Novel PDE10A-BRAF Fusion With Concomitant NF1 Mutation Identified in an Undifferentiated Sarcoma of Infancy With Sustained Response to Trametinib

Vairy, Stéphanie; Jouan, Loubna; Bilodeau, Mélanie; Dormoy-Raclet, Virginie; Gendron, Patrick; Couture, Françoise; Tihy, Frédérique; Lemyre, Emmanuelle; Soglio, Dorothée Bouron‐Dal; Jabado, Nada; Kleinman, Claudia L.; Marzouki, Monia; Cellot, Sonia

doi:10.1200/po.18.00007

Cited by 4 publications

(9 citation statements)

References 31 publications

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“…This unique PDE10A-BRAF fusion has been described previously in an isolated case of a 7.5 cm undifferentiated sarcoma of the pelvis in a 3-month-old female composed of spindled cells with clear cytoplasm and a high mitotic rate. 21 Initial workup of this 3-monthold revealed a complex karyotype but no rearrangements of SS18, ETV6, DUX4, nor CCNB3. The patient received chemotherapy with five cycles of doxorubicin and six cycles of ifosfamide as surgical resection was deemed to be too high risk for neurologic sequelae given the location of the tumor.…”

Section: Discussionmentioning

confidence: 92%

“…After local recurrence following frontline chemotherapy, the 3-month-old then responded to trametinib, a MEK (MAPK pathway) inhibitor. 21 To compare, in the case described herein, the 5-month-old was treated with surgical resection followed by fourteen cycles of the historical standard of vincristine, actinomycin-d and cyclophosphamide (VAC) in addition to proton radiation to the primary tumor site during the final 6 weeks of treatment. 14 Targeted MAPK therapy would have been considered in this case if the patient had relapsed.…”

Section: Discussionmentioning

confidence: 99%

“…Other BRAF fusions have been identified in unclassified spindle cell sarcomas with morphologic resemblance to IFS. 8,10,19,21 Kao et al reports five IFS-like pediatric sarcomas without the hallmark ETV6-NTRK3 fusion that were found to have alternative BRAF gene fusions. Four of the five were located in intra-abdominal and retroperitoneal sites; the fifth was located in the thigh.…”

Section: Discussionmentioning

confidence: 99%

“…Including this case, a total of seven cases of pediatric spindle cell sarcomas with BRAF gene fusions have been reported. 8,21 Additionally, three intragenic BRAF deletions have been identified in tumors with IFS-like morphology, of which the anatomic sites were not reported. Of the masses with known and documented anatomic sites, six of the seven (6/7) tumors were located within the abdomen or retroperitoneum.…”

Section: Discussionmentioning

confidence: 99%

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Second Report of PDE10A-BRAF Fusion in Pediatric Spindle Cell Sarcoma With Infantile Fibrosarcoma-Like Morphology Suggesting PDE10A-BRAF Fusion Is a Recurrent Event

et al. 2021

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Infantile/congenital fibrosarcoma (IFS) is the most common soft tissue tumor in children less than one year of age. The most common anatomic site of IFS is in the extremities or trunk, and rarely in the abdomen or retroperitoneum. Approximately 70-90% of cases are characterized by a distinct t(12;15)(p13;q25) translocation resulting in an ETV6-NTRK3 gene fusion. As such, TRK inhibitors are considered frontline therapy in TRK-fusion positive IFS. The ETV6-NTRK3 fusion is also detected in congenital mesoblastic nephroma (CMN) and less frequently in myeloid leukemias, secretory breast carcinoma, and mammary-type secretory carcinoma of the skin and salivary glands. Infrequently, cases of tumors with IFS-like morphology without the characteristic ETV6-NTRK3 gene fusion have been identified. Herein, an ETV6-NTRK3 fusion negative spindle cell sarcoma with IFS-like morphology subjected to genomic profiling revealed a PDE10A-BRAF fusion, a fusion event that has been detected previously in an isolated case of undifferentiated infantile sarcoma.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Second Report of PDE10A-BRAF Fusion in Pediatric Spindle Cell Sarcoma With Infantile Fibrosarcoma-Like Morphology Suggesting PDE10A-BRAF Fusion Is a Recurrent Event

et al. 2021

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“…Inhibition of the MAPK pathway can be achieved through trametinib, an allosteric MEK inhibitor that was approved by FDA for the treatment of melanoma and metastatic non‐small cell lung cancer harboring BRAF mutations. Trametinib also provides benefits for patients with relapsing undifferentiated sarcoma 7 …”

