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Loss of the p16INK4a and p15INK4b genes, as well as neighboring 9p21 markers, in sporadic melanoma

AuthorsFlores, José F.; Castresana, Javier S.; Fountain, Jane W.
Issue Date1996
PublisherAmerican Association for Cancer Research
CitationCancer Research 56(21): 5023-5032 (1996)
AbstractAlthough homozygous deletions of the cyclin-dependent kinase inhibitor 2 gene p16(INK4a) on 9p21 have been reported frequently in metastatic melanoma cell lines, and intragenic mutations within the p16(INK4a) gene have been detected in familial melanoma kindreds, specific targeting of this gene in the development of sporadic melanoma in vivo remains controversial. Southern analyses were performed in this study to initially assess the frequency of hemi- or homozygous losses of p16(INK4a), as well as its neighboring family member, p15(INK4b), and other candidate regions within 9p21, in sporadic melanoma. Overall, 22 of 40 (55%) uncultured sporadic melanoma DNAs were determined in harbor deletions of 1-11 markers/genes located on 9p21. This included 10 tumors (25%; 10 of 40) with homozygous deletions limited to either the p16(INK4a) gene only (20%; 2 of 10), both the p16(INK4a) and p15(INK4b) genes (10%; 1 of 10), another novel 9p21 gene, FB19 (10%; 1 of 10), or all three of these genes plus surrounding markers (60%; 6 of 10). In subsequent single-strand conformation polymorphism and sequencing analyses, intragenic mutations in the p16(INK4a) gene were also revealed in two (10%; 2 of 21) melanoma DNAs that retained one copy of this locus. By comparison, the frequency of p16(INK4a) and p15(INK4b) homozygous deletions, as well as p16(INK4a) mutations, in melanoma cell lines (analyzed in parallel) was 2-3- fold higher at 61 (23 of 38) and 24% (9 of 38), respectively. These findings indicate that (a) p16(INK4a) is inactivated in vivo in over one-fourth (27.5%; 11 of 40) of sporadic melanomas; (b) mutation/deletion of p16(INK4a) may confer a selective growth advantage in vitro; and (c) other 9p21 tumor suppressor genes could be targeted during the development of melanoma.
Identifiersissn: 0008-5472
e-issn: 1538-7445
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