Gastrointestinal stromal tumors with <scp><i>BRAF</i></scp> gene fusions. A report of two cases showing low or absent <scp>KIT</scp> expression resulting in diagnostic pitfalls

Torrence, Dianne; Xie, Ziyu; Zhang, Lei; Chi, Ping; Antonescu, Cristina R.

doi:10.1002/gcc.22991

Cited by 13 publications

(13 citation statements)

References 38 publications

(87 reference statements)

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“…9,31 Recently, we reported two cases of BRAF fusion-driven primary GISTs that showed weak to complete loss of KIT but preserved DOG1 immunoreactivity. 32 Our case is remarkable in that both KIT and DOG1 showed markedly diminished immunoreactivity, and could present a significant diagnostic pitfall in the absence of molecular evidence of GIST drivers. In mutant KIT-driven GISTs, the FGFR signaling pathway has been implicated as mechanisms of imatinib resistance in tumors lacking secondary KIT mutations.…”

Section: Discussionmentioning

confidence: 73%

“…Other rare cases of primary fusion driver events in quadruple WT GISTs included two cases of ETV6::NTRK3 , reported separately and at least one being diffusely positive for CD117 9,31 . Recently, we reported two cases of BRAF fusion‐driven primary GISTs that showed weak to complete loss of KIT but preserved DOG1 immunoreactivity 32 . Our case is remarkable in that both KIT and DOG1 showed markedly diminished immunoreactivity, and could present a significant diagnostic pitfall in the absence of molecular evidence of GIST drivers.…”

Section: Discussionmentioning

confidence: 99%

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FGFR2::TACC2 fusion as a novel KIT‐independent mechanism of targeted therapy failure in a multidrug‐resistant gastrointestinal stromal tumor

Dermawan

Vanderbilt

Chang

et al. 2022

Genes Chromosomes & Cancer

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Genetic alterations in FGF/FGFR pathway are infrequent in gastrointestinal stromal tumors (GIST), with rare cases of quadruple wildtype GISTs harboring FGFR1 gene fusions and mutations. Additionally, FGF/FGFR overexpression was shown to promote drug resistance to kinase inhibitors in GISTs. However, FGFR gene fusions have not been directly implicated as a mechanism of drug resistance in GISTs. Herein, we report a patient presenting with a primary small bowel spindle cell GIST and concurrent peritoneal and liver metastases displaying an imatinib‐sensitive KIT exon 11 in‐frame deletion. After an initial 9‐month benefit to imatinib, the patient experienced intraabdominal peritoneal recurrence owing to secondary KIT exon 13 missense mutation and FGFR4 amplification. Despite several additional rounds of tyrosine kinase inhibitors (TKI), the patient's disease progressed after 2 years and presented with multiple peritoneal and liver metastases, including one pericolonic mass harboring secondary KIT exon 18 missense mutation, and a concurrent transverse colonic mass with a FGFR2::TACC2 fusion and AKT2 amplification. All tumors, including primary and recurrent masses, harbored an MGA c.7272 T > G (p.Y2424*) nonsense mutation and CDKN2A/CDKN2B/MTAP deletions. The transcolonic mass showed elevated mitotic count (18/10 HPF), as well as significant decrease in CD117 and DOG1 expression, in contrast to all the other resistant nodules that displayed diffuse and strong CD117 and DOG1 immunostaining. The FGFR2::TACC2 fusion resulted from a 742 kb intrachromosomal inversion at the chr10q26.3 locus, leading to a fusion between exons 1–17 of FGFR2 and exons 7–17 TACC2, which preserves the extracellular and protein tyrosine kinase domains of FGFR2. We present the first report of a multidrug‐resistant GIST patient who developed an FGFR2 gene fusion as a secondary genetic event to the selective pressure of various TKIs. This case also highlights the heterogeneous escape mechanisms to targeted therapy across various tumor nodules, spanning from both KIT‐dependent and KIT‐independent off‐target activation pathways.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

FGFR2::TACC2 fusion as a novel KIT‐independent mechanism of targeted therapy failure in a multidrug‐resistant gastrointestinal stromal tumor

