EGAGenomicsIllumina HiSeq 2500Otherhttps://ega-archive.org/studies/EGAS00001001690EGAEGA study EGAS00001001690Whole-exome sequencing of retinoblastoma tumor-blood pairsEGArestrictedRetinoblastoma is a rare childhood cancer initiated by RB1 mutation or MYCN amplification, while additional alterations may be required for tumor development. However, the view on single nucleotide variants is very limited. To better understand oncogenesis, we determined the genomic landscape of retinoblastoma. We performed exome sequencing of 71 retinoblastomas and matched blood DNA. Next, we determined the presence of single nucleotide variants, copy number alterations and viruses. Aside from RB1, recurrent gene mutations were very rare. Only a limited fraction of tumors showed BCOR (7/71, 10%) or CREBBP alterations (3/71, 4%). No evidence was found for the presence of viruses. Instead, specific somatic copy number alterations were more common, particularly in patients diagnosed at later age. Recurrent alterations of chromosomal arms often involved less than one copy, also in highly pure tumor samples, suggesting within-tumor heterogeneity. Our results show that retinoblastoma is among the least mutated cancers and signify the extreme sensitivity of the childhood retina for RB1 loss. We hypothesize that retinoblastomas arising later in retinal development benefit more from subclonal secondary alterations and therefore, these alterations are more selected for in these tumors. Targeted therapy based on these subclonal events might be insufficient for complete tumor control.Somatic genomic alterations in retinoblastoma beyond RB1 are rare and limited to copy number changes.Kooi Irsan E IE, Mol Berber M BM, Massink Maarten P G MP, Ameziane Najim N, Meijers-Heijboer Hanne H, Dommering Charlotte J CJ, van Mil Saskia E SE, de Vries Yne Y, van der Hout Annemarie H AH, Kaspers Gertjan J L GJ, Moll Annette C AC, Te Riele Hein H, Cloos Jacqueline J, Dorsman Josephine C JCRB1, Sporadic, Complete Exome Sequencings, DNS, (Deoxyribonucleotide)n, Complete Exome, Retinal Neuroblastoma, DNAn+1, Sporadic Retinoblastomas, Exome, "Retinoblastoma NOS (morphologic abnormality)" EXACT [SNOMEDCT_2005_07_31:189935007], retinoblastoma, Double-Stranded, Cell, (Deoxyribonucleotide)n+m, Exome Sequencing, eye cancer, Deoxyribonucleic Acid, "retinoblastoma" EXACT [CSP2005:2018-3452], Eye Cancer, "RB" EXACT [NCI2004_11_17:C7541], "neuroblastoma of Retina" EXACT [NCI2004_11_17:C6956], Retinal Glioblastomas, "Retinoblastoma (disorder)" EXACT [SNOMEDCT_2005_07_31:370967009], Whole Transcriptome, Transcriptome Sequencing, Lymphoid Cell, Gliomas, ds-DNA, Retinal Glioma, desoxyribose nucleic acid, Retinoblastomas, Retinoblastoma, Retinal, Lymphoid Cells, Eye Cancers, Familial Retinoblastomas, WES, Complete Transcriptome, Familial Retinoblastoma, Retinoblastoma Eye Cancer, thymus nucleic acid, Complete, Retinal Gliomas, Retinoblastoma Eye, Complete Transcriptome Sequencing, Exome Sequencings, Sporadic Retinoblastoma, Glioblastoma, "RB - Retinoblastoma" EXACT [SNOMEDCT_2005_07_31:134191003], Neuroblastomas, Retinoblastoma Eye Cancers, Neuroblastoma, Retinal Neuroblastomas, Deoxyribonucleic acids., Complete Exome Sequencing, Whole Transcriptome Sequencing, Rb, Tissue, "Retinoblastoma (morphologic abnormality)" EXACT [SNOMEDCT_2005_07_31:19906005], Glioblastomas, Double Stranded, Familial, Deoxyribonucleic acid, Cancers, Sequencing, Hereditary Retinoblastoma, Whole Exome, Hereditary Retinoblastomas, Hereditary, Retinal Glioblastoma, Whole, Cells, ds DNA, Whole Exome Sequencing, Desoxyribonukleinsaeure, Glioma, Lymphoid, Double-Stranded DNA, (Deoxyribonucleotide)m, DNA, deoxyribonucleic acids, DNAn, "Retinoblastomas (morphologic abnormality)" EXACT [SNOMEDCT_2005_07_31:189934006], Transcriptome