Clear cell sarcoma of the kidney demonstrates an embryonic signature indicative of a primitive nephrogenic origin.
Clear cell sarcoma of the kidney (CCSK) is a tumor affecting children with a median age of 3 years at diagnosis. The cell of origin of CCSK is unknown and data on the molecular changes giving rise to CCSK is scarce. This has hindered the identification of positive diagnostic markers and development of molecularly targeted treatment protocols for CCSK. We have characterized a panel of CCSK to gain information regarding its molecular profile and possible origin. High-resolution genomic analysis with single nucleotide polymorphism array of 37 tumors did not reveal any clues to the mechanisms behind tumor development as remarkably few genetic imbalances were found. Gene expression analysis revealed a highly characteristic gene signature, enriched for pathways involved in embryonic development, including kidney formation. The presence of markers for two different developmental lineages in the embryonic kidney was therefore investigated in the tumor cells. FOXD1 which identifies cells giving rise to stromal elements, and CITED1, a marker for cells primed for nephrogenic epithelial differentiation, were both highly expressed in CCSK. In addition, the early embryonic marker OSR1 was expressed at higher levels in CCSK than in Wilms tumor, normal fetal kidney or adult kidney. As this marker discriminates the intermediate mesoderm from other mesodermal structures, our study could suggest that CCSK arises from a mesodermal cell type that retains the capacity to initiate differentiation towards both nephrons and stroma, but remains locked in a primitive state.
Department of Clinical Genetics, Lund University, University and Regional Laboratories, Lund, Sweden.
Jenny
J
Karlsson
Linda
L
Holmquist Mengelbier
Cristina D
CD
Ciornei
Arlene
A
Naranjo
Maureen J
MJ
O'Sullivan
David
D
Gisselsson
D051017:Apoptosis Regulatory Proteins; D002648:Child; D002675:Child, Preschool; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D007668:Kidney / Q000196:embryology / Q000473:pathology*; D007680:Kidney Neoplasms / Q000196:embryology / Q000235:genetics*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics; D016612:Paraffin Embedding; D020641:Polymorphism, Single Nucleotide; D018227:Sarcoma, Clear Cell / Q000196:embryology / Q000235:genetics*; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; C512688:CITED1 protein, human; C500800:FOXD1 protein, human; D051858:Forkhead Transcription Factors; D009687:Nuclear Proteins; C498490:OSR1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors