Prognostic Significance of c-kit Mutation in Localized Gastrointestinal Stromal Tumors

Abstract

Purpose: Constitutive mutational activation of c-kit has been found to be associated with the pathogenesis of gastrointestinal stromal tumors (GISTs). The prognostic significance of c-kit mutations, however, is still controversial.Experimental Design: We examined 86 patients curatively resected for localized GIST. Genomic DNA was extracted from paraffin-embedded tumor tissues. Exons 9, 11, 13, and 17 of the c-kit gene were amplified by PCR and sequenced.Results: Mutations in exon 11 were detected in 61 tumors, and mutations in exon 9 were observed in three tumors, whereas no mutations were detected in exons 13 or 17. The overall c-kit mutation frequency was 74%. Amino acid alterations in the 61 tumors with exon 11 mutations were deletion in 33 tumors, substitution in 20, both deletion and substitution in 4, insertion in 1, and duplication in 3. Histologically, tumors with c-kit mutations showed higher mitotic counts and higher cellularity. The 5-year relapse-free survival (RFS) in patients having GISTs with c-kit mutations was 21%, compared with 60% in those without c-kit mutations. Significantly higher RFS rates were observed in patients with tumors having mitotic counts < 5 mitoses/50 high power field, spindle-cell histology, tumor size < 5 cm, or gastric GISTs. Multivariate analyses indicated association of poorer RFS with a higher mitotic count [>5 of 50 high power fields; odds ratio (OR) ‫؍‬ 3.0], presence of c-kit mutations (OR ‫؍‬ 5.6), and a larger tumor size (>5 cm; OR ‫؍‬ 4.2).Conclusions: The presence of c-kit mutation, along with high mitotic count and larger tumor size, was an independent factor for poor prognosis in patients with localized GISTs.

KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs)

“…Although KIT exon 11 mutations have been reported in GISTs from different locations from esophagus to anus, [105][106][107][108][109][110][111][112] duplications showed strong predilection to gastric location; 59 of 67 (88%) reported GISTs with KIT exon 11 duplications originated from stomach. 61,74,76,77,83,84,97,101,113 …”

“…74,81,101 Technical problems limiting detection of duplications in FFPE tissues may contribute to this discrepancy, since other studies from Korea and China have been reported KIT exon 11 duplications in GISTs. 83,84,99,100 …”

Kinase Mutations and Efficacy of Imatinib in Korean Patients with Advanced Gastrointestinal Stromal Tumors

“…Polymerase Chain Reaction and Sequencing of KIT and PDGFRA Amplification and direct DNA sequencing of KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 were performed according to previously described procedures [2,14]. Patient samples negative for KIT or PDGFRA mutations were subsequently amplified with primers specific for KIT exons 8, 14, and 15 followed by direct DNA sequencing [18,19].…”

Improved Detection of KIT Exon 11 Duplications in Formalin-Fixed, Paraffin-Embedded Gastrointestinal Stromal Tumors

“…5,6,8,[12][13][14][15][16][17][18][19][20][21][22][23] All analyzed duplications, except two (2.1%), have been reported in the KIT region c.1729_1794 (g.75722_75787). Primers CK11.1F and CK11.3R closely flanking this region were used for PCR amplification of smaller products, yielding 129 bp in KIT-WT.…”