title: Allotype imbalance or microsatellite mutation in low-grade soft tissue sarcomas of the extremities in adults.
abstract: The ability to repair DNA double-strand breaks is essential to maintain chromosomal stability. Virtually all soft tissue sarcomas contain chromosomal instabilities, including clonal aberrations and cytogenetic aberrations. However, the relevance of DNA-dependent protein kinase (DNA-PK) in the pathogenesis of soft tissue sarcoma has not been clarified. The main aim of this work is to compare the prognostic impact of genotypic imbalance in low-grade soft tissue sarcomas of the extremities, and to correlate this with the translational level of DNA-PK. This study investigated 28 adult low-grade malignant spindle cell tumours of the extremities, predominantly fibrosarcomas, for loss of heterozygosity (LOH) and microsatellite mutation on flanking regions of each DNA-PK subunit, with identical immunophenotypes. Twelve different polymorphic markers flanking the specific loci of three subunits comprise the genetic map of DNA-PK, at 22q13, 2q35, and 8q11. Translational activity was also analysed by western blot and conventional immunohistochemistry. The overall sarcoma 5-year survival rate was 61.7%. LOH was identified in the specific coding region of DNA-PK in 39.29% for the DNA-PK catalytic subunit (cs), 17.86% for Ku70, and only 7.14% for Ku80. A positive LOH for DNA-PKcs was shown to be a significant factor for poor survival (log rank test p = 0.0160). Immunoreactivity and immunoblot results correlated with the loss of DNA-PKcs allotype in soft tissue sarcoma (Fisher's exact test p = 0.0037). Ku70 and DNA-PKcs were almost identical in terms of immunoreactivity. In conclusion, whereas microsatellite mutation seems an uncommon event during the evolution of low-grade fibrosarcoma of the extremities in adults, the loss of DNA-PKcs defines a biologically more aggressive subset.
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seodaemoon-Ku, Shinchon-Dong, Seoul, Korea. cho1988@yumc.yonsei.ac.kr
authors.forename: Nam Hoon
authors.initials: NH
authors.lastname: Cho
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: G C
authors.initials: GC
authors.lastname: Li
authors.forename: See Hyun
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D004273:DNA, Neoplasm / Q000235:genetics*; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D005260:Female; D005354:Fibrosarcoma / Q000235:genetics; D005500:Follow-Up Studies; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins; D011379:Prognosis; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012509:Sarcoma / Q000235:genetics*; D012983:Soft Tissue Neoplasms / Q000235:genetics*; D015996:Survival Rate
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases