Inactivating germline mutations in
P16 INK4A on the short arm of chromosome 9 cause up to 50% of familial atypical multiple mole melanoma (FAMMM) families.
18 The
INK4A-ARF locus encodes two alternative reading frame proteins—P16
INK4A (exons 1α, 2, and 3) and P14
ARF (exons 1β, 2, and 3)—both of which are involved in negative control of cell proliferation.
19 P16
INK4A facilitates cell cycle arrest in the G
1 phase by inhibition of retinoblastoma protein phosphorylation through the cyclin-dependent kinases cdk4 and cdk6. By contrast, P14
ARF acts on both G
1/S and G
2/M phases of the cell cycle through MDM2, which promotes degradation of P53.
20 In addition to the finding that mutations in
INK4A-ARF confer susceptibility to cutaneous melanomas, mutations in
CDK4 have been identified in a tiny fraction of hereditary cutaneous melanomas.
21 22 Other candidate melanoma susceptibility genes include the 9p21 neighbor of
P16 INK4A ,
P15 (
MTS2), which displays a high degree of homology to
P16 INK4A .
23 A number of observations suggest that the
CDKN genes (
P16 INK4A ,
P14 ARF , and
P15) predisposition the bearer to uveal melanoma. First, uveal melanoma is part of the clinical spectrum of FAMMM-affected families linked to 9p21.
24 Second, somatic changes in
P16 INK4A —-methylation, homozygous deletions, and intragenic deletions—and allelic imbalance at 9p21 are seen in sporadic uveal melanomas.
25 26 27 Furthermore, in 30% of uveal melanomas expression of P16
INK4A is reduced through promoter hypermethylation of the gene.
28 Other genes representing candidate genes for susceptibility to uveal melanoma are those predisposing to breast cancer in families that segregate uveal melanoma. Data from two large
BRCA2-linked families has provided evidence that the risk of uveal melanoma is elevated in mutation carriers.
29 In one family, uveal melanoma occurred in a 45-year-old obligate carrier. In the other family, ocular cancer, which almost certainly consisted of a uveal melanoma, developed in a 54-year-old obligate carrier. Easton et al.
29 computed the risk of uveal melanoma in the families. The incidence of uveal melanoma was 33 times greater than the expected incidence of 0.06.