Homozygous deletion of MTAP gene as a poor prognosticator in gastrointestinal stromal tumors.
OBJECTIVE
Chromosome 9 is frequently deleted in high-risk gastrointestinal stromal tumors (GISTs), whereas its specific tumor suppressor genes (TSGs) are less understood. We did an integrative study of MTAP gene at 9p21 to analyze its implication in GISTs.


METHODS
To search TSGs on chromosome 9, we used ultrahigh-resolution array comparative genomic hybridization to profile DNA copy number alterations of 22 GISTs, with special attention to MTAP gene. MTAP immunoexpression was assessable for 306 independent GISTs on tissue microarrays, with 146 cases analyzed for MTAP homozygous deletion, 181 for mutations of KIT and PDGFRA receptor tyrosine kinase genes, and 7 for MTAP hypermethylation.


RESULTS
Array comparative genomic hybridization identified 11 candidate TSGs on 9p and six on 9q. MTAP and/or CDKN2A/CDKN2B at 9p21.3 were deleted in one intermediate-risk (11%) and seven high-risk (70%) GISTs with two cases homozygously codeleted at both loci. MTAP homozygous deletion, present in 25 of 146 cases, was highly associated with larger size and higher mitotic rate, Ki-67 index, and risk level (all P < 0.01) but not with receptor tyrosine kinase genotypes. Whereas MTAP homozygous deletion correlated with MTAP protein loss (P < 0.001), 7 of 30 GISTs without MTAP expression did not show homozygous deletion, including three MTAP-hypermethylated cases. MTAP homozygous deletion was univariately predictive of decreased disease-free survival (P < 0.0001) and remained multivariately independent (P = 0.0369, hazard ratio = 2.166), together with high-risk category (P < 0.0001), Ki-67 index >5% (P = 0.0106), and nongastric location (P = 0.0416).


CONCLUSIONS
MTAP homozygous deletion, the predominant mechanism to deplete protein expression, is present in 17% of GISTs. It correlates with important prognosticators and independently predicts worse outcomes, highlighting the role in disease progression.
Huang
Hsuan-Ying
HY
Departments of Pathology, Surgery, and Radiation Oncology, and Divisions of Oncology and Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Li
Shau-Hsuan
SH
Yu
Shih-Chen
SC
Chou
Fong-Fu
FF
Tzeng
Ching-Cherng
CC
Hu
Tsung-Hui
TH
Uen
Yih-Huei
YH
Tian
Yu-Fang
YF
Wang
Yu-Hui
YH
Fang
Fu-Min
FM
Huang
Wen-Wei
WW
Wei
Yu-Ching
YC
Wu
Jing-Mei
JM
Li
Chien-Feng
CF
D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000628:therapy; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000628:therapy; D017353:Gene Deletion; D018628:Gene Dosage; D016147:Genes, Tumor Suppressor; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics*
D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase