COOPERATIVE EFFECTS OF INK4A AND RAS IN MELANOMA SUSCEPTIBILITY IN-VIVO

The familial melanoma gene (INK4a/MTS1/CDKN2) encodes potent tumor sup pressor activity. Although mice null for the ink4a homolog develop a c ancer-prone condition, a pathogenetic link to melanoma susceptibility has yet to be established. Here we report that mice with melanocyte-sp ecific expression of activated H-ras(G12V) on an ink4a-deficient backg round develop spontaneous cutaneous melanomas after a short latency an d with high penetrance. Consistent loss of the wild-type ink4a allele was observed in tumors arising in ink4a heterozygous transgenic mice. No homozygous deletion of the neighboring ink4b gene was detected. Mor eover, as in human melanomas, the p53 gene remained in a wild-type con figuration with no observed mutation or allelic loss. These results sh ow that loss of ink4a and activation of Ras can cooperate to accelerat e the development of melanoma and provide the first in vivo experiment al evidence for a causal relationship between ink4a deficiency and the pathogenesis of melanoma. In addition, this mouse model affords a sys tem in which to identify and analyze pathways involved in tumor progre ssion against the backdrop of genetic alterations encountered in human melanomas.