Chromosome band 9p21 is frequently altered in malignant peripheral nerve sheath tumors: studies of CDKN2A and other genes of the pRB pathway.
Malignant peripheral nerve sheath tumors (MPNSTs) are frequently associated with the disease neurofibromatosis type 1. Only few recurrent cytogenetic changes have been reported, including rearrangements of the short arm of chromosome 9. By fluorescence in situ hybridization with a centromere 9 probe, and by allelic imbalance studies with seven 9p21-23 markers in nine familial and three sporadic MPNSTs, we found interstitial deletions that supported CDKN2A as a possible target gene. Nine MPNSTs showed aberrations of CDKN2A by Southern blot analyses, and in four of these, expression of CDKN2A could not be detected by Northern blot analysis. No mutations of CDKN2A were identified by sequencing of the coding region, and gene inactivation by promoter methylation was not found. In the 9p allelic imbalance studies, a novel allele was detected at one locus in one tumor. Analyses of additional markers (n = 8) excluded mismatch repair deficiency as an important mechanism in the genesis of these tumors. The tumors were analyzed further for alterations in other candidate cell cycle-associated genes. In total, 11/12 MPNSTs showed DNA changes in one or more of the genes CDKN2A, CDKN2B, RB1, CDK4, MDM2, and CCND2. The present study suggests that disruption of the pRB pathway is common in MPNST, and that dose reduction of CDKN2A is particularly frequent and contributes to MPNST development. Genes Chromosomes Cancer 26:151-160, 1999.
Berner
J M
JM
Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, Oslo, Norway.
Sørlie
T
T
Mertens
F
F
Henriksen
J
J
Saeter
G
G
Mandahl
N
N
Brøgger
A
A
Myklebost
O
O
Lothe
R A
RA
D000293:Adolescent; D000328:Adult; D000368:Aged; D002871:Chromosome Banding; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D005260:Female; D019942:Genes, p16 / Q000235:genetics*; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D019042:Muscle Neoplasms / Q000235:genetics*; D018317:Nerve Sheath Neoplasms / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics*
D016160:Retinoblastoma Protein