Systematic identification of genes with coding microsatellites mutated in DNA mismatch repair-deficient cancer cells.
Microsatellite instability (MSI) caused by deficient DNA mismatch-repair functions is a hallmark of cancers associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome but is also found in about 15% of all sporadic tumors. Most affected microsatellites reside in untranslated intergenic or intronic sequences. However, recently few genes with coding microsatellites were also shown to be mutational targets in MSI-positive cancers and might represent important mutation targets in their pathogenesis. The systematic identification of such genes and the analysis of their mutation frequency in MSI-positive cancers might thus reveal major clues to their functional role in MSI-associated carcinogenesis. We therefore initiated a systematic database search in 33,595 distinctly annotated human genes and identified 17,654 potentially coding mononucleotide repeats (cMNRs) and 2,028 coding dinucleotide repeats (cDNRs), which consist of n > or = 6 and n > or = 4 repeat units, respectively. Expression pattern and mutation frequency of 19 of these genes with the longest repeats were compared between DNA mismatch repair-deficient (MSI(+)) and proficient (MSS) cancer cells. Instability frequencies in these coding microsatellite genes ranged from 10% to 100% in MSI-H tumor cells, whereas MSS cancer cells did not show mutations. RT-PCR analysis further showed that most of the affected genes (10/15) were highly expressed in tumor cells. The approach outlined here identified a new set of genes frequently affected by mutations in MSI-positive tumor cells. It will lead to novel and highly specific diagnostic and therapeutic targets for microsatellite unstable cancers.
Woerner
S M
SM
Division of Molecular Diagnostics and Therapy, Department of Surgery, University of Heidelberg, Heidelberg, Germany.
Gebert
J
J
Yuan
Y P
YP
Sutter
C
C
Ridder
R
R
Bork
P
P
von Knebel Doeberitz
M
M
D000230:Adenocarcinoma / Q000235:genetics*; D020137:Base Pair Mismatch / Q000235:genetics; D001483:Base Sequence; D003110:Colonic Neoplasms / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D017931:DNA Primers; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D018900:Dinucleotide Repeats / Q000235:genetics; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D009154:Mutation; D012004:Rectal Neoplasms / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D004273:DNA, Neoplasm