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Kari Hemminki - One of the best experts on this subject based on the ideXlab platform.
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mapping of deletion breakpoints at the cdkn2a locus in melanoma detection of mtap anril fusion transcripts
Oncotarget, 2016Co-Authors: Sivaramakrishna P Rachakonda, Kari Hemminki, Barbara Heidenreich, Eduardo Nagore, Antje Sucker, Dirk Schadendorf, Rajiv KumarAbstract:// Huaping Xie 1, 2 , P. Sivaramakrishna Rachakonda 2 , Barbara Heidenreich 2 , Eduardo Nagore 3 , Antje Sucker 4 , Kari Hemminki 2, 5 , Dirk Schadendorf 4, 6 , Rajiv Kumar 2 1 Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 2 Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany 3 Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain 4 Department of Dermatology, University Hospital Essen, Essen, Germany 5 Center for Primary Health Care Research, Lund University, Malmo, Sweden 6 German Cancer Consortium (DKTK), Essen, Germany Correspondence to: Rajiv Kumar, e-mail: r.kumar@dkfz.de Keywords: melanoma, CDKN2A, deletions, break points Received: December 28, 2015 Accepted: February 11, 2016 Published: February 19, 2016 ABSTRACT Genomic locus at chromosome 9p21 that contains the CDKN2A and CDKN2B tumor suppressor genes is inactivated through mutations, deletions and promoter methylation in multiple human cancers. Additionally, the locus encodes an anti-sense RNA ( ANRIL ). Both hemizygous and homozygous deletions at the locus targeting multiple genes are fairly common in different cancers. We in this study investigated breakpoints in five melanoma cell lines, derived from metastasized tumors, with previously identified homozygous deletions using array comparative genomic hybridization (aCGH). For breakpoint mapping, we used primer approximation multiplex PCR (PAMP) and inverse PCR techniques. Our results showed that three cell lines carried complex rearrangements. In two other cell lines, with focal deletions of 141 kb and 181 kb, we identified fusion gene products, involving MTAP and ANRIL . We also confirmed the complex rearrangements and focal deletions in DNA from tumor tissues corresponding to three cell lines. The rapid amplification of 3’cDNA ends (3’RACE) carried out on transcripts resulted in identification of three isoforms of MTAP-ANRIL fusion gene. Screening of cDNA from 64 melanoma cell lines resulted in detection of fusion transcripts in 13 (20%) cell lines that involved exons 4-7 of the MTAP and exon 2 or 5 of the ANRIL genes. We also detected fusion transcripts involving MTAP and ANRIL in two of the seven primary melanoma tumors with focal deletion at the locus. The results from the study, besides identifying complex rearrangements involving CDKN2A locus, show frequent occurrence of fusion transcripts involving MTAP and ANRIL genes.
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a single nucleotide polymorphism in the 3 untranslated region of the cdkn2a gene is common in sporadic primary melanomas but mutations in the cdkn2b CDKN2C cdk4 and p53 genes are rare
International Journal of Cancer, 2001Co-Authors: Rajiv Kumar, Johanna Smeds, Petra Berggren, Oddbjandorn Straume, Barbro Lundh Rozell, Lars A Akslen, Kari HemminkiAbstract:In this report we present the results of mutational analysis of the CDKN2B, CDKN2C, CDK4, p53 genes and 5′UTR of the CDKN2A gene in a set of 44 sporadic primary melanomas, which had been earlier analysed for mutations in the CDKN2A (p16/p14ARF) gene. No tumour-associated mutations were detected except in 1 melanoma where we found a CC>T* deletion-mutation in the codon 151–152 (exon 5) of the p53 gene. On the basis of our preliminary results, we did extended genotyping of the 500 C>G and 540 C>T polymorphisms in the 3′UTR of the CDKN2A gene in 229 melanoma cases and 235 controls. The T-allele frequency (for 540 C>T polymorphism) in melanomas was significantly higher than in controls (0.14 vs. 0.08; χ2 = 5.95, p = 0.01; OR = 1.71, 95%CI = 1.11–2.66). The heterozygote frequency for this polymorphism was 0.26 (59/229) in melanomas compared to 0.13 (30/235) in healthy controls (χ2 = 11.4; p = 0.0007; OR = 2.34, 95% CI = 1.40–3.92). The frequency of the 500 C>G polymorphism in the 3′UTR in the CDKN2A gene was not significantly higher in melanomas compared to healthy controls. The 500 C>G polymorphism, however, was in linkage disequilibrium with ∼50 kb apart the C>A intronic polymorphism in the CDKN2B gene (determined in 44 melanomas and 90 controls; Fisher exact test, p<0.0001). Finally, the sequence analysis of genomic DNA isolated from T cell lymphocytes of healthy individuals exhibited that the codon reported as last of exon 2 of the CDKN2C gene is rather the first codon of exon 3. © 2001 Wiley-Liss, Inc.
