Premium
Systematic identification of genes with coding microsatellites mutated in DNA mismatch repair‐deficient cancer cells
Author(s) -
Woerner Stefan M.,
Gebert Johannes,
Yuan Yan P.,
Sutter Christian,
Ridder Ruediger,
Bork Peer,
von Knebel Doeberitz Magnus
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.1299
Subject(s) - microsatellite instability , dna mismatch repair , biology , gene , microsatellite , carcinogenesis , genetics , dna repair , cancer , mutation , coding region , cancer research , allele
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 ≥ 6 and n ≥ 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. © 2001 Wiley‐Liss, Inc.