereas genomic loss of heterozygosity (gLOH) has been used as a surrogate marker of HRD in other solid tumors, the prognostic or clinical value of gLOH in LMS (gLOH-LMS) remains poorly defined. We explore the genomic drivers associated with gLOH-LMS and their clinical import. Although the distribution of gLOH-LMS scores are similar to that of carcinomas, outside of BRCA2, there was no overlap with previously published gLOH-associated genes from studies in carcinomas. We note that early stage tumors with elevated gLOH demonstrated a longer disease-free interval following resection in LMS patients. Taken together, and despite similarities to carcinomas in gLOH distribution and clinical import, gLOH-LMS are driven by different genomic signals. Additional studies will be required to isolate and confirm the unique differences in biological factors driving these differences.

Mutations in Homologous Recombination Genes and Loss of Heterozygosity Status in Advanced-Stage Breast Carcinoma

“…Genomic alterations in BRCA1/2 have been highly associated with HRD in many cancers [25,38]. Sokol et al showed that a BRCA1/2 alteration was consistently associated with LOH-high in many cancer types, including breast cancer, and the magnitude was variable for each cancer type.…”

Gene partners of the EWSR1 fusion may represent molecularly distinct entities

“…This study is reported in accordance with the Strengthening the Reporting of Genetic Association Studies ( STREGA ) reporting guideline [12] . Genomic profiling data from EWSR1 fusion positive tumors was collected as assayed during clinical care using FMI's hybrid-capture-based next-generation sequencing (NGS) platform as previously described [13] , [14] , [15] . Approval for the retrospective collection of genomic data from FMI, including a waiver of informed consent and a HIPAA waiver of authorization, was obtained from the Western Institutional Review Board (protocol: 20,152,817).…”

Long-Time Progression-Free Survival with Trabectedin in Chemorefractory Metastatic Leiomyosarcoma of the Retroperitoneum: A Case Report

“…At this point, it is important to highlight the need to establish predictive markers of response to systemic therapies, especially for patients who do not respond to standard chemotherapy. Research is being conducted into genomic profiling of uterine and non-uterine LMS [9][10][11] which will support the identification of targeted therapies for patients who currently have no adequate treatment options.…”