Sequencings, Lymphocyte, CancerRB1, Viridae, 8430401K06Rik, Materials, single-organism developmental process, Sporadic Retinoblastomas, postnatal development, mycna, mycnb, growth and development, RBF, Tumor, Mutations, RBR, "retinoblastoma" EXACT [CSP2005:2018-3452], RB, rb, Virus, RETINOBLASTOMA PROTEIN, Whole Transcriptome, Transcriptome Sequencing, mKIAA1575, rbf, prevention and control, D930024N20Rik, Arm, class I PurE, treatment, Inner layer of eyeball, thymus nucleic acid, reference sample, pp110, Complete Exome Sequencing, Whole Transcriptome Sequencing, Rb, RTS, Childhood Cancer, tunica interna of eyeball, prevention., Familial, Nmyc1, N-myc, Upper, allergic reaction, preventive measures, malignant neoplasm, Vira, XN-myc, Retinal Glioblastoma, disease management, Therapies, CG7413, Malignancies, Double-Stranded DNA, deoxyribonucleic acids, DNAn, Nucleotide, somatic mutation, Tumors, Therapy, Upper Arms, retinoblastoma-related 1, MAA2, preventive therapy, RGD1562735, rbf1, Exome, "Retinoblastoma NOS (morphologic abnormality)" EXACT [SNOMEDCT_2005_07_31:189935007], KAT3A, retinoblastoma, Double-Stranded, inner layer of eyeball, RETINOBLASTOMA 1, ANOP2, hereditary retinoblastoma, results, (Deoxyribonucleotide)n+m, rhabdomyosarcoma alveolar, RSTS, Benign, RENBP, rhabdomyosarcoma 2, Retinal Glioblastomas, ATRBR1, Genetic Materials, Amplification Refractory Mutation System, Gliomas, rsts, desoxyribose nucleic acid, Genetic Material, Retinal, nucleotides, pRb, xN-myc1, Complete Transcriptome, Familial Retinoblastoma, Retinoblastoma Eye Cancer, Retinal Gliomas, Glioblastoma, DmelCG7413, Neuroblastomas, "Retinoblastoma (morphologic abnormality)" EXACT [SNOMEDCT_2005_07_31:19906005], Benign Neoplasms, common, INSDC_feature:gene, Treatments, PurE, Hereditary Retinoblastoma, Malignant Neoplasms, AGE, p105-Rb, metastatic, familial retinoblastoma, Patient, Brachiums, Specificity and Sensitivity, Material, Hereditary, ds DNA, Whole Exome Sequencing, Animal Viruses, Cistron, Glioma, DNA, EG:34F3.3, other neoplasm, Transcriptome Sequencings, Rbf1, RBF1, kat3a, N5-carboxyaminoimidazole ribonucleotide mutase activity, Sporadic, DNS, (Deoxyribonucleotide)n, Retinal Neuroblastoma, FBF, Complete Exome, Nmyc, Neoplasms, ODED, Benign Neoplasm, number, Gene, Malignant, autosomal dominant, dRBF, presence, rhabdomyosarcoma, Deoxyribonucleic acids, BcorR, mycn, eye cancer, 5830466J11Rik, Deoxyribonucleic Acid, sensitive, NMYC, Eye Cancer, "neuroblastoma of Retina" EXACT [NCI2004_11_17:C6956], OSRC, Animal, Retinal Glioma, nmyc, Upper Arm, sensitivity, Netzhaut, Eye Cancers, WES, Animal Virus, Retinoblastoma Eye, Complete, Sporadic Retinoblastoma, Exome Sequencings, "RB - Retinoblastoma" EXACT [SNOMEDCT_2005_07_31:134191003], Genetic, Viruses, Malignancy, Retinoblastoma Eye Cancers, retinas, retina of camera-type eye, Retinal Neuroblastomas, MCOPS2, Double Stranded, Deoxyribonucleic acid, Brachium, Nmuc1, Sequencing, Neoplasias, MODED, Whole Exome, Hereditary Retinoblastomas, Clients, retinal development, Whole, heterogeneity, Ora Serrata, 5-carboxyamino-1-(5-phospho-D-ribosyl)imidazole carboxymutase activity, Sensitivity, (Deoxyribonucleotide)m, bHLHe37, "Retinoblastomas (morphologic abnormality)" EXACT [SNOMEDCT_2005_07_31:189934006], alveolar, XNmyc, Controlled, Cancer, Controlling, Malignant Neoplasm, Complete Exome Sequencings, whole blood, ARMS, RnBP, DNAn+1, GlcNAc 2-epimerase, Cistrons, Client, RMS2, development, viruses, Exome Sequencing, count in organism, N-acetyl-D-glucosamine 2-epimerase, N5-CAIR mutase activity, Arms, c-nmyc, "RB" EXACT [NCI2004_11_17:C7541], Neoplasm, "Retinoblastoma (disorder)" EXACT [SNOMEDCT_2005_07_31:370967009], PPP1R130, rare (European definition), ds-DNA, Zoophaginae, Retinoblastomas, Retinoblastoma, Tunica interna of eyeball, Familial