“…Despite the presence of fusions involving established oncogenes including ABL1 , JAK2 , or FGFR2 with different partner genes, and RET -intergenic fusion, these patients maintained disease control with EGFR-TKIs for more than 2 years, suggesting that fusions with these known oncogenes did not lead to clinical drug resistance. To understand this discrepancy and to establish the clinical significance of putative fusions in patients who have not undergone EGFR-TKI treatment, including case #3 with putative FGFR1 fusion, we performed bulk RNA-sequencing, followed by bioinformatic analyses – this approach previously led us to discover an unknown oncogenic fusion 15 . Fig.…”
Section: Resultsmentioning
confidence: 99%
“…RNA-based targeted NGS can detect unknown fusions only in cases where the specific exons of at least the 5′ or 3′ genes have been pre-designed 14 . However, we have recently shown that bulk RNA sequencing (RNA-seq) offers an unbiased genome-wide method to identify oncogenic fusions that are missed by hybrid capture NGS 15 .…”
The clinical significance of gene fusions detected by DNA-based next generation sequencing remains unclear as resistance mechanisms to EGFR tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer. By studying EGFR inhibitor-resistant patients treated with a combination of an EGFR inhibitor and a drug targeting the putative resistance-causing fusion oncogene, we identify patients who benefit and those who do not from this treatment approach. Through evaluation including RNA-seq of potential drug resistance-imparting fusion oncogenes in 504 patients with EGFR mutant lung cancer, we identify only a minority of them as functional, potentially capable of imparting EGFR inhibitor resistance. We further functionally validate fusion oncogenes in vitro using CRISPR-based editing of EGFR mutant cell lines and use these models to identify known and unknown drug resistance mechanisms to combination therapies. Collectively, our results partially reveal the complex nature of fusion oncogenes as potential drug resistance mechanisms and highlight approaches that can be undertaken to determine their functional significance.
“…Despite the presence of fusions involving established oncogenes including ABL1 , JAK2 , or FGFR2 with different partner genes, and RET -intergenic fusion, these patients maintained disease control with EGFR-TKIs for more than 2 years, suggesting that fusions with these known oncogenes did not lead to clinical drug resistance. To understand this discrepancy and to establish the clinical significance of putative fusions in patients who have not undergone EGFR-TKI treatment, including case #3 with putative FGFR1 fusion, we performed bulk RNA-sequencing, followed by bioinformatic analyses – this approach previously led us to discover an unknown oncogenic fusion 15 . Fig.…”
Section: Resultsmentioning
confidence: 99%
“…RNA-based targeted NGS can detect unknown fusions only in cases where the specific exons of at least the 5′ or 3′ genes have been pre-designed 14 . However, we have recently shown that bulk RNA sequencing (RNA-seq) offers an unbiased genome-wide method to identify oncogenic fusions that are missed by hybrid capture NGS 15 .…”
The clinical significance of gene fusions detected by DNA-based next generation sequencing remains unclear as resistance mechanisms to EGFR tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer. By studying EGFR inhibitor-resistant patients treated with a combination of an EGFR inhibitor and a drug targeting the putative resistance-causing fusion oncogene, we identify patients who benefit and those who do not from this treatment approach. Through evaluation including RNA-seq of potential drug resistance-imparting fusion oncogenes in 504 patients with EGFR mutant lung cancer, we identify only a minority of them as functional, potentially capable of imparting EGFR inhibitor resistance. We further functionally validate fusion oncogenes in vitro using CRISPR-based editing of EGFR mutant cell lines and use these models to identify known and unknown drug resistance mechanisms to combination therapies. Collectively, our results partially reveal the complex nature of fusion oncogenes as potential drug resistance mechanisms and highlight approaches that can be undertaken to determine their functional significance.
“…17 However, there were no clinical or pathology details nor descriptions of the fusion partner gene. 17 Regarding RASGRF1-fused tumors described outside of the skin, only acute myeloid leukemia with a TMEM154:: RASGRF1 fusion 23 and a non-small cell lung cancer with TMEM87A::RASGRF1 fusion 24 have been so far reported. This underscores the overall scarcity of data regarding RASGRF1-fused neoplasms.…”
Spitz neoplasms, according to 2018 WHO Blue Book, are morphologically defined by spindled and/or epithelioid melanocytes and genetically by either HRAS mutations or kinase gene fusions. The terminology "spitzoid" refers to lesions with similar morphology but with alternate or undefined genetic anomalies. Herein, we present 3 melanocytic neoplasms with a spitzoid cytomorphology, variable nuclear atypia, and harboring undescribed fusions involving RASGRF1. Two cases presented as unpigmented papules on the heel of a 26-year-old female (case 1) and the forearm of a 13-year-old boy (case 2). They were classified as low-grade melanocytomas (WHO 2018). The third case appeared as a pigmented ulcer on the sole of a 72-year-old female (case 3) that displayed diagnostic features of an invasive melanoma (Breslow thickness 6 mm, Clark level V). A wide skin reexcision identified an epidermotropic metastasis, and sentinel lymph node biopsy displayed multiple subcapsular metastatic deposits. RNA sequencing revealed CD63::RASGRF1, EHBP1::RASGRF1, and ABCC2:: RASGRF1 fusions in cases 1 to 3, respectively. They were confirmed by a RASGRF1 break-apart fluorescence in situ hybridization technique. Translocations of RASGRF1, a gene coding a guanine nucleotide exchange factor but not a kinase, have rarely been reported in tumors. While all these cases showed spitzoid cytomorphology, it is too early to tell if they are true Spitz neoplasms as currently defined.
“…TMEM87A and TMEM87B have been associated with protein transport to and from the Golgi, mechanosensitive cation channel activity, and cardiac and other developmental processes 2–5 . In humans, TMEM87 proteins have been implicated in developmental diseases and cancers 6–9 .…”
Section: Introductionmentioning
confidence: 99%
“…In a patient with a severe cardiac phenotype, whole-exome sequencing uncovered a paternally inherited TMEM87B missense mutation and chromosome 2 deletion inherited from an unaffected mother 8 . Both TMEM87A and TMEM87B have additionally been implicated in cancers such as non-small cell lung cancer through fusion or suspected interaction with oncogenes 6,7,10 .…”
TMEM87s are eukaryotic transmembrane proteins with two members (TMEM87A and TMEM87B) in humans. TMEM87s have proposed roles in protein transport to and from the Golgi, as mechanosensitive ion channels, and in developmental signaling. TMEM87 disruption has been implicated in cancers and developmental disorders. To better understand TMEM87 structure and function, we determined a cryo-EM structure of human TMEM87A in lipid nanodiscs. TMEM87A consists of a Golgi-dynamics (GOLD) domain atop a membrane spanning seven-transmembrane helix domain with a large cavity open to solution and the membrane outer leaflet. Structural and functional analyses suggest TMEM87A may not function as an ion channel or G-protein coupled receptor. We find TMEM87A shares its characteristic domain arrangement with seven other proteins in humans; three that had been identified as evolutionary related (TMEM87B, GPR107, and GPR108) and four previously unrecognized homologs (GPR180, TMEM145, TMEM181, and WLS)). Among these structurally related GOLD domain seven-transmembrane helix (GOST) proteins, WLS is best characterized as a membrane trafficking and secretion chaperone for lipidated Wnt signaling proteins. We find key structural determinants for WLS function are conserved in TMEM87A. We propose TMEM87A and structurally homologous GOST proteins could serve a common role in trafficking membrane-associated cargo.
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