Discovery of New Fusion Transcripts in a Cohort of Pediatric Solid Cancers at Relapse and Relevance for Personalized Medicine

Abstract

We hypothetized that pediatric cancers would more likely harbor fusion transcripts. To dissect the complexity of the fusions landscape in recurrent solid pediatric cancers, we conducted a study on 48 patients with different relapsing or resistant malignancies. By analyzing RNA sequencing data with a new in-house pipeline for fusions detection named Chim-Comp, followed by verification by real-time PCR, we identified and classified the most confident fusion transcripts (FTs) according to their potential biological function and druggability. The majority of FTs were predicted to affect key cancer pathways and described to be involved in oncogenesis. Contrary to previous descriptions, we found no significant correlation between the number of fusions and mutations, emphasizing the particularity to study pre-treated pediatric patients. A considerable proportion of FTs containing tumor suppressor genes was detected, reflecting their importance in pediatric cancers. FTs containing non-receptor tyrosine kinases occurred at low incidence and predominantly in brain tumors. Remarkably, more than 30% of patients presented a potentially druggable high-confidence fusion. In conclusion, we detected new oncogenic FTs in relapsing pediatric cancer patients by establishing a robust pipeline that can be applied to other malignancies, to detect and prioritize experimental validation studies leading to the development of new therapeutic options.

MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

“…Although we cannot exclude that some of the primary tumors might express the MGMT fusion at subclonal level, and therefore possibly lower than the RNA-seq detection limits, we speculate that the MGMT rearrangements have been acquired during the course of TMZ treatment and then positively selected due to their ability of driving TMZ resistance. Very recently, another MGMT gene fusion, ASAP2-MGMT, with similar features to the fusions that we have described here in gliomas, has been identified in a medulloblastoma patient that relapsed after TMZ treatment 21 . These data would suggest that MGMT genomic rearrangements could represent a relevant mechanism of resistance to alkylating agents across a broader spectrum of tumor types.…”

Towards Immunotherapy for Pediatric Brain Tumors

“…With this knowledge has come a much-needed new approach towards the discovery of tumor-specific targets unique to childhood brain tumors, instead of basing treatments and trials on that of adult cancers, as has occurred in the past [95]. Many drivers of pediatric cancers are fusions [96]. Consequently, many past efforts have focused on RNA sequence analysis as the most efficient way to detect these fusions, alongside whole-genome and whole-exome sequencing [97].…”

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

“…Using the primers described in Table S1, LMO3-BORCS5 was identified together with the characteristic fusion oncogene of Ewing sarcoma EWS-FLI1 after in silico RNA-seq analysis of a 20-year-old male EwS patient, included in the cohort of pediatric MOSCATO-01 (ClinicalTrials.gov: NCT01566019) patients that we previously analyzed [16]. He had relapsed 3.4 years after initial diagnosis treated with chemotherapy (vincristine, ifosfamide, doxorubicin, etoposide, dactinomycin, and cyclophosphamide).…”

“…Previously, we performed a retrospective study on RNAsequencing data of pediatric resistant or relapsing patients included in the molecular profiling trial MOSCATO-01 conducted at Gustave Roussy [14,15]. Interestingly, we detected a new fusion transcript, LMO3-BORCS5 at diagnosis and at relapse in the tumor of a patient with Ewing sarcoma (EwS) [16].…”