Homozygous Deletion of MTAP Gene as a Poor Prognosticator in Gastrointestinal Stromal Tumors (GISTs)
CF Li, WW Huang, SC Yu, HY Huang. Chi-Mei Fountational Medical Center, Yung Kung, Taiwan; Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan; Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung, Taiwan
Background: While chromosomal losses on 9p and/or 9q preferentially affect high-risk cases, little is known about the candidate tumor suppressor genes (TSG) implicating GIST progression, except for CDKN2A/B. Using 385K array CGH (aCGH), we screened DNA copy number alterations (CNAs) to fine map potential TSGs on chromosome 9 (Chr9) with special attention given to MTAP (methylthioadenosine phosphorylase), a TSG frequently co-deleted with CDKN2A/B.
Design: To search TSGs as potential prognosticators, aCGH was profiled for 22 GISTs and criteria for evaluating CNAs on Chr9 were those recurrently deleted in 40% of high-risk samples and but in <40% of intermediate-risk and low-risk samples. MTAP immunostain was assessed in 306 independent cases on tissue microarrays of primary GISTs, 146 of which were measured for MTAP homozygous deletion (HD) by coupling quantitative PCR with laser microdissection. Additionally, 187 cases had known mutation status of KIT and PDGFRA receptor tyrosine kinase (RTK) genes. MTAP gene status was correlated with immunostain, NIH risk level, Ki-67 labeling index (LI), RTK genotypes, and disease-free survival (DFS).
Results: aCGH identified 10 candidate TSGs on 9p and six on 9q. MTAP and/or CDKN2A/B at 9p21.3 were deleted in 1 intermediate-risk (11%) and 7 high-risk (70%) GISTs, with 2 cases homozygously co-deleted at both loci. MTAP HD, present in 25 cases, was significantly associated with poor DFS (p<0.0001, univariately), gastric site (p=0.041), larger size (p<0.001), and higher mitotic rate (p=0.008), Ki-67 LI (p<0.001), and risk level (p<0.001), but not related to RTK genotypes. While MTAP HD correlated with its protein loss (p<0.001), GISTs without MTAP expression did not necessarily show HD. In multivariate analysis, MTAP HD remained independently predictive of adverse outcome (p=0.0369, RR=2.166), along with high risk category (p<0.0001, RR=3.202), Ki-67 LI>5% (p=0.0106, RR=2.456), and non-gastric site (p=0.0416, RR=1.960).
Conclusions: MTAP HD, present in 17% of GISTs, is one mechanism to deplete its protein expression. It correlates with several prognosticators and independently predicts poor DFS in GISTs, highlighting its role in disease progression. MTAP HD may also provide a target of alternative therapy for GISTs, since cells with this change are susceptible to MTAP-directed agents, such as L-alanosine.
Category: Bone & Soft Tissue
Monday, March 9, 2009 1:00 PM
Poster Session II # 25, Monday Afternoon