Coamplification of Myc/Pvt1 and homozygous deletion of Nlrp1 locus are frequent genetics changes in mouse osteosarcoma.
Osteosarcomas (OSs) are characterized by high levels of genomic instability (GI). To gain insights into the GI and its contribution toward understanding the genetic basis of OS, we characterized 19 primary and 13 metastatic mouse tumors in a genetically engineered novel mouse model of OS by a combination of genomic techniques. Through the bone-specific deletion of the wild-type Trp53 locus or activation of a metastatic-promoting missense R172Hp53 allele, C57BL/6 mice developed either localized or metastatic OS. Subsequent tumors were isolated and primary cultures created from primary bone and/or distal metastatic lesions, for example, lung and liver. These tumors exhibited high levels of GI with complex chromosomal rearrangements, amplifications, and deletions comparable to human OS. The combined genomic approaches identified frequent amplification of chromosome 15D1 and loss of 11B4 by CGH and/or SKY. Both 15D1 and 11B4 have homology with frequently altered chromosomal bands 8q24 and 17p13 in human OS, respectively. Subsequent array CGH, FISH, and qRT-PCR analysis identified coamplification and overexpression of Myc/Pvt1 transcripts from the 15D1 amplicon and loss and decreased expression of the Nlrp1b from 11B4. The Nlrp1 gene is the key mediator of apoptosis and interacts strongly with caspase 2.
Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030.
Pulivarthi H
PH
Rao
Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030.
Shuying
S
Zhao
Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030.
Yi-Jue
YJ
Zhao
Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030.
Alexander
A
Yu
Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030.
Nino
N
Rainusso
Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030.
Matteo
M
Trucco
Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030.
Wendy
W
Allen-Rhoades
Integrative Molecular and Biological Sciences Program, Baylor College of Medicine, Houston, TX, 77030.
Laura
L
Satterfield
Integrative Molecular and Biological Sciences Program, Baylor College of Medicine, Houston, TX, 77030.
Daniel
D
Fuja
Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030.
Vishnupriya J
VJ
Borra
Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030.
Tsz-Kwong
TK
Man
Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030.|Integrative Molecular and Biological Sciences Program, Baylor College of Medicine, Houston, TX, 77030.|Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX, 77030.|Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX, 77030.
Lawrence A
LA
Donehower
Texas Children's Cancer and Hematology Centers, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030.|Integrative Molecular and Biological Sciences Program, Baylor College of Medicine, Houston, TX, 77030.|Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX, 77030.
Jason T
JT
Yustein
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D053143:Caspase 2 / Q000378:metabolism; D002872:Chromosome Deletion; D005784:Gene Amplification; D056426:Genetic Loci; D042822:Genomic Instability; D006720:Homozygote; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology; D061251:Primary Cell Culture; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics*; D012513:Sarcoma, Experimental / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation
D051017:Apoptosis Regulatory Proteins; C489428:Myc protein, mouse; C509168:Nalp1b protein, mouse; C000609195:PVT1 long-non-coding RNA, mouse; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; D016159:Tumor Suppressor Protein p53; C090208:Casp2 protein, mouse; D053143:Caspase 2