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The familial melanoma gene ( INK4a/MTS1/CDKN2 ) encodes potent tumor suppressor activity. Although mice null for the  ink4a homolog develop a cancer-prone condition, a pathogenetic link to melanoma susceptibility has yet to be established. Here we report that mice with melanocyte-specific expression of activated H- ras G12V   on an  ink4a -deficient background develop spontaneous cutaneous melanomas after a short latency and 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. Moreover, as in human melanomas, the  p53  gene remained in a wild-type configuration with no observed mutation or allelic loss. These results show that loss of  ink4a  and activation of Ras can cooperate to accelerate the development of melanoma and provide the first in vivo experimental evidence for a causal relationship between  ink4a  deficiency and the pathogenesis of melanoma. In addition, this mouse model affords a system in which to identify and analyze pathways involved in tumor progression against the backdrop of genetic alterations encountered in human melanomas.

Cooperative effects of INK4a and ras in melanoma susceptibility in vivo