Distinct gene expression-defined classes of gastrointestinal stromal tumor.
OBJECTIVE
The majority of gastrointestinal stromal tumors (GIST) can be cured by surgery alone, but relapse occurs in 20% to 40% of cases. GISTs are considered to invariably arise through gain of function KIT or PDGFA mutation of the interstitial cells of Cajal (ICC). However, the genetic basis of the malignant progression of GISTs are poorly understood.


METHODS
The expression levels of 54,613 probe sets in 32 surgical samples of untreated GISTs of the stomach and small intestine were analyzed with oligonucleotide microarrays. The representative GeneChip data were validated by real-time reverse transcriptase polymerase chain reaction and immunohistochemistry.


RESULTS
Unbiased hierarchical clustering consistently separated the 32 cases of GIST into two major classes according to tumor site. The two major classes were further separated into novel subclasses, which were significantly correlated with various pathological prognostic parameters, the frequency of metastasis (P < .05), and clinical outcome. Immunohistochemical analysis of 152 independent patients with gastric GISTs revealed that the expression of dipeptidyl peptidase IV (T-cell activation antigen CD26) protein was significantly associated with poorer overall and disease-free survival (P < .00001).


CONCLUSIONS
CD26 appears to be a reliable biomarker of malignant GISTs of the stomach. The postoperative recurrence rate of CD26-negative cases was as low as 2.0% (two of 102). Therefore, postoperative follow-up of such patients might be made less intensive. CD26 may play an important role in the malignant progression of gastric GISTs and serve as a therapeutic target.
Yamaguchi
Umio
U
Chemotherapy Division and Cancer Proteomics Project, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Nakayama
Robert
R
Honda
Kazufumi
K
Ichikawa
Hitoshi
H
Hasegawa
Tadashi
T
Shitashige
Miki
M
Ono
Masaya
M
Shoji
Ayako
A
Sakuma
Tomohiro
T
Kuwabara
Hideya
H
Shimada
Yasuhiro
Y
Sasako
Mitsuru
M
Shimoda
Tadakazu
T
Kawai
Akira
A
Hirohashi
Setsuo
S
Yamada
Tesshi
T