Abstract
BackgroundGenomic instability has been reported at microsatellite tracts in few coding sequences. We have shown that the Bloom syndrome BLM gene may be a target of microsatelliteinstability (MSI) in a short poly-adenine repeat located in its coding region. To further characterize the involvement of BLM in tumorigenesis, we have investigated mutations in nine genes containing coding microsatellites in microsatellite mutator phenotype (MMP) positive and negative gastric carcinomas (GCs).MethodsWe analyzed 50 gastric carcinomas (GCs) for mutations in the BLM poly(A) tract aswell as in the coding microsatellites of the TGFβ1-RII, IGFIIR, hMSH3, hMSH6, BAX, WRN, RECQL and CBL genes.ResultsBLM mutations were found in 27% of MMP+ GCs (4/15 cases) but not in any of the MMP negative GCs (0/35 cases). The frequency of mutations in the other eight coding regions microsatellite was the following: TGFβ1-RII (60 %), BAX (27%), hMSH6 (20%),hMSH3 (13%), CBL (13%), IGFIIR (7%), RECQL (0%) and WRN (0%). Mutations in BLM appear to be more frequently associated with frameshifts in BAX and in hMSH6and/or hMSH3. Tumors with BLM alterations present a higher frequency of unstable mono- and trinucleotide repeats located in coding regions as compared with mutator phenotype tumors without BLM frameshifts.ConclusionsBLM frameshifts are frequent alterations in GCs specifically associated with MMP+tumors. We suggest that BLM loss of function by MSI may increase the genetic instability of a pre-existent unstable genotype in gastric tumors.
Highlights
Genomic instability has been reported at microsatellite tracts in few coding sequences
BLM frameshifts are frequent alterations in gastric carcinomas (GCs) associated with microsatellite mutator phenotype (MMP)+tumors
We suggest that BLM loss of function by MSI may increase the genetic instability of a pre-existent unstable genotype in gastric tumors
Summary
Genomic instability has been reported at microsatellite tracts in few coding sequences. Microsatellite instability (MSI) has been described as a frequent genetic alteration in various human solid tumors including sporadic and familial gastric carcinomas (GCs). In almost all patients with hereditary nonpolyposis colorectal cancer (HNPCC), molecular studies have shown that MSI is caused by germline mutations in genes encoding proteins required for DNA mismatch repair (MMR) [4]. Genes such as hMSH2, hMLH1, PMS1, PMS2 and hMSH6/GTBP[5,6,7,8], were defined as "caretakers" because, when disrupted, they favor the acquisition of mutations at high frequency in several genes including oncogenes and tumor suppressor genes [9]. Gene silencing by promoter hypermethylation was recently shown for the hMLH1 gene [11,12,13]
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