Alterations of INK4A and INK4B genes in adult soft tissue sarcomas: Effecton survival

Background: The INK4A and INK4B genes map to chromosome 9p21, with the INK4 A gene encoding two protein products, p16 and pl9(ARF). Alterations of the INK4A and INK4B genes occur frequently in certain primary malignant neoplas ms, This study was undertaken to evaluate the frequency of INK4A and INK4B gene alterations in a cohort of adult soft tissue sarcomas, Methods: The st atus of the INK4A and INK4B genes was determined in 46 soft tissue sarcomas by use of the following methods: Southern blotting, polymerase chain react ion (PCR), single-strand conformation polymorphism analysis, comparative mu ltiplex PCR, and a methylation assay focusing on the p16 promoter. Associat ions between alterations of the INK4A and INK4B genes and clinicopathologic variables, as well as with p53 and PRE (retinoblastoma protein) status, we re evaluated by use of the two-tailed Fisher's exact test. Disease-specific survival was evaluated by use of the Kaplan-Meier method and the logrank t est. Proportional hazards analysis was used to obtain estimates of relative risks. All P values are two-sided. Results: Homozygous and hemizygous dele tions, but no point mutations, were observed in these two genes. The overal l frequency of gene alteration (deletion or rearrangement) was approximatel y 15% for the INK4A and INK4B genes, with changes restricted to high-grade sarcomas, Statistically significant associations were observed between INK4 A/INK4B deletions (P = .036) or alterations (P = .005) and poor survival. A lteration of the INK4A and INK4B genes was the only statistically significa nt predictor for poor survival when controlling for tumor grade and size (P = .03), Conclusion/Implications: Coincident homozygous deletion of the INK 4A and INK4B genes occurs frequently in adult soft tissue sarcomas, Loss of p16 and pl9ARF function in primary tumors, although not equivalent to alte rations in p53 and pRB function, appears to be associated with cancers that have an aggressive biologic behavior.