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A single nucleotide polymorphism in the 3'untranslated region of the CDKN2A gene is common in sporadic primary melanomas but mutations in the CDKN2B, CDKN2C, CDK4 and p53 genes are rare.
International journal of cancer, 2001Co-Authors: Rajiv Kumar, Johanna Smeds, Petra Berggren, Oddbjandorn Straume, Barbro Lundh Rozell, Lars A Akslen, Kari HemminkiAbstract:In this report we present the results of mutational analysis of the CDKN2B, CDKN2C, CDK4, p53 genes and 5′UTR of the CDKN2A gene in a set of 44 sporadic primary melanomas, which had been earlier analysed for mutations in the CDKN2A (p16/p14ARF) gene. No tumour-associated mutations were detected except in 1 melanoma where we found a CC>T* deletion-mutation in the codon 151–152 (exon 5) of the p53 gene. On the basis of our preliminary results, we did extended genotyping of the 500 C>G and 540 C>T polymorphisms in the 3′UTR of the CDKN2A gene in 229 melanoma cases and 235 controls. The T-allele frequency (for 540 C>T polymorphism) in melanomas was significantly higher than in controls (0.14 vs. 0.08; χ2 = 5.95, p = 0.01; OR = 1.71, 95%CI = 1.11–2.66). The heterozygote frequency for this polymorphism was 0.26 (59/229) in melanomas compared to 0.13 (30/235) in healthy controls (χ2 = 11.4; p = 0.0007; OR = 2.34, 95% CI = 1.40–3.92). The frequency of the 500 C>G polymorphism in the 3′UTR in the CDKN2A gene was not significantly higher in melanomas compared to healthy controls. The 500 C>G polymorphism, however, was in linkage disequilibrium with ∼50 kb apart the C>A intronic polymorphism in the CDKN2B gene (determined in 44 melanomas and 90 controls; Fisher exact test, p
Rajiv Kumar - One of the best experts on this subject based on the ideXlab platform.
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mapping of deletion breakpoints at the cdkn2a locus in melanoma detection of mtap anril fusion transcripts
Oncotarget, 2016Co-Authors: Sivaramakrishna P Rachakonda, Kari Hemminki, Barbara Heidenreich, Eduardo Nagore, Antje Sucker, Dirk Schadendorf, Rajiv KumarAbstract:// Huaping Xie 1, 2 , P. Sivaramakrishna Rachakonda 2 , Barbara Heidenreich 2 , Eduardo Nagore 3 , Antje Sucker 4 , Kari Hemminki 2, 5 , Dirk Schadendorf 4, 6 , Rajiv Kumar 2 1 Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 2 Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany 3 Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain 4 Department of Dermatology, University Hospital Essen, Essen, Germany 5 Center for Primary Health Care Research, Lund University, Malmo, Sweden 6 German Cancer Consortium (DKTK), Essen, Germany Correspondence to: Rajiv Kumar, e-mail: r.kumar@dkfz.de Keywords: melanoma, CDKN2A, deletions, break points Received: December 28, 2015 Accepted: February 11, 2016 Published: February 19, 2016 ABSTRACT Genomic locus at chromosome 9p21 that contains the CDKN2A and CDKN2B tumor suppressor genes is inactivated through mutations, deletions and promoter methylation in multiple human cancers. Additionally, the locus encodes an anti-sense RNA ( ANRIL ). Both hemizygous and homozygous deletions at the locus targeting multiple genes are fairly common in different cancers. We in this study investigated breakpoints in five melanoma cell lines, derived from metastasized tumors, with previously