Targetable BRAF and RAF1 Alterations in Advanced Pediatric Cancers

Abstract

RAF family protein kinases signal through the MAPK pathway to orchestrate cellular proliferation, survival, and transformation. Identifying BRAF alterations in pediatric cancers is critically important as therapeutic agents targeting BRAF or MEK may be incorporated into the clinical management of these patients. In this study, we performed comprehensive genomic profiling on 3,633 pediatric cancer samples and identified a cohort of 221 (6.1%) cases with known or novel alterations in BRAF or RAF1 detected in extracranial solid tumors, brain tumors, or hematological malignancies. Eighty percent (176/221) of these tumors had a knownactivating short variant (98, 55.7%), fusion (72, 40.9%), or insertion/deletion (6, 3.4%). Among BRAF altered cancers, the most common tumor types were brain tumors (74.4%), solid tumors (10.8%), hematological malignancies (9.1%), sarcomas (3.4%), and extracranial embryonal tumors (2.3%). RAF1 fusions containing intact RAF1 kinase domain (encoded by exons 10-17) were identified in seven tumors, including two novel fusions TMF1-RAF1 and SOX6-RAF1. Additionally, we highlight a subset of patients with brain tumor with positive clinical response to BRAF inhibitors, demonstrating the rationale for incorporating precision medicine into pediatric oncology. The Oncologist 2020;25:1-11 Implications for Practice: Precision medicine has not yet gained a strong foothold in pediatric cancers. This study describes the landscape of BRAF and RAF1 genomic alterations across a diverse spectrum of pediatric cancers, primarily brain tumors, but also encompassing melanoma, sarcoma, several types of hematologic malignancy, and others. Given the availability of multiple U.S. Food and Drug Administration-approved BRAF inhibitors, identification of these alterations may assist with treatment decision making, as described here in three cases of pediatric cancer.

Gene fusions and oncogenic mutations in MLH1 deficient and BRAFV600E wild-type colorectal cancers

“…BRAF fusions with partners AGAP3, TRIM24 and MKRN1 found in our study have also been previously reported to occur in CRC [15,16,34]. STARD3NL::BRAF fusion has earlier been described at least in one paediatric sarcoma [35], whereas to our best knowledge, LMTK2::BRAF has not been reported before in any tumour type. Two of the four Lung v2 NGS-detected RET fusions were detected by the Idylla assay as both RET-specific fusion and expression imbalance.…”

AGAP3: A novel BRAF fusion partner in pediatric pancreatic‐type acinar cell carcinoma

“…The most significant results were extracted from a study of a large series of 3633 pediatric tumors screened for BRAF alterations: the sole two pPACC included in this series showed a PPP1CC::BRAF fusion in one case and BRAF mutation in the other case (Table 1 ). 13 Interestingly, the case with BRAF fusion also presented MYC amplification (formerly known as c‐MYC ). Cramer et al had also described a case of pPACC that harbored a BRAF (V600E) mutation associated with a MLL3 (R2463C) mutation (Table 1 ).…”

Atypical Molecular Features of Pediatric Tectal Glioma: A Single Institutional Series

“…Our patient with SRGAP3-RAF-1 fusion also had a relatively more indolent course, responding to both surgical resection and chemotherapy. RAF-1 known activating fusions have previously been described in pediatric solid tumors 10,11. One study specifically comments on the SRGAP3:RAF1 fusion gene and its role in producing proto-oncogene through the MAPK pathways in pilocytic astrocytomas11 and another study described mutations in 5 distinct brain tumor subtypes, including pilocytic astrocytoma, and low-grade and high-grade glioma 10.…”

“…RAF-1 known activating fusions have previously been described in pediatric solid tumors. 10,11 One study specifically comments on the SRGAP3:RAF1 fusion gene and its role in producing protooncogene through the MAPK pathways in pilocytic astrocytomas 11 and another study described mutations in 5 distinct brain tumor subtypes, including pilocytic astrocytoma, and low-grade and high-grade glioma. 10 Our study adds an additional case to the literature describing 1 patient with a specific clinical course.…”