Newly identified LMO3-BORCS5 fusion oncogene in Ewing sarcoma at relapse is a driver of tumor progression

Abstract

Recently, we detected a new fusion transcript LMO3-BORCS5 in a patient with Ewing sarcoma within a cohort of relapsed pediatric cancers. LMO3-BORCS5 was as highly expressed as the characteristic fusion oncogene EWS/FLI1. However, the expression level of LMO3-BORCS5 at diagnosis was very low. Sanger sequencing depicted two LMO3-BORCS5 variants leading to loss of the functional domain LIM2 in LMO3 gene, and disruption of BORCS5. In vitro studies showed that LMO3-BORCS5 (i) increases proliferation, (ii) decreases expression of apoptosis-related genes and treatment sensitivity, and (iii) downregulates genes involved in differentiation and upregulates proliferative and extracellular matrix-related pathways. Remarkably, in vivo LMO3-BORCS5 demonstrated its high oncogenic potential by inducing tumors in mouse fibroblastic NIH-3T3 cell line. Moreover, BORCS5 probably acts, in vivo, as a tumor-suppressor gene. In conclusion, functional studies of fusion oncogenes at relapse are of great importance to define mechanisms involved in tumor progression and resistance to conventional treatments.

The TCGA and GEO databases identify COL5A2 as a poorly prognostic gene in patients with advanced gastric cancer

“…Previously, high-throughput bioinformatics approaches, such as gene chip and gene sequencing, have been widely used to identify cancer biomarkers [10]. Some high-throughput storage databases are publicly available [11,12], and investigators can reuse these databases for data mining according to their study design.…”

The ever-changing world of gene fusions in cancer: a secondary gene fusion and progression

“…One reason this avoided discovery up to this date was that the most common lesion, TMPRSS-ERG, is caused by a small intrachromosomal deletion of 3MB not a large interchromosomal rearrangement, and it was originally the overexpression of portions of the ERG (and other ETS gene family members) mRNA that lead to this discovery. The LMO3-BORCS5 fusion in Dupain et al [2] arises from a similar small deletion mechanism. In the last decade there has been an explosion of gene fusion discovery across all cancer types both rare and common.…”

“…Which leads us to Dupain et al [2] and the discoveries within. While not an absolute rule, we often focus as one predominant gene fusion in cancer such as EWSR1-FLI1 as the main driver of a sarcoma known as Ewing sarcoma, an unusual tumor with a primitive neuroectodermal phenotype but a predilection for bones and soft tissues.…”

“…Fusions were then discovered in more common carcinomas including a group of gene fusions that were not specific to tissue type leading to common diagnostic use and tissue agnostic therapeutics. In this issue of Oncogene, Dupain et al [2], expand on some recent discoveries and increase the known complexity of the role gene fusions play in cancer: a second driver gene fusion (LMO3-BORCS5) in a cancer already defined by a gene fusion (Ewing sarcoma: EWSR1-FLI1) with greatly increased in expression from initial diagnosis to relapse. If past trends in gene fusions are any predictor, this rare phenomenon in a sarcoma will likely become a common diagnostic necessity across many cancers both common and rare increasing the need for more complex diagnostic tools if we are ever to fulfill the promise of precision medicine in a world where diagnostic samples are getting smaller for a variety of reasons.…”

“…As the history of BCR-ABL was progressing, a number of other gene fusions were discovered, many in acute leukemia, along with the genetic fusions of lymphocyte enhancers with oncogenes in lymphomas leading to overexpression [3]. Some sarcomas were defined as a group of tumors with diagnostically specific recurrent gene fusions [4] (i.e., Ewing sarcoma, the focus of the study by Dupain et al [2], EWSR1-FLI1). Common carcinomas remained free from discover of their gene fusions at this time, except for thyroid carcinoma, which showed a number of translocations involving RET, especially in those exposed to radiation [5].…”