Dermawan

Vanderbilt

Chang

et al. 2022

Genes Chromosomes & Cancer

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“…The protein is mainly physiologically expressed in brain cortex, while overexpression has been reported in colorectal carcinoma and adenoma 16 . The AGAP3::BRAF fusion has previously been reported in a few cases from various tumor origins: colorectal carcinoma, lung adenocarcinoma, ovarian serous carcinoma, melanoma, and gastrointestinal stromal tumor 17–19 . The detection of this AGAP3::BRAF fusion seems important for the choice of a targeted treatment since it has been described to confer resistance to EGFR‐targeted and BRAF‐targeted therapies, in colorectal carcinoma and melanoma, respectively 20,21 .…”

Section: Discussionmentioning

confidence: 99%

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

Paoli

Burel‐Vandenbos

Coulomb-L’Herminé

et al. 2022

Genes Chromosomes & Cancer

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Most available molecular data on pancreatic acinar cell carcinoma (PACC) are provided by studies of adult cases. BRAF, RAF1, or RET rearrangements have been described in approximately 30% of cases. To the best of our knowledge, only seven cases with molecular data have been reported in pediatric PACC. We report here the comprehensive study of a pancreatic-type ACC from a 6-year-old patient. We detected an AGAP3::BRAF fusion. This result showing a BRAF rearrangement demonstrates a molecular link between adult and pediatric PACC. Moreover, it identifies AGAP3, a gene located at 7q36.1 that encodes a major component of the N-methyl-D-aspartate (NMDA) receptor signaling complex, as a partner gene of BRAF. The variability of BRAF partners is consistent with a driver role of BRAF alterations in PACC. The identification of such alterations is noteworthy for considering the use of MEK inhibitors in metastatic cases. We did not detect associated genomic instability.The better outcome of pediatric cases might be related to their stable genomic background.

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“…Phenotypically and morphologically, BRAF -mutant GISTs are similar to KIT/PDGFRA positive GISTs [ 67 , 68 , 69 ]. More recently, BRAF fusions have been described in GISTs [ 70 ].…”

Section: Molecular Classification Of Gistsmentioning

confidence: 99%

Current Molecular Profile of Gastrointestinal Stromal Tumors and Systemic Therapeutic Implications

Mathias-Machado¹,

Jesus

Oliveira³

et al. 2022

Cancers

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Gastrointestinal stromal tumors (GISTs) are malignant mesenchymal tumors arising from the intestinal pacemaker cells of Cajal. They compose a heterogenous group of tumors due to a variety of molecular alterations. The most common gain-of-function mutations in GISTs are either in the KIT (60–70%) or platelet-derived growth factor receptor alpha (PDGFRA) genes (10–15%), which are mutually exclusive. However, a smaller subset, lacking KIT and PDGFRA mutations, is considered wild-type GISTs and presents distinct molecular findings with the activation of different proliferative pathways, structural chromosomal and epigenetic changes, such as inactivation of the NF1 gene, mutations in the succinate dehydrogenase (SDH), BRAF, and RAS genes, and also NTRK fusions. Currently, a molecular evaluation of GISTs is imperative in many scenarios, aiding in treatment decisions from the (neo)adjuvant to the metastatic setting. Here, we review the most recent data on the molecular profile of GISTs and highlight therapeutic implications according to distinct GIST molecular subtypes.

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Gastrointestinal stromal tumors with BRAF gene fusions. A report of two cases showing low or absent KIT expression resulting in diagnostic pitfalls

Cited by 13 publications

References 38 publications

FGFR2::TACC2 fusion as a novel KIT‐independent mechanism of targeted therapy failure in a multidrug‐resistant gastrointestinal stromal tumor

FGFR2::TACC2 fusion as a novel KIT‐independent mechanism of targeted therapy failure in a multidrug‐resistant gastrointestinal stromal tumor

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

Current Molecular Profile of Gastrointestinal Stromal Tumors and Systemic Therapeutic Implications

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