identified homozygous deletions using array comparative genomic hybridization (aCGH). For breakpoint mapping, we used primer approximation multiplex PCR (PAMP) and inverse PCR techniques. Our results showed that three cell lines carried complex rearrangements. In two other cell lines, with focal deletions of 141 kb and 181 kb, we identified fusion gene products, involving MTAP and ANRIL . We also confirmed the complex rearrangements and focal deletions in DNA from tumor tissues corresponding to three cell lines. The rapid amplification of 3’cDNA ends (3’RACE) carried out on transcripts resulted in identification of three isoforms of MTAP-ANRIL fusion gene. Screening of cDNA from 64 melanoma cell lines resulted in detection of fusion transcripts in 13 (20%) cell lines that involved exons 4-7 of the MTAP and exon 2 or 5 of the ANRIL genes. We also detected fusion transcripts involving MTAP and ANRIL in two of the seven primary melanoma tumors with focal deletion at the locus. The results from the study, besides identifying complex rearrangements involving CDKN2A locus, show frequent occurrence of fusion transcripts involving MTAP and ANRIL genes.
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a single nucleotide polymorphism in the 3 untranslated region of the cdkn2a gene is common in sporadic primary melanomas but mutations in the cdkn2b CDKN2C cdk4 and p53 genes are rare
International Journal of Cancer, 2001Co-Authors: Rajiv Kumar, Johanna Smeds, Petra Berggren, Oddbjandorn Straume, Barbro Lundh Rozell, Lars A Akslen, Kari HemminkiAbstract:In this report we present the results of mutational analysis of the CDKN2B, CDKN2C, CDK4, p53 genes and 5′UTR of the CDKN2A gene in a set of 44 sporadic primary melanomas, which had been earlier analysed for mutations in the CDKN2A (p16/p14ARF) gene. No tumour-associated mutations were detected except in 1 melanoma where we found a CC>T* deletion-mutation in the codon 151–152 (exon 5) of the p53 gene. On the basis of our preliminary results, we did extended genotyping of the 500 C>G and 540 C>T polymorphisms in the 3′UTR of the CDKN2A gene in 229 melanoma cases and 235 controls. The T-allele frequency (for 540 C>T polymorphism) in melanomas was significantly higher than in controls (0.14 vs. 0.08; χ2 = 5.95, p = 0.01; OR = 1.71, 95%CI = 1.11–2.66). The heterozygote frequency for this polymorphism was 0.26 (59/229) in melanomas compared to 0.13 (30/235) in healthy controls (χ2 = 11.4; p = 0.0007; OR = 2.34, 95% CI = 1.40–3.92). The frequency of the 500 C>G polymorphism in the 3′UTR in the CDKN2A gene was not significantly higher in melanomas compared to healthy controls. The 500 C>G polymorphism, however, was in linkage disequilibrium with ∼50 kb apart the C>A intronic polymorphism in the CDKN2B gene (determined in 44 melanomas and 90 controls; Fisher exact test, p<0.0001). Finally, the sequence analysis of genomic DNA isolated from T cell lymphocytes of healthy individuals exhibited that the codon reported as last of exon 2 of the CDKN2C gene is rather the first codon of exon 3. © 2001 Wiley-Liss, Inc.
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A single nucleotide polymorphism in the 3'untranslated region of the CDKN2A gene is common in sporadic primary melanomas but mutations in the CDKN2B, CDKN2C, CDK4 and p53 genes are rare.
