Microsatellite instability of selective target genes in HNPCC-associated colon adenomas.
Microsatellite instability (MSI) occurs in most hereditary nonpolyposis colorectal cancers (HNPCC) and less frequently in sporadic tumors as the result of DNA mismatch repair (MMR) deficiency. Instability at coding microsatellites (cMS) in specific target genes causes frameshift mutations and functional inactivation of affected proteins, thereby providing a selective growth advantage to MMR deficient cells. At present, little is known about Selective Target Gene frameshift mutations in preneoplastic lesions. In this study, we examined 30 HNPCC-associated MSI-H colorectal adenomas of different grades of dysplasia for frameshift mutations in 26 cMS-bearing genes, which, according to our previous model, represent Selective Target genes of MSI. About 30% (8/26) of these genes showed a high mutation frequency (> or =50%) in colorectal adenomas, similar to the frequencies reported for colorectal carcinomas. Mutations in one gene (PTHL3) occurred significantly less frequently in MSI adenomas compared to published mutation rates in MSI carcinomas (36.0 vs 85.7%, P=0.023). Biallelic inactivation was observed in nine genes, thus emphasizing the functional impact of cMS instability on MSI tumorigenesis. Some genes showed a high frequency of frameshift mutations already at early stages of MSI colorectal tumorigenesis that increased with grade of dysplasia and transition to carcinoma. These include known Target Genes like BAX and TGFBR2, as well as three novel candidates, MACS, NDUFC2, and TAF1B. Overall, we have identified genes of potential relevance for the initiation and progression of MSI tumorigenesis, thus representing promising candidates for novel diagnostic and therapeutic approaches directed towards MMR-deficient tumors.
Woerner
Stefan M
SM
Institute of Molecular Pathology, University of Heidelberg, Germany.
Kloor
Matthias
M
Mueller
Annegret
A
Rueschoff
Josef
J
Friedrichs
Nicolaus
N
Buettner
Reinhard
R
Buzello
Moriz
M
Kienle
Peter
P
Knaebel
Hanns-Peter
HP
Kunstmann
Erdmute
E
Pagenstecher
Constanze
C
Schackert
Hans K
HK
Möslein
Gabriela
G
Vogelsang
Holger
H
von Knebel Doeberitz
Magnus
M
Gebert
Johannes F
JF
D000236:Adenoma / Q000235:genetics* / Q000503:physiopathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D043171:Chromosomal Instability; D003110:Colonic Neoplasms / Q000235:genetics* / Q000503:physiopathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000150:complications / Q000235:genetics*; D004249:DNA Damage; D004252:DNA Mutational Analysis; D004260:DNA Repair; D016368:Frameshift Mutation; D006801:Humans; D007150:Immunohistochemistry; D018895:Microsatellite Repeats; D009857:Oncogenes