title: Whole genome analyses of a well-differentiated liposarcoma reveals novel SYT1 and DDR2 rearrangements.
abstract: Liposarcoma is the most common soft tissue sarcoma, but little is known about the genomic basis of this disease. Given the low cell content of this tumor type, we utilized flow cytometry to isolate the diploid normal and aneuploid tumor populations from a well-differentiated liposarcoma prior to array comparative genomic hybridization and whole genome sequencing. This work revealed massive highly focal amplifications throughout the aneuploid tumor genome including MDM2, a gene that has previously been found to be amplified in well-differentiated liposarcoma. Structural analysis revealed massive rearrangement of chromosome 12 and 11 gene fusions, some of which may be part of double minute chromosomes commonly present in well-differentiated liposarcoma. We identified a hotspot of genomic instability localized to a region of chromosome 12 that includes a highly conserved, putative L1 retrotransposon element, LOC100507498 which resides within a gene cluster (NAV3, SYT1, PAWR) where 6 of the 11 fusion events occurred. Interestingly, a potential gene fusion was also identified in amplified DDR2, which is a potential therapeutic target of kinase inhibitors such as dastinib, that are not routinely used in the treatment of patients with liposarcoma. Furthermore, 7 somatic, damaging single nucleotide variants have also been identified, including D125N in the PTPRQ protein. In conclusion, this work is the first to report the entire genome of a well-differentiated liposarcoma with novel chromosomal rearrangements associated with amplification of therapeutically targetable genes such as MDM2 and DDR2.
authors: Comprehensive Cancer Center, Mayo Clinic, Scottsdale, Arizona, United States of America.
authors: Jan B
authors: JB
authors: Egan
authors: Clinical Translational Research Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors: Michael T
authors: MT
authors: Barrett
authors: Department of Biomedical Statistics and Informatics, Mayo Clinic, Scottsdale, Arizona, United States of America ; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors: Mia D
authors: MD
authors: Champion
authors: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America.
authors: Sumit
authors: S
authors: Middha
authors: Clinical Translational Research Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors: Elizabeth
authors: E
authors: Lenkiewicz
authors: Clinical Translational Research Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors: Lisa
authors: L
authors: Evers
authors: Research, Mayo Clinic, Scottsdale, Arizona, United States of America.
authors: Princy
authors: P
authors: Francis
authors: Research, Mayo Clinic, Scottsdale, Arizona, United States of America.
authors: Jessica
authors: J
authors: Schmidt
authors: Research, Mayo Clinic, Scottsdale, Arizona, United States of America.
authors: Chang-Xin
authors: CX
authors: Shi
authors: Research, Mayo Clinic, Scottsdale, Arizona, United States of America.
authors: Scott
authors: S
authors: Van Wier
authors: Research, Mayo Clinic, Scottsdale, Arizona, United States of America.
authors: Sandra
authors: S
authors: Badar
authors: Research, Mayo Clinic, Scottsdale, Arizona, United States of America.
authors: Gregory
authors: G
authors: Ahmann
authors: Hematology, Mayo Clinic, Scottsdale, Arizona, United States of America.
authors: K Martin
authors: KM
authors: Kortuem
authors: Mayo Graduate School, Mayo Clinic, Rochester, Minnesota, United States of America.
authors: Nicole J
authors: NJ
authors: Boczek
authors: Comprehensive Cancer Center, Mayo Clinic, Scottsdale, Arizona, United States of America ; Division of Hematology/Oncology Mayo Clinic, Scottsdale, Arizona, United States of America.
authors: Rafael
authors: R
authors: Fonseca
authors: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors: David W
authors: DW
authors: Craig
authors: Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors: John D
authors: JD
authors: Carpten
authors: Comprehensive Cancer Center, Mayo Clinic, Scottsdale, Arizona, United States of America ; Division of Hematology/Oncology Mayo Clinic, Scottsdale, Arizona, United States of America.
authors: Mitesh J
authors: MJ
authors: Borad
authors: Comprehensive Cancer Center, Mayo Clinic, Scottsdale, Arizona, United States of America ; Division of Hematology/Oncology Mayo Clinic, Scottsdale, Arizona, United States of America.
authors: A Keith
authors: AK
authors: Stewart
mesh_terms: D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D000070818:Discoidin Domain Receptors; D005260:Female; D005784:Gene Amplification; D015321:Gene Rearrangement; D052138:Genes, Neoplasm; D055106:Genome-Wide Association Study; D042822:Genomic Instability; D006801:Humans; D008080:Liposarcoma / Q000235:genetics*; D008297:Male; D005810:Multigene Family; D009363:Neoplasm Proteins / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases; D011975:Receptors, Mitogen; D050863:Synaptotagmin I / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D011975:Receptors, Mitogen; C494310:SYT1 protein, human; D050863:Synaptotagmin I; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases