KRAS and BRAF Mutations Predict Primary Resistance to Imatinib in Gastrointestinal Stromal Tumors

Miranda, Claudia; Nucifora, Martina; Molinari, Francesca; Conca, Elena; Anania, Maria Chiara; Bordoni, Andrea; Saletti, Piercarlo; Mazzucchelli, Luca; Pilotti, Silvana; Pierotti, Marco A.; Tamborini, Elena; Greco, Angela; Frattini, Milo

doi:10.1158/1078-0432.ccr-11-2230

Cited by 156 publications

(135 citation statements)

References 33 publications

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“…BRAF mutations are thought to be mutually exclusive with KIT or PDGFRA mutations and are more frequently reported in lesions occurring in the small intestine [3,4]. Recently, a Swiss-Italian study [9] identified, for the first time, a BRAF mutation in a patient who also harbored a KIT mutation from a series of 47 Italian GIST patients with mutations in KIT or PDGFRA. The authors also identified a KRAS mutation in 2 KIT-and 1 PDGFRApositive patients from a series of 38 Swiss patients with mutations in KIT or PDGFRA.…”

Section: Discussionmentioning

confidence: 99%

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Molecular characterization of an Italian series of sporadic GISTs

et al. 2013

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Purpose Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract. Most (80 %) contain activating mutations in the KIT receptor tyrosine kinase, roughly 10 % in platelet-derived growth factor receptor-alpha (PDGFRA). In a small subset, BRAF mutations are an alternative molecular pathway. GISTs respond well to imatinib, but low response is seen in patients with wild-type KIT or PDGFRA. Resistance has also been reported as a result of mutations in downstream effectors such as BRAF. Methods We provide here a molecular characterization of a series of primary GISTs from Italian patients. Of 121 GIST cases diagnosed between 2000 and 2012, 83 were evaluated by PCR amplification and direct sequencing for mutations in KIT exons 8, 9, 11, 13, and 17, PDGFRA exons 12, 14, and 18, and BRAF exon 15. Eighty-one GISTs also underwent K-RAS testing. Results Sixty-four GISTs were positive: 55 had mutations in KIT and 9 in PDGFRA; 16 patients were mutation negative. Three samples came from NF1 patients and were KIT-and PDGFRA negative. Overall, we identified six

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Section: Discussionmentioning

confidence: 99%

“…Interestingly, a recent study reported for the first time the presence of both KRAS and BRAF mutations in GISTs that also harbored mutations in KIT and PDGFRA [9].…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of an Italian series of sporadic GISTs

et al. 2013

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“…Between 7% and 15% of these tumors harbor an activating mutation in BRAF, and additional small percentages have an NF1 or RAS gene mutation. [24][25][26][27] Approximately 40% of wildtype GISTs show loss of SDHB protein expression, and half of these tumors harbor one or more mutations in SDHA, SDHB, SDHC, or SDHD.…”

Section: 3mentioning

confidence: 99%

Pathologic and Molecular Features Correlate With Long-Term Outcome After Adjuvant Therapy of Resected Primary GI Stromal Tumor: The ACOSOG Z9001 Trial

Corless

Ballman

Antonescu

et al. 2014

JCO

263

200

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A B S T R A C T PurposeThe ACOSOG (American College of Surgeons Oncology Group) Z9001 (Alliance) study, a randomized, placebo-controlled trial, demonstrated that 1 year of adjuvant imatinib prolonged recurrence-free survival (RFS) after resection of primary GI stromal tumor (GIST). We sought to determine the pathologic and molecular factors associated with patient outcome. Patients and MethodsThere were 328 patients assigned to the placebo arm and 317 to the imatinib arm. Median patient follow-up was 74 months. There were 645 tumor specimens available for mitotic rate or mutation analysis. ResultsRFS remained superior in the imatinib arm (hazard ratio, 0.6; 95% CI, 0.43 to 0.75; Cox model-adjusted P Ͻ .001). On multivariable analysis of patients in the placebo arm, large tumor size, small bowel location, and high mitotic rate were associated with lower RFS, whereas tumor genotype was not significantly associated with RFS. Multivariable analysis of patients in the imatinib arm yielded similar findings. When comparing the two arms, imatinib therapy was associated with higher RFS in patients with a KIT exon 11 deletion of any type, but not a KIT exon 11 insertion or point mutation, KIT exon 9 mutation, PDGFRA mutation, or wild-type tumor, although some of these patient groups were small. Adjuvant imatinib did not seem to alter overall survival. ConclusionOur findings show that tumor size, location, and mitotic rate, but not tumor genotype, are associated with the natural history of GIST. Patients with KIT exon 11 deletions assigned to 1 year of adjuvant imatinib had a longer RFS.

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“…These gene mutations play important roles in cancer generation, development, metastasis, and treatment. With the emergence of the target therapy medicine imatinib (Eisenberg and Judson, 2004;Pisters and Colombo, 2011;Joensuu et al, 2012;Li et al, 2012;Miranda et al, 2012), the response and recovery of GIST patients has been greatly improved. However, in a subset of cases, the tumor remains unstable under imatinib treatment, and in a minority of cases, tumor regrowth is observed (Heinrich et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Physical properties of gastrointestinal stromal tumors based on atomic force microscope analysis

Zhao

Zhang²,

Bao³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. This study was designed to detect the stiffness of single living gastrointestinal stromal tumor (GIST) cells in vitro using an atomic force microscope as a probe tool. We determined that the stiffness of living GIST cells was 3913 Pa, the stiffness of the membrane was 642 Pa, and the stiffness of the cytoplasm was 17,550 Pa. For comparison, we also determined the stiffness of a normal stomach cell, which was 7374 Pa, and that of in vitro GIST cells after 2 h of exposure, which was 10,680 Pa. Measuring the mechanical properties of individual GIST cells might provide more complementary information for the diagnosis and treatment of GISTs from the perspective of physical characteristics.

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KRAS and BRAF Mutations Predict Primary Resistance to Imatinib in Gastrointestinal Stromal Tumors

Cited by 156 publications

References 33 publications

Molecular characterization of an Italian series of sporadic GISTs

Molecular characterization of an Italian series of sporadic GISTs

Pathologic and Molecular Features Correlate With Long-Term Outcome After Adjuvant Therapy of Resected Primary GI Stromal Tumor: The ACOSOG Z9001 Trial

Physical properties of gastrointestinal stromal tumors based on atomic force microscope analysis

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