Retinoblastomas, Complete Transcriptome Sequencing, Neuroblastoma, prophylaxis, CBP, postnatal growth, Glioblastomas, Rb-1, Specificity, retina, Cancers, BCoR, Nmyc-1, Rb1, Therapeutic, control, cardinality, RETINOBLASTOMA-RELATED PROTEIN 1, RETINOBLASTOMA-RELATED, Desoxyribonukleinsaeure, cbp, renin-binding protein, Treatment, RbF, trilateral, growth, Neoplasia, crebbpRB1, Sporadic, retinoblastoma-related 1, Retinal Neuroblastoma, FBF, rbf1, Sporadic Retinoblastomas, number, "Retinoblastoma NOS (morphologic abnormality)" EXACT [SNOMEDCT_2005_07_31:189935007], retinoblastoma, RBF, autosomal dominant, RETINOBLASTOMA 1, dRBF, presence, hereditary retinoblastoma, RBR, count in organism, eye cancer, "retinoblastoma" EXACT [CSP2005:2018-3452], Eye Cancer, "RB" EXACT [NCI2004_11_17:C7541], "neuroblastoma of Retina" EXACT [NCI2004_11_17:C6956], Retinal Glioblastomas, OSRC, RB, rb, "Retinoblastoma (disorder)" EXACT [SNOMEDCT_2005_07_31:370967009], PPP1R130, ATRBR1, RETINOBLASTOMA PROTEIN, Gliomas, rare (European definition), rbf, Retinal Glioma, Retinoblastomas, Retinoblastoma, Retinal, Eye Cancers, pRb, Familial Retinoblastomas, Familial Retinoblastoma, Retinoblastoma Eye Cancer, Retinal Gliomas, Retinoblastoma Eye, Sporadic Retinoblastoma, Glioblastoma, DmelCG7413, "RB - Retinoblastoma" EXACT [SNOMEDCT_2005_07_31:134191003], Neuroblastomas, Retinoblastoma Eye Cancers, Neuroblastoma, Retinal Neuroblastomas, pp110, Rb, "Retinoblastoma (morphologic abnormality)" EXACT [SNOMEDCT_2005_07_31:19906005], Glioblastomas, Rb-1, Familial, Cancers, cardinality., Hereditary Retinoblastoma, Rb1, p105-Rb, Hereditary Retinoblastomas, familial retinoblastoma, Hereditary, Retinal Glioblastoma, RETINOBLASTOMA-RELATED PROTEIN 1, RETINOBLASTOMA-RELATED, Glioma, CG7413, RbF, EG:34F3.3, "Retinoblastomas (morphologic abnormality)" EXACT [SNOMEDCT_2005_07_31:189934006], trilateral, somatic mutation, Rbf1, RBF1, CancerRB1, Viridae, 8430401K06Rik, Materials, single-organism developmental process, Sporadic Retinoblastomas, postnatal development, mycna, mycnb, growth and development, RBF, Tumor, Mutations, RBR, "retinoblastoma" EXACT [CSP2005:2018-3452], RB, rb, Virus, RETINOBLASTOMA PROTEIN, Whole Transcriptome, Transcriptome Sequencing, mKIAA1575, rbf, prevention and control, D930024N20Rik, Arm, class I PurE, treatment, Inner layer of eyeball, thymus nucleic acid, reference sample, pp110, Complete Exome Sequencing, Whole Transcriptome Sequencing, Rb, RTS, Childhood Cancer, tunica interna of eyeball, prevention., Familial, Nmyc1, N-myc, Upper, allergic reaction, preventive measures, malignant neoplasm, Vira, XN-myc, Retinal Glioblastoma, disease management, Therapies, CG7413, Malignancies, Double-Stranded DNA, deoxyribonucleic acids, DNAn, Nucleotide, somatic mutation, Tumors, Therapy, Upper Arms, retinoblastoma-related 1, MAA2, preventive therapy, RGD1562735, rbf1, Exome, "Retinoblastoma NOS (morphologic abnormality)" EXACT [SNOMEDCT_2005_07_31:189935007], KAT3A, retinoblastoma, Double-Stranded, inner layer of eyeball, RETINOBLASTOMA 1, ANOP2, hereditary retinoblastoma, results, (Deoxyribonucleotide)n+m, rhabdomyosarcoma alveolar, RSTS, Benign, RENBP, rhabdomyosarcoma 2, Retinal Glioblastomas, ATRBR1, Genetic Materials, Amplification Refractory Mutation System, Gliomas, rsts, desoxyribose nucleic acid, Genetic Material, Retinal, nucleotides, pRb, xN-myc1, Complete Transcriptome, Familial Retinoblastoma, Retinoblastoma Eye Cancer, Retinal Gliomas, Glioblastoma, DmelCG7413, Neuroblastomas, "Retinoblastoma (morphologic abnormality)" EXACT [SNOMEDCT_2005_07_31:19906005], Benign Neoplasms, common, INSDC_feature:gene, Treatments, PurE, Hereditary Retinoblastoma, Malignant Neoplasms, AGE, p105-Rb, metastatic, familial retinoblastoma, Patient, Brachiums, Specificity and Sensitivity, Material, Hereditary, ds