Loss of chromosome 9p21 and decreased p16 expression correlate with malignant gastrointestinal stromal tumor.
OBJECTIVE
To investigate loss of heterozygosity (LOH) of chromosome 9p21 and the prognostic relevance of p16 expression in gastrointestinal stromal tumor (GIST).


METHODS
Fifty-one GIST patients (30 men and 21 women; median age 59 years; range 29-80 years) treated surgically within a 10-year period were grouped by aggressive behavior risk (17 with very low and low, 14 intermediate, and 20 high risk). GISTs were characterized immunohistochemically and evaluated for LOH of 9p21 by microsatellite analysis at D9S1751, D9S1846, D9S942, and D9S1748. LOH of 9p21 and immunohistochemical expression of p16 protein encoded at 9p21 were correlated with clinicopathological parameters, and the prognostic significance of p16 alterations was evaluated.


RESULTS
Thirty-one (63.3%) cases showed LOH with at least one microsatellite marker. LOH frequency was 37.0% at D9S1751, 37.5% at D9S1846, 42.1% at D9S942, and 24.2% at D9S1748. There was a higher LOH frequency of D9S942 in high-risk than in non-high-risk tumors (P < 0.05, χ(2) = 4.47). Gender, age, tumor size and site were not correlated with allelic loss. Ninety percent (18/20) of the GIST patients in the high risk group showed LOH with at least one of the 9p21 markers, while 57.1% (8/14) in the intermediate risk group and 33.3% (5/15) in the very low and low risk groups, respectively (P < 0.05, χ(2) = 12.16). Eight (28.5%) of 31 patients with LOH and 1 (5.6%) of 18 patients without LOH died of the disease during the follow-up period. Loss of p16 protein expression occurred in 41.2%, but in 60% of the high risk group and 23.5% of the very low and low risk groups (P < 0.05, χ(2) = 4.98). p16 loss was associated with poor prognosis (P < 0.05, χ(2) = 4.18): the 3- and 5-year overall survival rates were 84.8% and 70.8% for p16-negative and 100% and 92.0% for p16-positive patients, respectively.


CONCLUSIONS
LOH at 9p21 appears to play an important role in GIST progression; decreased p16 expression in GIST is highly predictive of poor outcome.
Zhang
Yun
Y
Department of General Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Cao
Hui
H
Wang
Ming
M
Zhao
Wen-Yi
WY
Shen
Zhi-Yong
ZY
Shen
Dan-Ping
DP
Ni
Xing-Zhi
XZ
Wu
Zhi-Yong
ZY
Shen
Yan-Ying
YY
Song
Yan-Yan
YY
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D011379:Prognosis; D012307:Risk Factors
D019941:Cyclin-Dependent Kinase Inhibitor p16