SOMATIC MUTATIONS IN VNTR-LOCUS D1S7 IN HUMAN COLORECTAL CARCINOMAS ARE ASSOCIATED WITH MICROSATELLITE INSTABILITY

To elucidate mutation mechanisms in hypervariable VNTR loci, we have s tudied somatic mutation events with the minisatellite probe MS1 (VNTR locus D1S7) in 224 colorectal carcinomas (CRC). The D1S7 locus consist s of a 9 basepair (bp) repeat unit. The copy number varies from about 100 to 2000, and the germline mutation rate is high. Here we demonstra te a high D1S7 somatic mutation rate in CRC (37/224), higher than indi cated earlier by others. We also, demonstrate that the most frequent m utational event by far (n=34) involves small reductions in VNTR fragme nt size (median loss 22 repeat units, range 2-154), furthermore, in on e-half of these cases, this event is biallelic. We wanted to test whet her these somatic mutations mirror the same genetic instability as see n by RER (replication error), a phenomenon recently described in tumou r DNA from both sporadic and familiar cases of CRC. All blood/tumour D NA pairs displaying MS1 mutation (n=37) as well as 37 randomly selecte d pairs without MS1 mutation were tested with four tetranucleotide sho rt tandem repeats (STRs, microsatellites). There is a strong associati on between mutations at the D1S7 locus and the occurrence of new STR a lleles (P<0.001). This is the first report of the existence of a minis atellite as a marker for genetic instability/RER in colorectal carcino mas. The findings may also cast light upon the mechanism for somatic m utations in this minisatellite. (C) 1995 Wiley-Liss, Inc.