title: Genomic aberrations frequently alter chromatin regulatory genes in chordoma.
abstract: Chordoma is a rare primary bone neoplasm that is resistant to standard chemotherapies. Despite aggressive surgical management, local recurrence and metastasis is not uncommon. To identify the specific genetic aberrations that play key roles in chordoma pathogenesis, we utilized a genome-wide high-resolution SNP-array and next generation sequencing (NGS)-based molecular profiling platform to study 24 patient samples with typical histopathologic features of chordoma. Matching normal tissues were available for 16 samples. SNP-array analysis revealed nonrandom copy number losses across the genome, frequently involving 3, 9p, 1p, 14, 10, and 13. In contrast, copy number gain is uncommon in chordomas. Two minimum deleted regions were observed on 3p within a ∼8 Mb segment at 3p21.1-p21.31, which overlaps SETD2, BAP1 and PBRM1. The minimum deleted region on 9p was mapped to CDKN2A locus at 9p21.3, and homozygous deletion of CDKN2A was detected in 5/22 chordomas (∼23%). NGS-based molecular profiling demonstrated an extremely low level of mutation rate in chordomas, with an average of 0.5 mutations per sample for the 16 cases with matched normal. When the mutated genes were grouped based on molecular functions, many of the mutation events (∼40%) were found in chromatin regulatory genes. The combined copy number and mutation profiling revealed that SETD2 is the single gene affected most frequently in chordomas, either by deletion or by mutations. Our study demonstrated that chordoma belongs to the C-class (copy number changes) tumors whose oncogenic signature is non-random multiple copy number losses across the genome and genomic aberrations frequently alter chromatin regulatory genes. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Zehir
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Khedoudja
authors.initials: K
authors.lastname: Nafa
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Nengyi
authors.initials: N
authors.lastname: Zhou
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.|Department of Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Jacklyn
authors.initials: J
authors.lastname: Casanova
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Justyna
authors.initials: J
authors.lastname: Sadowska
authors.affiliation: Department of Laboratory of Chromatin Biology and Epigenetics, the Rockefeller University, New York, NY.
authors.forename: Chao
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Laboratory of Chromatin Biology and Epigenetics, the Rockefeller University, New York, NY.
authors.forename: C David
authors.initials: CD
authors.lastname: Allis
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Mrinal
authors.initials: M
authors.lastname: Gounder
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Chandhanarat
authors.initials: C
authors.lastname: Chandhanayingyong
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.|Department of Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Boland
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Meera
authors.initials: M
authors.lastname: Hameed
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002817:Chordoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D002869:Chromosome Aberrations; D004268:DNA-Binding Proteins; D005260:Female; D005500:Follow-Up Studies; D059014:High-Throughput Nucleotide Sequencing; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics
chemical_list: C400134:BAP1 protein, human; D014408:Biomarkers, Tumor; D002843:Chromatin; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human; D043222:Ubiquitin Thiolesterase