KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs)

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Mutually exclusive KIT and PDGFRA mutations are central events in GIST pathogenesis, and their understanding is becoming increasingly important, because specific treatment targeting oncogenic KIT and PDGFRA activation (especially imatinib mesylate) has become available. KIT mutations in GIST are clustered in four exons. Most common are exon 11 (juxtamembrane domain) mutations that include deletions, point mutations (affecting a few codons), and duplications (mostly in the 3′ region). The latter mutations most often occur in gastric GISTs. Among gastric GISTs, tumors with deletions are more aggressive than those with point mutations; this does not seem to hold true in small intestinal GISTs. Exon 9 mutations (5-10%) usually are 2-codon 502-503 duplications, and these occur predominantly in intestinal versus gastric GISTs. Lesser imatinib sensitivity of these tumors has been noted. Kinase domain mutations are very rare; GISTs with such mutations are variably sensitive to imatinib. PDGFRA mutations usually occur in gastric GISTs, especially in the epithelioid variants; their overall frequency is approximately 30% to 40% of KIT mutation negative GISTs. Most common is exon 18 mutation leading Asp842Val at the protein level. This mutation causes imatinib resistance. Exon 12 and 14 mutations are rare. Most mutations are somatic (in tumor tissue only), but patients with familial GIST syndrome have consitutitonal KIT/PDGFRA mutations; >10 families have been reported worldwide with mutations generally similar to those in sporadic GISTs. GISTs in neurofibromatosis 1 patients, children, and Carney triad seem to lack GIST-specific KIT and PDGFRA mutations and may have a different disease mechanism. Secondary mutations usually occur in KIT kinase domains in patients after imatinib treatment resulting in resistance to this drug. Mutation genotyping is a tool in GIST diagnosis and in assessment of sensitivity to kinase inhibitors.

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Overview of KIT and PDGFRA mutations in GISTs

The mutation nomenclature used in this review follows recommendations of the Human Genome Variation Society (http://www.hgvs.org). Nucleotide numbering is based on human KIT (X06182) and PDGFRA (M21574) mRNA sequences and dog KIT (AF044249) mRNA from GeneBank (at http://www.ncbi.nlm.nih.gov).

Gain-of-function KIT and PDGFRA mutations are considered to be a major driving force in the pathogenesis of sporadic, nonfamilial GISTs.15, 16 Based on location, these mutations can be divided in two

KIT regulatory domain mutations (exon 9, exon 11)

Nearly all mutations identified in KIT exon 9, a distal part of the KIT-EC domain, represent short, structurally identical duplications of six nucleotides, 1525_1530dupGCCTAT leading to the Ala502_Tyr503dup at the protein level.61, 71, 72, 73 However, more recently, another duplication 1537_1545dupTTTGCATTT leading to the Phe506_Phe508dup at the protein level was reported.72 Two such duplications have been found among 60 (3.3%) KIT exon 9 mutant GISTs identified at AFIP. An Ala502_Phe506dup

KIT enzymatic domain mutations (exon 13, exon 14, exon 17)

A 1945A>G point mutation resulting in Lys642Glu substitution at the protein level was initially reported in two GISTs negative for KIT-JM mutation.39 This mutation affects exon 13 encoding proximal part of the KIT-TK1 (ATP-binding domain) and has been found to lead to constitutive KIT tyrosine phosphorylation.39 A subsequent study of a relatively large number of GISTs from different locations estimated the frequency of this mutation to be no higher than 2.5%.40, 56

Recent studies on GISTs, based

PDGFRA regulatory domain mutations (exon 12)

Mutations in PDGFRA-JM domain are relatively rare and represent approximately 6% to 9% of all PDGFRA mutations reported in GISTs.42, 43 These mutations consist of point mutations, deletions, deletion–insertions, and insertions.16, 42, 43 The most common is 1821T>A leading to Val561Asp substitution at the protein level followed in frequency by deletion/deletion insertions and insertions. In general, these mutations affect the vicinity of codon 561 or a region located immediately 3′ to this codon.

PDGFRA enzymatic domain mutation (exon 14, exon 18)

An Asn659Lys in PDGFRA exon 14 was first reported in KIT-negative gastric GIST.116 Subsequently, 2 more cases with such missense mutations were reported,43 and a study based on 200 GISTs negative for KIT exon 9, 11, 13, and 17 and PDGFRA exon 12 and 18 mutations identified 11 PDGFRA exon 14 mutations.42 A majority of these 11 mutations represented 2125C>A and 2125C>G leading to Asn659Lys at the protein level. However, in 3 cases, variant point mutations, 2123A>T leading to Asn659Tyr, were found

KIT and PDGFRA mutational status in NF1 and pediatric and Carney triad GISTs

Several studies evaluated KIT and PDGFRA mutation status in GISTs from neurofibromatosis type 1 (NF1) patients.118, 119, 120, 121, 122, 123, 124 In general, no mutations in GIST-specific KIT or PDGFRA mutational “hot spots” have been found in multiple tumors from NF1 patients. However, one study identified two KIT (Pro627Leu and Ile653Thr) and two PDGFRA (Pro589Lys and Arg822Ser) missense mutations in two separate lesions from two patients.120 These mutations might be random genetic events

Frequency of KIT and PDGFRA mutations

Frequency of the KIT and PDGFRA mutations differs between the studies. Several factors contribute to these differences. First, KIT and PDGFRA mutations are unequally distributed among GISTs. For example, studies with a large number of intestinal GISTs will show a higher frequency of KIT exon 9 mutants, whereas studies with a higher number of gastric epithelioid tumors will show a lower number of KIT-mutants and a higher number of PDGFRA-mutants. Moreover, studies based on material from cancer

Prognostic value of KIT and PDGFRA mutations

The prognostic value of KIT and PDGFRA mutations in primary tumors is controversial. Some of the early studies reported that KIT exon 11 mutations are more common in large and malignant GISTs,54, 55 and adverse prognostic significance of such mutations was suggested.54, 55, 90 However, others have also shown these mutations in diminutive, clinically indolent incidental tumors.64

More recent studies, based on larger numbers of cases and evaluating both KIT and PDGFRA mutational status, indicated

Primary KIT and PDGFRA mutations and imatinib-based treatment

Imatinib mesylate, STI571, commercially known as Gleevec/Glivec™ (http://www.novartis.com) that inhibits KIT, PDGFRA, and ABL tyrosine kinases has been used in the treatment of clinically advanced, unresectable, and metastatic GISTs.135, 136 More recently, sunitinib malate, also known as SU11248 (http://www.pfizer.com), that inhibits KIT and some other tyrosine kinases has also been approved on the same indication.137, 138

A great majority of patients benefit from imatinib mesylate-based

Secondary KIT and PDGFRA mutations acquired during imanitib-based treatment

An acquired resistance has been reported during imatinib-based treatment and linked to secondary KIT or PDGFRA mutations.66, 142 Initial studies showed that secondary KIT mutations occur in the allele that harbors primary gain-of-function KIT mutation and in a great majority of cases represents missense point mutation affecting the first or second tyrosine kinase domain (Figure 9).66, 89, 143, 144, 145 Subsequently, polyclonal evolution of multiple secondary KIT mutations has also been reported.

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    The opinions and assertions contained herein are the expressed views of the authors and are not to be construed as official or reflecting the views of the Departments of the Army or Defense.

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