Loss of heterozygosity on chromosome 11q22-23 in melanoma is associated with retention of the insertion polymorphism in the matrix metalloproteinase-1 promoter

Matrix metalloproteinase-1 (MMP-1, collagenase-1). which degrades interstit ial collagen, is expressed at high levels by some tumor cells and is though t to enhance their invasiveness and metastatic potential. We recently descr ibed a common single nucleotide insertion polymorphism (2G allele) at -1,60 7 bp in the promoter of the MMP-1 gene that creates a binding site for the ETS family of transcription factors, and that is associated with enhanced t ranscription of this gene and increased enzyme activity. Allelic loss at th e MMP-1 locus on chromosome 11 occurs in many tumors including melanoma, an invasive and aggressive cancer. We hypothesized that although loss of eith er the 1G or 2G allele from 1G/2G heterozygotes is random, retention of the transcriptionally more active 2G allele would, favor tumor invasion and me tastasis, As a result, a higher proportion of metastases would contain the 2G genotype than the 1G genotype. We report here the development of quantit ative methods for assessing allelic loss at the MMP-1 locus, and demonstrat e that 83% of the metastatic melanomas with loss of heterozygosity at this locus retained the 2G allele. This supports the hypothesis that retention o f the 2G allele favors tumor invasion and metastasis in melanoma.