International journal of cancer, 2001Co-Authors: Rajiv Kumar, Johanna Smeds, Petra Berggren, Oddbjandorn Straume, Barbro Lundh Rozell, Lars A Akslen, Kari HemminkiAbstract:In this report we present the results of mutational analysis of the CDKN2B, CDKN2C, CDK4, p53 genes and 5′UTR of the CDKN2A gene in a set of 44 sporadic primary melanomas, which had been earlier analysed for mutations in the CDKN2A (p16/p14ARF) gene. No tumour-associated mutations were detected except in 1 melanoma where we found a CC>T* deletion-mutation in the codon 151–152 (exon 5) of the p53 gene. On the basis of our preliminary results, we did extended genotyping of the 500 C>G and 540 C>T polymorphisms in the 3′UTR of the CDKN2A gene in 229 melanoma cases and 235 controls. The T-allele frequency (for 540 C>T polymorphism) in melanomas was significantly higher than in controls (0.14 vs. 0.08; χ2 = 5.95, p = 0.01; OR = 1.71, 95%CI = 1.11–2.66). The heterozygote frequency for this polymorphism was 0.26 (59/229) in melanomas compared to 0.13 (30/235) in healthy controls (χ2 = 11.4; p = 0.0007; OR = 2.34, 95% CI = 1.40–3.92). The frequency of the 500 C>G polymorphism in the 3′UTR in the CDKN2A gene was not significantly higher in melanomas compared to healthy controls. The 500 C>G polymorphism, however, was in linkage disequilibrium with ∼50 kb apart the C>A intronic polymorphism in the CDKN2B gene (determined in 44 melanomas and 90 controls; Fisher exact test, p
Naifa L. Busaidy - One of the best experts on this subject based on the ideXlab platform.
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Novel use of a Clinical Laboratory Improvements Amendments (CLIA)-certified Cyclin-Dependent Kinase N2C (CDKN2C) loss assay in sporadic medullary thyroid carcinoma.
Surgery, 2019Co-Authors: Jessica E. Maxwell, Gilbert J. Cote, Maria Gule-monroe, Vivek Subbiah, Nancy D. Perrier, Maria E. Cabanillas, Jeffery E. Lee, Paul H. Graham, Naifa L. BusaidyAbstract:Abstract Background The cyclin-dependent-kinase inhibitor/retinoblastoma pathway has been implicated in sporadic medullary thyroid carcinoma tumorigenesis. Somatic CDKN2C loss has been associated with decreased overall survival in medullary thyroid carcinoma patients. We evaluated CDKN2C loss in a prospective clinical environment using a novel Clinical Laboratory Improvement Amendments–certified assay to confirm its association with aggressive disease and to interrogate response to targeted therapy. Methods Patients with advanced sporadic medullary thyroid carcinoma underwent tumor genotyping for the purpose of management of targeted therapy and prognostication. Results Of patients with informative CDKN2C assay results, 30 (51.8%) were haploinsufficient/1N and 28 (48.3%) were 2N. Forty patients (69.0%) had a somatic RET mutation, and 36.9% had alterations of both genes. Thirty patients (51.7%) were treated with systemic therapy. Presence of genetic alterations in CDKN2C or RET did not predict treatment response. Patients with 1N CDKN2C loss had significantly shorter time-to-distant-metastasis than patients with normal copy number (P = .03). Conclusion This is the first evaluation in the clinical setting of CDKN2C haploinsufficiency in sporadic medullary thyroid carcinoma. Although a larger cohort and longer follow-up will be required, loss seems to be associated with more aggressive disease and may indicate patients that might receive benefit from treatment with a CDK inhibitor.
Julia Andrea Elvin - One of the best experts on this subject based on the ideXlab platform.
