ABSTRACT: WES files for Newman MAP3K8 melanoma paper titled "Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas"
Project description:RNASeq files for MAP3K8 melanoma paper titled "Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas"
Project description:WGS files for Newman MAP3K8 melanoma paper titled "Clinical genome sequencing uncovers potentially targetable truncations and fusions of MAP3K8 in spitzoid and other melanomas"
Project description:The newest WHO classification suggests eliminating cases with BRAF and NRAS mutations from the categories of Spitz tumors (ST) and Spitz melanoma (SM). We aimed to better characterize the genomics of Spitz neoplasms and assess whether integrating genomic data with morphologic diagnosis improves classification and prognostication. We performed DNA and RNA sequencing on 80 STs, 26 SMs, and 22 melanomas with Spitzoid features (MSF). NGS data was used to reclassify tumors by moving BRAF/NRAS-mutated cases to MSF. Eighty-one percent of STs harbored kinase fusions/truncations. Of SMs, 77% had fusions/truncations, 8 involving MAP3K8. Novel fusions identified were MYO5A-FGFR1, MYO5A-ERBB4, and PRKDC-CTNNB1. The majority of MSFs (84%) had BRAF, NRAS, or NF1 mutations, and 62% had TERT promoter mutations. Only after reclassification, the following was observed: 1) mRNA expression showed distinct clustering of MSF; 2) 6/7 cases with recurrence and all distant metastases were MSFs; 3) RFS was worse in MSF than ST and SM groups (p=0.0073); 4) classification incorporating genomic data was highly predictive of recurrence (OR 13.20, p=0.0197). The majority of STs and SMs have kinase fusions as primary initiating genomic events. Eliminating BRAF/NRAS-mutated neoplasms from these categories results in improved classification and prognostication of melanocytic neoplasms with Spitzoid cytomorphology.
Project description:The newest WHO classification suggests eliminating cases with BRAF and NRAS mutations from the categories of Spitz tumors (ST) and Spitz melanoma (SM). We aimed to better characterize the genomics of Spitz neoplasms and assess whether integrating genomic data with morphologic diagnosis improves classification and prognostication. We performed DNA and RNA sequencing on 80 STs, 26 SMs, and 22 melanomas with Spitzoid features (MSF). NGS data was used to reclassify tumors by moving BRAF/NRAS-mutated cases to MSF. Eighty-one percent of STs harbored kinase fusions/truncations. Of SMs, 77% had fusions/truncations, 8 involving MAP3K8. Novel fusions identified were MYO5A-FGFR1, MYO5A-ERBB4, and PRKDC-CTNNB1. The majority of MSFs (84%) had BRAF, NRAS, or NF1 mutations, and 62% had TERT promoter mutations. Only after reclassification, the following was observed: 1) mRNA expression showed distinct clustering of MSF; 2) 6/7 cases with recurrence and all distant metastases were MSFs; 3) RFS was worse in MSF than ST and SM groups (p=0.0073); 4) classification incorporating genomic data was highly predictive of recurrence (OR 13.20, p=0.0197). The majority of STs and SMs have kinase fusions as primary initiating genomic events. Eliminating BRAF/NRAS-mutated neoplasms from these categories results in improved classification and prognostication of melanocytic neoplasms with Spitzoid cytomorphology.
Project description:Spitzoid melanoma is a specific morphologic variant of melanoma that most commonly affects children and adolescents and ranges on the spectrum of malignancy from low-grade to overtly malignant. These tumors are generally driven by fusions of ALK, RET, NTRK1/3, MET, ROS1 and BRAF. However, in approximately 50% of cases, no genetic driver has been established. Clinical whole genome and transcriptome sequencing (RNA-Seq) of a spitzoid tumor from an adolescent revealed a novel gene fusion of MAP3K8, encoding a serine−threonine kinase that activates MEK. The patient who had exhausted all other therapeutic options was treated with a MEK inhibitor and underwent a transient clinical response. We subsequently analyzed spitzoid tumors from 49 patients by RNA-Seq and found in-frame fusions or C-terminal truncations in 33% of cases. The fusion transcripts and truncated genes all contained MAP3K8 exons 1-8 but lacked the autoinhibitory final exon. Data mining of RNA-Seq from the Cancer Genome Atlas (TCGA) uncovered analogous MAP3K8 rearrangements in 1.5% of adult melanomas. Thus, MAP3K8 rearrangements - uncovered by comprehensive clinical sequencing of a single case - are the most common genetic event in spitzoid melanoma, are present in adult melanomas, and could be amenable to MEK inhibition.
Project description:WES files for CHEN WTPDX paper titled "Forty-Five patient-derived xenografts capture the clinical and biological heterogeneity of Wilms tumor"
Project description:Supporting MS data for paper (doi: ) by Deneke, Blaha et al (2024), titled “A conserved fertilization complex bridges sperm and egg in vertebrates”. Related to Figure 3B, Figure S4B-C.
Project description:SNP arrays were used to derive copy number estimates and identify amplifications and deletions in melanomas These copy number breakpoints were compared to gene fusions identified by second generation sequencing of cDNA