DNA, Whole Exome Sequencing, Animal Viruses, Cistron, Glioma, DNA, EG:34F3.3, other neoplasm, Transcriptome Sequencings, Rbf1, RBF1, kat3a, N5-carboxyaminoimidazole ribonucleotide mutase activity, Sporadic, DNS, (Deoxyribonucleotide)n, Retinal Neuroblastoma, FBF, Complete Exome, Nmyc, Neoplasms, ODED, Benign Neoplasm, number, Gene, Malignant, autosomal dominant, dRBF, presence, rhabdomyosarcoma, Deoxyribonucleic acids, BcorR, mycn, eye cancer, 5830466J11Rik, Deoxyribonucleic Acid, sensitive, NMYC, Eye Cancer, "neuroblastoma of Retina" EXACT [NCI2004_11_17:C6956], OSRC, Animal, Retinal Glioma, nmyc, Upper Arm, sensitivity, Netzhaut, Eye Cancers, WES, Animal Virus, Retinoblastoma Eye, Complete, Sporadic Retinoblastoma, Exome Sequencings, "RB - Retinoblastoma" EXACT [SNOMEDCT_2005_07_31:134191003], Genetic, Viruses, Malignancy, Retinoblastoma Eye Cancers, retinas, retina of camera-type eye, Retinal Neuroblastomas, MCOPS2, Double Stranded, Deoxyribonucleic acid, Brachium, Nmuc1, Sequencing, Neoplasias, MODED, Whole Exome, Hereditary Retinoblastomas, Clients, retinal development, Whole, heterogeneity, Ora Serrata, 5-carboxyamino-1-(5-phospho-D-ribosyl)imidazole carboxymutase activity, Sensitivity, (Deoxyribonucleotide)m, bHLHe37, "Retinoblastomas (morphologic abnormality)" EXACT [SNOMEDCT_2005_07_31:189934006], alveolar, XNmyc, Controlled, Cancer, Controlling, Malignant Neoplasm, Complete Exome Sequencings, whole blood, ARMS, RnBP, DNAn+1, GlcNAc 2-epimerase, Cistrons, Client, RMS2, development, viruses, Exome Sequencing, count in organism, N-acetyl-D-glucosamine 2-epimerase, N5-CAIR mutase activity, Arms, c-nmyc, "RB" EXACT [NCI2004_11_17:C7541], Neoplasm, "Retinoblastoma (disorder)" EXACT [SNOMEDCT_2005_07_31:370967009], PPP1R130, rare (European definition), ds-DNA, Zoophaginae, Retinoblastomas, Retinoblastoma, Tunica interna of eyeball, Familial Retinoblastomas, Complete Transcriptome Sequencing, Neuroblastoma, prophylaxis, CBP, postnatal growth, Glioblastomas, Rb-1, Specificity, retina, Cancers, BCoR, Nmyc-1, Rb1, Therapeutic, control, cardinality, RETINOBLASTOMA-RELATED PROTEIN 1, RETINOBLASTOMA-RELATED, Desoxyribonukleinsaeure, cbp, renin-binding protein, Treatment, RbF, trilateral, growth, Neoplasia, crebbpfalseWhole exome sequencing on primary retinoblastoma tissues and matching lymphocyte DNA.Retinoblastoma is a rare childhood cancer initiated by RB1 mutation or MYCN amplification, while additional alterations may be required for tumor development. However, the view on single nucleotide variants is very limited. To better understand oncogenesis, we determined the genomic landscape of retinoblastoma. We performed exome sequencing of 71 retinoblastomas and matched blood DNA. Next, we determined the presence of single nucleotide variants, copy number alterations and viruses. Aside from RB1, recurrent gene mutations were very rare. Only a limited fraction of tumors showed BCOR (7/71, 10%) or CREBBP alterations (3/71, 4%). No evidence was found for the presence of viruses. Instead, specific somatic copy number alterations were more common, particularly in patients diagnosed at later age. Recurrent alterations of chromosomal arms often involved less than one copy, also in highly pure tumor samples, suggesting within-tumor heterogeneity. Our results show that retinoblastoma is among the least mutated cancers and signify the extreme sensitivity of the childhood retina for RB1 loss. We hypothesize that retinoblastomas arising later in retinal development benefit more from subclonal secondary alterations and therefore, these alterations are more selected for in these tumors. Targeted therapy based on these subclonal events might be insufficient for complete tumor control.2017-07-26 15:39:26EGAS00001001690960627126562EGAD00001001909EGAC00001000431