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comprehensive genomic profiling of esthesioneuroblastoma reveals additional treatment options
Oncologist, 2017Co-Authors: Kyle Fedorchak, Madappa N Kundranda, Yazmin Odia, Chaitali Singh Nangia, James D Battiste, Gerardo Colonotero, Steven Francis Powell, Jeffery S Russell, Julia Andrea ElvinAbstract:BACKGROUND: Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant neoplasm of the olfactory mucosa. Despite surgical resection combined with radiotherapy and adjuvant chemotherapy, ENB often relapses with rapid progression. Current multimodality, nontargeted therapy for relapsed ENB is of limited clinical benefit. MATERIALS AND METHODS: We queried whether comprehensive genomic profiling (CGP) of relapsed or refractory ENB can uncover genomic alterations (GA) that could identify potential targeted therapies for these patients. CGP was performed on formalin-fixed, paraffin-embedded sections from 41 consecutive clinical cases of ENBs using a hybrid-capture, adaptor ligation based next-generation sequencing assay to a mean coverage depth of 593X. The results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes (amplifications and homozygous deletions). RESULTS: Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in clinical trials. A total of 28 ENBs harbored GA, with a mean of 1.5 GA per sample. Approximately half of the ENBs (21, 51%) featured at least one CRGA, with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), with GA in PIK3CA, NF1, CDKN2A, and CDKN2C occurring in 7% of samples. CONCLUSION: We report comprehensive genomic profiles for 41 ENB tumors. CGP revealed potential new therapeutic targets, including targetable GA in the mTOR, CDK and growth factor signaling pathways, highlighting the clinical value of genomic profiling in ENB. IMPLICATIONS FOR PRACTICE: Comprehensive genomic profiling of 41 relapsed or refractory ENBs reveals recurrent alterations or classes of mutation, including amplification of tyrosine kinases encoded on chromosome 5q and mutations affecting genes in the mTOR/PI3K pathway. Approximately half of the ENBs (21, 51%) featured at least one clinically relevant genomic alteration (CRGA), with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), and alterations in PIK3CA, NF1, CDKN2A, or CDKN2C were identified in 7% of samples. Responses to treatment with the kinase inhibitors sunitinib, everolimus, and pazopanib are presented in conjunction with tumor genomics.
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Comprehensive Genomic Profiling of Esthesioneuroblastoma Reveals Additional Treatment Options
The oncologist, 2017Co-Authors: Sungeun Kim, Kyle Fedorchak, Madappa N Kundranda, Yazmin Odia, Chaitali Singh Nangia, James D Battiste, Steven Francis Powell, Jeffery S Russell, Gerardo Colon-otero, Julia Andrea ElvinAbstract:BACKGROUND Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant neoplasm of the olfactory mucosa. Despite surgical resection combined with radiotherapy and adjuvant chemotherapy, ENB often relapses with rapid progression. Current multimodality, nontargeted therapy for relapsed ENB is of limited clinical benefit. MATERIALS AND METHODS We queried whether comprehensive genomic profiling (CGP) of relapsed or refractory ENB can uncover genomic alterations (GA) that could identify potential targeted therapies for these patients. CGP was performed on formalin-fixed, paraffin-embedded sections from 41 consecutive clinical cases of ENBs using a hybrid-capture, adaptor ligation based next-generation sequencing assay to a mean coverage depth of 593X. The results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes (amplifications and homozygous deletions). RESULTS Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in clinical trials. A total of 28 ENBs harbored GA, with a mean of 1.5 GA per sample. Approximately half of the ENBs (21, 51%) featured at least one CRGA, with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), with GA in PIK3CA, NF1, CDKN2A, and CDKN2C occurring in 7% of samples. CONCLUSION We report comprehensive genomic profiles for 41 ENB tumors. CGP revealed potential new therapeutic targets, including targetable GA in the mTOR, CDK and growth factor signaling pathways, highlighting the clinical value of genomic profiling in ENB. IMPLICATIONS FOR PRACTICE Comprehensive genomic profiling of 41 relapsed or refractory ENBs reveals recurrent alterations or classes of mutation, including amplification of tyrosine kinases encoded on chromosome 5q and mutations affecting genes in the mTOR/PI3K pathway. Approximately half of the ENBs (21, 51%) featured at least one clinically relevant genomic alteration (CRGA), with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), and alterations in PIK3CA, NF1, CDKN2A, or CDKN2C were identified in 7% of samples. Responses to treatment with the kinase inhibitors sunitinib, everolimus, and pazopanib are presented in conjunction with tumor genomics.
Yazmin Odia - One of the best experts on this subject based on the ideXlab platform.
