Alterations of INK4A and INK4B genes in adult soft tissue sarcomas: effect on survival.
BACKGROUND
The INK4A and INK4B genes map to chromosome 9p21, with the INK4A gene encoding two protein products, p16 and pl9ARF. Alterations of the INK4A and INK4B genes occur frequently in certain primary malignant neoplasms. This study was undertaken to evaluate the frequency of INK4A and INK4B gene alterations in a cohort of adult soft tissue sarcomas.


METHODS
The status of the INK4A and INK4B genes was determined in 46 soft tissue sarcomas by use of the following methods: Southern blotting, polymerase chain reaction (PCR), single-strand conformation polymorphism analysis, comparative multiplex PCR, and a methylation assay focusing on the p16 promoter. Associations between alterations of the INK4A and INK4B genes and clinicopathologic variables, as well as with p53 and pRB (retinoblastoma protein) status, were 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 test. Proportional hazards analysis was used to obtain estimates of relative risks. All P values are two-sided.


RESULTS
Homozygous and hemizygous deletions, but no point mutations, were observed in these two genes. The overall frequency of gene alteration (deletion or rearrangement) was approximately 15% for the INK4A and INK4B genes, with changes restricted to high-grade sarcomas. Statistically significant associations were observed between INK4A/INK4B deletions (P = .036) or alterations (P = .005) and poor survival. Alteration of the INK4A and INK4B genes was the only statistically significant predictor for poor survival when controlling for tumor grade and size (P = .03).


CONCLUSIONS
Coincident homozygous deletion of the INK4A and INK4B genes occurs frequently in adult soft tissue sarcomas. Loss of p16 and pl9ARF function in primary tumors, although not equivalent to alterations in p53 and pRB function, appears to be associated with cancers that have an aggressive biologic behavior.
Orlow
I
I
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Drobnjak
M
M
Zhang
Z F
ZF
Lewis
J
J
Woodruff
J M
JM
Brennan
M F
MF
Cordon-Cardo
C
C
D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D015331:Cohort Studies; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D016161:Genes, Retinoblastoma; D019942:Genes, p16; D016158:Genes, p53; D006801:Humans; D015993:Life Tables; D019656:Loss of Heterozygosity; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011379:Prognosis; D012509:Sarcoma / Q000235:genetics* / Q000401:mortality; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000401:mortality; D025521:Tumor Suppressor Proteins
D000911:Antibodies, Monoclonal; C493966:CDKN2B protein, human; D002352:Carrier Proteins; C493968:Cdkn2b protein, mouse; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins