AGAP3: a novel BRAF-fusion partner in pediatric pancreatic acinar cell carcinoma
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PROVIDER: PRJNA838965 | ENA |
REPOSITORIES: ENA
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Project description: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 PACC from a 6-year-old patient. We detected a novel 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 new 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.
2022-05-18 | GSE203175 | GEO
Project description: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.
| S-EPMC9804258 | biostudies-literature
Project description:Fusion genes can be oncogenic drivers in a variety of cancer types and represent potential targets for targeted therapy. The BRAF gene is frequently involved in oncogenic fusions, with fusion frequencies of 0.2-3% throughout different cancers. However, BRAF fusions rarely occur in the same gene configuration, potentially challenging personalized therapy design. In particular, the influence that is imposed by the wide variety of fusion partners on the oncogenic role of BRAF during tumor growth and drug response is unknown. Here, we used patient-derived colorectal cancer organoids to functionally characterize and cross-compare previously identified BRAF fusions containing various partner genes (AGAP3, DLG1 and TRIM24) with respect to cellular behaviour, downstream signaling activation and response to targeted therapies. We demonstrate that 5’ partner choice of BRAF fusions affects their subcellular localization and intracellular signaling capacity. In particular the DLG1-BRAF fusion protein showed distinct localization to the plasma membrane and exhibited increased activation of downstream MAPK signaling under unperturbed conditions. Moreover, phosphoproteomics and RNA sequencing identified distinct subsets of affected signaling pathways and altered gene expression of BRAF fusions. The different BRAF fusions exhibited varying sensitivities to simultaneous targeted inhibition of MEK and the EGF receptor family. However, all BRAF fusions conveyed resistance to targeted monotherapy against the EGF receptor family, suggesting that BRAF fusions should be screened alongside other MAPK pathway alterations to identify mCRC patients to exclude from cetuximab treatment
2020-01-16 | PXD013461 | Pride
Project description:Fusion genes may be oncogenic drivers and potential targets for personalized therapies in a variety of cancer types. The BRAF gene is frequently involved in oncogenic fusions, with fusion frequencies of 0.2-3% throughout different cancers. BRAF can be fused to a wide variety of genes, however, BRAF fusions rarely occur in the exact same gene configuration, making assessment of the fusion relevance and decision for drug treatment challenging. Here, we devised a colorectal cancer organoid-based platform to functionally characterize diverse BRAF fusions, containing various partner genes (AGAP3, DLG1 and TRIM24). We compared these BRAF fusions with respect to cellular behaviour, downstream signaling activation and response to targeted therapies. We found that 5’ partner choice of BRAF affects cellular localization and intracellular signaling capacities of the fusion genes. The DLG1-BRAF fusion gene showed distinct localization to the plasma membrane and exhibited increased levels of MAPK pathway activation under unperturbed conditions. Furthermore, the different BRAF fusions showed varying sensitivities to the targeted inhibition of ERK and BRAF, with the DLG1-BRAF fusion being the most sensitive. Additionally, RNA-sequencing identified distinct subsets of genes affected by the DLG1-BRAF fusion gene. Importantly, all fusion genes conveyed resistance to the clinically relevant EGFR/HER2/HER4-inhibitor afatinib, suggesting that BRAF fusions should be screened alongside other MAPK pathway alterations to identify mCRC patients amenable to cetuximab treatment. In summary, we developed a platform to efficiently assess molecular and cellular effects of fusion genes, and revealed that differential drug responses and distinct gene expression profiles can be induced by different BRAF fusions .
| EGAS00001003558 | EGA
Project description:Chromosomal rearrangements of the Mixed Lineage Leukemia (MLL) gene result in fusion proteins which retain the N-terminal portion of MLL fused with one of more than 70 different fusion partners. The high diversity of MLL fusion partners raises a question whether it is possible to develop a general therapeutic strategy to block the oncogenic activity of MLL fusion proteins in a fusion partner independent manner. We have demonstrated that blocking the menin-MLL interaction using small molecule inhibitor inhibits oncogenic activity of different MLL fusion proteins according to a mechanism that is independent on the fusion partner.
2018-06-09 | GSE69740 | GEO
Project description:Exposure to ionizing radiation during childhood markedly increases the risk of developing papillary thyroid cancer. We identified non-overlapping somatic driver mutations in all 26 cases of post-Chernobyl thyroid cancers we studied through candidate gene assays and next generation RNA-sequencing. We found that 22/26 harbored fusion oncogenes arising primarily through intrachromosomal rearrangements. Altogether 23/26 of the oncogenic drivers identified in this cohort aberrantly activate MAPK signaling, including the two novel somatic rearrangements ETV6-NTRK3 and AGK-BRAF. Two other tumors harbored distinct fusions leading to overexpression of the nuclear receptor PPARγ. A lower prevalence of fusion oncogenes was found in a cohort of pediatric thyroid cancers from children from the same geographical regions that were not exposed to radiation. Radiation-induced thyroid cancers are a paradigm of tumorigenesis driven by fusion oncogenes that activate MAPK signaling or, less frequently, a PPARγ-driven transcriptional program. Examination of transcriptome profiles and genetic somatic changes in thyroid cancer.
