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 interstitial collagen, is expressed at high levels by some tumor cells and is thought to enhance their invasiveness and metastatic potential. We recently described a common single nucleotide insertion polymorphism (2G allele) at -1,607 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 transcription of this gene and increased enzyme activity. Allelic loss at the MMP-1 locus on chromosome 11 occurs in many tumors including melanoma, an invasive and aggressive cancer. We hypothesized that although loss of either the 1G or 2G allele from 1G/2G heterozygotes is random, retention of the transcriptionally more active 2G allele would favor tumor invasion and metastasis. As a result, a higher proportion of metastases would contain the 2G genotype than the 1G genotype. We report here the development of quantitative methods for assessing allelic loss at the MMP-1 locus, and demonstrate that 83% of the metastatic melanomas with loss of heterozygosity at this locus retained the 2G allele. This supports the hypothesis that retention of the 2G allele favors tumor invasion and metastasis in melanoma.
Noll
W W
WW
Department of Pathology, Dartmouth Medical School, Hanover, New Hamphire 03755, USA.
Belloni
D R
DR
Rutter
J L
JL
Storm
C A
CA
Schned
A R
AR
Titus-Ernstoff
L
L
Ernstoff
M S
MS
Brinckerhoff
C E
CE
D000328:Adult; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D004586:Electrophoresis / Q000379:methods; D005260:Female; D005838:Genotype; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D010761:Phosphorus Radioisotopes; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*
D004273:DNA, Neoplasm; D010761:Phosphorus Radioisotopes; D020781:Matrix Metalloproteinase 1