Homozygous deletion of MTAP gene as a poor prognosticator in gastrointestinal stromal tumors

Hsuan Ying Huang, Shau Hsuan Li, Shih Chen Yu, Fong Fu Chou, Ching Cherng Tzeng, Tsung Hui Hu, Yih Huei Uen, Yu Fang Tian, Yu Hui Wang, Fu Min Fang, Wen Wei Huang, Yu Ching Wei, Jing Mei Wu, Chien Feng Li

研究成果: Article同行評審

32 引文 斯高帕斯(Scopus)


Purpose: 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. Experimental Design: 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. (Clin Cancer Res 2009;15(22):6963-72)

頁(從 - 到)6963-6972
期刊Clinical Cancer Research
出版狀態Published - 2009 11月 15

All Science Journal Classification (ASJC) codes

  • 腫瘤科
  • 癌症研究


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