2013-10-25 | E-GEOD-48850 | biostudies-arrayexpress
Project description:CONTEXT: BRAF V600E mutation (BRAF-mut.) confers aggressiveness in papillary thyroid carcinoma, but unidentified genomic abnormalities may be required for full phenotypic expression. OBJECTIVE: To perform deep sequencing to identify genes differentially expressed between BRAF-mut. and BRAF-wild-type (BRAF-WT) tumors, and to compare to patient clinical status. DESIGN: BRAF-mut. and BRAF-WT tumors were identified in patients with T1N0 and with T23N1 tumors. Expression levels of genes were determined from RNA sequencing (RNA-Seq) data and fusion transcripts were detected. NanoString was used to validate the RNA-Seq data for immune genes. SETTING: Patients were seen at two sites of a major referral medical center. PATIENTS: Twenty patients were studied. BRAF-mut. patients included 9 women, 3 men; 9 were TNM stage I and 3 were stage III; 3 (25%) had lymphocytic thyroiditis. BRAF-WT included 5 women; 3 men; all were stage I; 5 (62.5%) had lymphocytic thyroiditis. RESULTS: 560 of 13,085 genes were differentially expressed by RNA-Seq, and MetaCore analysis identified 55 immune function genes that were differentially expressed as a function of BRAF mutational status. Immune function genes were broadly underexpressed in BRAF-mut. tumors, with only 4 genes (HLA-G, CXCL14, TIMP1, IL1RAP) more highly expressed. NanoString validated the RNA Seq data for immune genes. Eleven high confidence fusion transcripts were detected, four being inter-chromosomal and seven intra-chromosomal. CONCLUSION: BRAF-mut. papillary thyroid cancers have less expression of immune and inflammatory response genes than BRAF-WT tumors. Thirteen of 20 (65%) tumors had between one and three fusion transcripts. Functional studies will be required to determine the potential role of the newly identified genomic abnormalities in contributing to the aggressiveness of BRAF-mut. and wild-type tumors. RNA-seq was performed on 20 thyroid carcinoma tumors
2015-07-01 | E-GEOD-48953 | biostudies-arrayexpress
Project description:Fusion partner directed chromatin occupancy drives the transcriptome heterogeneity of MLL-fusion acute lymphoblastic leukemia
| PRJNA407757 | ENA
Project description:Exposure to ionizing radiation during childhood markedly increases the risk of developing papillary thyroid cancer. We identified non-overlapping somatic driver mutations in all 26 cases of post-Chernobyl thyroid cancers we studied through candidate gene assays and next generation RNA-sequencing. We found that 22/26 harbored fusion oncogenes arising primarily through intrachromosomal rearrangements. Altogether 23/26 of the oncogenic drivers identified in this cohort aberrantly activate MAPK signaling, including the two novel somatic rearrangements ETV6-NTRK3 and AGK-BRAF. Two other tumors harbored distinct fusions leading to overexpression of the nuclear receptor PPARγ. A lower prevalence of fusion oncogenes was found in a cohort of pediatric thyroid cancers from children from the same geographical regions that were not exposed to radiation. Radiation-induced thyroid cancers are a paradigm of tumorigenesis driven by fusion oncogenes that activate MAPK signaling or, less frequently, a PPARγ-driven transcriptional program.
2013-10-25 | GSE48850 | GEO
Project description:CONTEXT: BRAF V600E mutation (BRAF-mut.) confers aggressiveness in papillary thyroid carcinoma, but unidentified genomic abnormalities may be required for full phenotypic expression. OBJECTIVE: To perform deep sequencing to identify genes differentially expressed between BRAF-mut. and BRAF-wild-type (BRAF-WT) tumors, and to compare to patient clinical status. DESIGN: BRAF-mut. and BRAF-WT tumors were identified in patients with T1N0 and with T23N1 tumors. Expression levels of genes were determined from RNA sequencing (RNA-Seq) data and fusion transcripts were detected. NanoString was used to validate the RNA-Seq data for immune genes. SETTING: Patients were seen at two sites of a major referral medical center. PATIENTS: Twenty patients were studied. BRAF-mut. patients included 9 women, 3 men; 9 were TNM stage I and 3 were stage III; 3 (25%) had lymphocytic thyroiditis. BRAF-WT included 5 women; 3 men; all were stage I; 5 (62.5%) had lymphocytic thyroiditis. RESULTS: 560 of 13,085 genes were differentially expressed by RNA-Seq, and MetaCore analysis identified 55 immune function genes that were differentially expressed as a function of BRAF mutational status. Immune function genes were broadly underexpressed in BRAF-mut. tumors, with only 4 genes (HLA-G, CXCL14, TIMP1, IL1RAP) more highly expressed. NanoString validated the RNA Seq data for immune genes. Eleven high confidence fusion transcripts were detected, four being inter-chromosomal and seven intra-chromosomal. CONCLUSION: BRAF-mut. papillary thyroid cancers have less expression of immune and inflammatory response genes than BRAF-WT tumors. Thirteen of 20 (65%) tumors had between one and three fusion transcripts. Functional studies will be required to determine the potential role of the newly identified genomic abnormalities in contributing to the aggressiveness of BRAF-mut. and wild-type tumors.
2015-07-01 | GSE48953 | GEO