Deletion mapping of chromosome region 9p21-p22 surrounding the CDKN2 locus in melanoma.
The cyclin-dependent kinase-4 inhibitor gene CDKN2, localized at chromosome region 9p21, has been shown to be a familial melanoma gene, though we found that mutations of it are rare in uncultured sporadic melanomas. To determine Whether the region of allelic loss at 9p21 frequently observed in sporadic melanomas includes the CDKN2 locus, new polymorphic microsatellite probes were isolated from the genomic segments surrounding the CDKN2 gene and used for the study of loss of heterozygosity (LOH) in melanoma. The LOH study of matched uncultured tumor-constitutional DNA pairs from 66 metastatic cutaneous and 19 primary uveal melanomas showed that 63% and 32% of the respective tumors suffered allelic loss in the 9p21 region. Two regions of common losses which did not include the CDKN2 locus were observed: in a region of common loss near the D9S157 locus, telomeric to the CDKN2 locus, deletions were observed in 51% of informative cases; in the other region of common loss, near the D9S171 locus, centromeric to the CDKN2 locus, deletions were observed in 47% of informative cases. At the D9S974 locus, located within 20 kb of the CDKN2 gene, deletions were observed in 43% of informative cases. Homozygous deletions of the CDKN2 locus were observed in 8 cases of cutaneous melanoma and 2 cases of uveal melanoma; mutations in CDKN2 exon 2 were found in 2 of the 46 cases with allelic deletion in 9p21. Our results support the following conclusions: (i) somatic mutation of the CDKN2 gene is rare in sporadic melanomas with allelic loss at 9p21; (ii) homozygous loss is more frequent than mutation of the CDKN2 gene in sporadic melanomas; (iii) at 9p21-p23 genes other than CDKN2 may be involved in the development of sporadic melanomas.
Ohta
M
M
Jefferson Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Berd
D
D
Shimizu
M
M
Nagai
H
H
Cotticelli M-G
Mastrangelo
M
M
Shields
J A
JA
Shields
C L
CL
Croce
C M
CM
Huebner
K
K
D000483:Alleles; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002874:Chromosome Mapping / Q000379:methods*; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics; D002899:Chromosomes, Human, Pair 9; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm / Q000235:genetics; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D008969:Molecular Sequence Data; D012878:Skin Neoplasms / Q000235:genetics*; D014604:Uveal Neoplasms / Q000235:genetics*
D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm