C-KIT mutations were closely associated with the response to Imatinib in Chinese advanced gastrointestinal stromal tumor patients

Abstract

To investigate the correlation between C-KIT/PDGFRα mutations and Imatinib response or survival in Chinese advanced gastrointestinal stromal tumor (GIST) patients. Clinical data and paraffin-embedded tumor specimens were collected from 158 advanced GIST patients receiving first-line Imatinib. Mutation analyses of C-KIT gene (Exons 9, 11, 13, and 17) and PDGFRα gene (exons 12 and 18) were performed by PCR amplification and Sanger sequencing. A total of 135 patients harboring C-KIT mutations (exon 11 mutation: 108; exon 9 mutation: 23; exon 13 mutation: 2; exon 17 mutation: 2) and one patients carrying PDGFRα mutation (exon 18) were found in this study. Twenty-two patients (13.9 %) with neither C-KIT nor PDGFRα mutations were named as wild type. The response rate (64.7 vs. 36.4 %, P = 0.000) and median progression-free survival (28 vs. 8 months, P = 0.000) of mutant patients (n = 136) were significantly higher than those of wild-type patients (n = 22). Moreover, the response rate and median progression-free survival in patients with exon 11 mutations (n = 108), exon 9 mutations (n = 23), and wild-type patients (n = 22) were 68.5, 47.8, and 36.4 % (P = 0.001), and 31 months, 13 months, and 8 months (P = 0.000), respectively. No significant differences of response rate or median progression-free survival were seen in patients with exon 11 deletion mutations, point mutations, and mixed-type mutations. C-KIT mutations were closely associated with Imatinib response and progression-free survival of Chinese advanced GIST patients. Other predictive markers for Imatinib would be further investigated.

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

“…DNA fragments aligned respectively with exons 9, 11, 13 and 17 of KIT, and exons 12 and 18 of PDGFRA were amplified by PCR using different primers. 21 RR53A, TAKARA PCR Kit were used to amplification the target region with 1 μl of genomic DNA, and 10 μmol/l of each primers in a final volume of 20 μl. The cycling conditions were 35 cycles of 98°C for 10 s, X°C for 30 s and 72°C for 30 s, final extension at 72°C for 3 min, and ended at 4°C (Supplementary Table 1).…”

Succinate dehydrogenase deficiency is associated with decreased 5-hydroxymethylcytosine production in gastrointestinal stromal tumors: implications for mechanisms of tumorigenesis

“…Although many patients with such tumors develop peritoneal and liver metastases, these tumors tend to pursue a protracted, indolent clinical course. Finally, although SDH-deficient tumors express high levels of KIT by immunohistochemistry, they respond poorly to treatment with imatinib, 23 suggesting that alternative signaling pathways are driving tumor formation. Although the distinct clinicopathologic features of SDH-deficient GISTs have been well documented, the mechanism by which SDH-deficiency promotes oncogenesis remains unclear.…”

Practical Role of Mutation Analysis for Imatinib Treatment in Patients With Advanced Gastrointestinal Stromal Tumors: A Meta-Analysis

“…Briefly, 2 HRs ([11,22]) were estimated with the reported data, and the rest ([10,12,14,16,19,23,24],) were calculated with the Kaplan-Meier curve (Table S4). …”

“…The HRs of PFS were estimated in 8 studies (group 2 [10–12,14,16,19,22,23]:). Overall meta-analysis showed that pooled HRs of KIT exon 11-mutant group vs KIT exon 9-mutant group, KIT exon 11-mutant group vs wild type group and KIT exon 9-mutant group vs wild type group were 0.365 (95% CI: 0.301-0.444, p <0.001), 0.375 (95% CI: 0.270-0.519, p <0.001) and 0.905 (95% CI: 0.622-1.316, p=0.601), respectively (Table 3).…”