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comprehensive genomic profiling of esthesioneuroblastoma reveals additional treatment options
Oncologist, 2017Co-Authors: Kyle Fedorchak, Madappa N Kundranda, Yazmin Odia, Chaitali Singh Nangia, James D Battiste, Gerardo Colonotero, Steven Francis Powell, Jeffery S Russell, Julia Andrea ElvinAbstract:BACKGROUND: Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant neoplasm of the olfactory mucosa. Despite surgical resection combined with radiotherapy and adjuvant chemotherapy, ENB often relapses with rapid progression. Current multimodality, nontargeted therapy for relapsed ENB is of limited clinical benefit. MATERIALS AND METHODS: We queried whether comprehensive genomic profiling (CGP) of relapsed or refractory ENB can uncover genomic alterations (GA) that could identify potential targeted therapies for these patients. CGP was performed on formalin-fixed, paraffin-embedded sections from 41 consecutive clinical cases of ENBs using a hybrid-capture, adaptor ligation based next-generation sequencing assay to a mean coverage depth of 593X. The results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes (amplifications and homozygous deletions). RESULTS: Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in clinical trials. A total of 28 ENBs harbored GA, with a mean of 1.5 GA per sample. Approximately half of the ENBs (21, 51%) featured at least one CRGA, with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), with GA in PIK3CA, NF1, CDKN2A, and CDKN2C occurring in 7% of samples. CONCLUSION: We report comprehensive genomic profiles for 41 ENB tumors. CGP revealed potential new therapeutic targets, including targetable GA in the mTOR, CDK and growth factor signaling pathways, highlighting the clinical value of genomic profiling in ENB. IMPLICATIONS FOR PRACTICE: Comprehensive genomic profiling of 41 relapsed or refractory ENBs reveals recurrent alterations or classes of mutation, including amplification of tyrosine kinases encoded on chromosome 5q and mutations affecting genes in the mTOR/PI3K pathway. Approximately half of the ENBs (21, 51%) featured at least one clinically relevant genomic alteration (CRGA), with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), and alterations in PIK3CA, NF1, CDKN2A, or CDKN2C were identified in 7% of samples. Responses to treatment with the kinase inhibitors sunitinib, everolimus, and pazopanib are presented in conjunction with tumor genomics.
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Comprehensive Genomic Profiling of Esthesioneuroblastoma Reveals Additional Treatment Options
The oncologist, 2017Co-Authors: Sungeun Kim, Kyle Fedorchak, Madappa N Kundranda, Yazmin Odia, Chaitali Singh Nangia, James D Battiste, Steven Francis Powell, Jeffery S Russell, Gerardo Colon-otero, Julia Andrea ElvinAbstract:BACKGROUND Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare malignant neoplasm of the olfactory mucosa. Despite surgical resection combined with radiotherapy and adjuvant chemotherapy, ENB often relapses with rapid progression. Current multimodality, nontargeted therapy for relapsed ENB is of limited clinical benefit. MATERIALS AND METHODS We queried whether comprehensive genomic profiling (CGP) of relapsed or refractory ENB can uncover genomic alterations (GA) that could identify potential targeted therapies for these patients. CGP was performed on formalin-fixed, paraffin-embedded sections from 41 consecutive clinical cases of ENBs using a hybrid-capture, adaptor ligation based next-generation sequencing assay to a mean coverage depth of 593X. The results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes (amplifications and homozygous deletions). RESULTS Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in clinical trials. A total of 28 ENBs harbored GA, with a mean of 1.5 GA per sample. Approximately half of the ENBs (21, 51%) featured at least one CRGA, with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), with GA in PIK3CA, NF1, CDKN2A, and CDKN2C occurring in 7% of samples. CONCLUSION We report comprehensive genomic profiles for 41 ENB tumors. CGP revealed potential new therapeutic targets, including targetable GA in the mTOR, CDK and growth factor signaling pathways, highlighting the clinical value of genomic profiling in ENB. IMPLICATIONS FOR PRACTICE Comprehensive genomic profiling of 41 relapsed or refractory ENBs reveals recurrent alterations or classes of mutation, including amplification of tyrosine kinases encoded on chromosome 5q and mutations affecting genes in the mTOR/PI3K pathway. Approximately half of the ENBs (21, 51%) featured at least one clinically relevant genomic alteration (CRGA), with an average of 1 CRGA per sample. The most commonly altered gene was TP53 (17%), and alterations in PIK3CA, NF1, CDKN2A, or CDKN2C were identified in 7% of samples. Responses to treatment with the kinase inhibitors sunitinib, everolimus, and pazopanib are presented in conjunction with tumor genomics.