Gj. Walker et al., VIRTUALLY 100-PERCENT OF MELANOMA CELL-LINES HARBOR ALTERATIONS AT THE DNA LEVEL WITHIN CDKN2A, CDKN2B, OR ONE OF THEIR DOWNSTREAM TARGETS, Genes, chromosomes & cancer, 22(2), 1998, pp. 157-163
The cyclin-dependent kinase inhibitor 2A (CDKN2A), or p16(INK4a), gene
on 9p21 is important in the genesis of both familiar and sporadic mel
anoma. Homozygous deletions and intragenic mutations of this gene have
been identified in both melanoma cell lines and uncultured tumors, al
though the frequency of these alterations is higher in the cell lines.
A proportion of melanoma cell lines and tumors without deletion/mutat
ion of CDKN2A have also been determined to harbor transcriptionally in
active CDKN2A alleles or carry alterations in other components of the
pathway through which p16(INK4a) acts On pRb to mediate cell cycle arr
est. We sought to determine the frequency of these alternative events
(in relationship to those that specifically inactivate CDKN2A) in a pa
nel of 45 melanoma cell lines. Surprisingly, at the DNA level alone, 9
6% (43/45) of melanoma cell lines examined were found to be deleted/mu
tated/methylated for CDKN2A (34/45), homozygously deleted for CDKN2A's
neighbor and homolog CDKN2B (6/45), and/or mutated/amplified for CDK4
(5/45). In two of these 43 cases, homozygous deletions of CDKN2A were
detected along with a CDK4 mutation or amplification of the cyclin D1
(CCND1) gene. The latter discoveries were made in two of three cell l
ines which harbored extremely large (3-6 Mb) homozygous deletions on 9
p21; all other homozygous deletions in similarly affected cell lines (
N = 23) were confined to a region immediately surrounding the CDKN2A/C
DKN2B loci. These results suggest that (I) only melanoma cells with al
terations in this pathway can be propagated in culture, and (2) the ho
mozygous deletions on 9p21 in the cell lines, which are also mutated/a
mplified for CDK4 or CCND1, could serve to target tumor suppressor gen
es other than CDKN2A. (C) 1998 Wiley-Liss, Inc.