Section: Introductionmentioning

confidence: 99%

Identification of a novel PHIP::BRAF gene fusion in infantile fibrosarcoma

Boulouadnine

Villenfagne

Galant

et al. 2022

Genes Chromosomes & Cancer

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Introduction:The ETV6::NTRK3 fusion is the most common gene alteration in infantile fibrosarcoma, a soft tissue tumor affecting patients under two years of age.Less frequently, these tumors harbor fusions of genes encoding other kinases, such as BRAF, which activates MEK in the mitogen-activated protein kinase pathway.The identification and characterization of these oncogenes are crucial to facilitate diagnosis, validate new treatments, and better understand the pathophysiology of these neoplasms.Methods: Herein, we analyzed an ETV6::NTRK3-negative infantile fibrosarcoma from a 5-day-old patient by RNA-sequencing to identify new fusion transcripts. Functional exploration of the fusion of interest was performed by in vitro assays to study its activity, oncogenicity, and sensitivity to the MEK inhibitor trametinib.Results: We identified a novel fusion involving the PHIP and BRAF genes. The corresponding fusion protein constitutively activated the mitogen-activated protein kinase pathway, resulting in fibroblast transformation. Treatment of transfected cells with trametinib effectively inhibited signaling by PHIP::BRAF.

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BRAFmutations and concurrent alterations in patients with soft tissue sarcoma

Kobayashi

Zhang

Okajima

et al. 2023

Genes Chromosomes & Cancer

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BRAF alterations, including V600E and non‐V600E mutations and fusions, in soft tissue sarcoma (STS) have been identified in a limited case series. Here, we aimed to evaluate the frequency of BRAF mutations and concurrent alterations in STS to understand their therapeutic action. In this retrospective analysis, we included data from 1964 patients with advanced STS who underwent comprehensive genomic profiling tests at hospitals in Japan between June 2019 and March 2023. The prevalence of BRAF and recurrent concurrent gene alterations were also investigated. BRAF mutations were detected in 24 (1.2%) of 1964 STS patients, with a median age of 47 (range 1–69) years. BRAF V600E was detected in 11 (0.6%) of the 1964 patients with STS, BRAF non‐V600E mutations in 9 (4.6%), and BRAF fusions were detected in 4 (0.2%). BRAF V600E was identified in 4 (0.2%) cases of malignant peripheral nerve sheath tumors. The most common concurrent alteration was CDKN2A (11 cases, 45.8%), and the frequency was equivalent to that of the BRAF V600E (5/11 cases, 45.5%) and non‐V600E (5/9 cases, 55.6%) groups. Recurrent concurrent alterations, such as TERT promoter mutations (7 cases, 29.2%), were detected at the same frequency in the V600E and non‐V600E groups. In contrast, TP53 alterations (4/9 cases, 44.4%) and mitogen‐activated protein kinase (MAPK)‐activating genes, including NF1, GNAQ, and GNA11 (3/9 cases, 33.3%), were identified as relatively higher in the non‐V600E group than in the V600E group (each 1/11 case, 9.1%). We identified BRAF alterations at a rate of 1.2% in all patients with advanced STS. Among them, BRAF V600E and BRAF fusions account for 45.8% and 16.7%, respectively. Collectively, our findings support the clinical characteristics and therapeutic strategies for patients with BRAF‐altered advanced STS.

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Novel PDE10A-BRAF Fusion With Concomitant NF1 Mutation Identified in an Undifferentiated Sarcoma of Infancy With Sustained Response to Trametinib

Cited by 4 publications

References 31 publications

Second Report of PDE10A-BRAF Fusion in Pediatric Spindle Cell Sarcoma With Infantile Fibrosarcoma-Like Morphology Suggesting PDE10A-BRAF Fusion Is a Recurrent Event

Second Report of PDE10A-BRAF Fusion in Pediatric Spindle Cell Sarcoma With Infantile Fibrosarcoma-Like Morphology Suggesting PDE10A-BRAF Fusion Is a Recurrent Event

Identification of a novel PHIP::BRAF gene fusion in infantile fibrosarcoma

BRAFmutations and concurrent alterations in patients with soft tissue sarcoma

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