Gastrointestinal stromal tumors with KIT exon 9 mutations: Update on genotype-phenotype correlation and validation of a high-resolution melting assay for mutational testing.
KIT exon 9 mutations in gastrointestinal stromal tumors (GISTs) are highly relevant and have direct therapeutic implications. In this context, we established and validated a fast and sensitive high-resolution melting assay. Analyzing 126 primary and 18 metastatic KIT exon 9-mutated cases from our registry, we demonstrate that the mutational spectrum of exon 9 is broader than previously thought and describe 3 novel mutations. Including these cases and the common p.A502_Y503dup mutation, we provide a comprehensive list of all known KIT exon 9 mutations according to the Human Genome Variation Society nomenclature. Two of the newly described mutations were associated with an aggressive phenotype and tumor progression while being treated with 400 mg imatinib, indicating that also GIST with rare exon 9 mutations could be treated with increased imatinib dosage. On the basis of >1500 GISTs from our registry, we have determined the frequency of KIT exon 9 mutations to be 9.2% among all GISTs and 22.5% among small-bowel cases. We describe for the first time that nearly 20% of exon 9-mutated GIST occur in the stomach or rectum. Furthermore, we provide first evidence that exon 9-mutated GISTs metastasize significantly more often to the peritoneum than to the liver. Performing extensive statistical analyses on data from our registry and from the literature, we demonstrate that KIT exon 9 mutations are neither associated with intermediate-risk/high-risk status nor overrepresented among metastatic lesions. Thus, we conclude that exon 9 mutations per se do not have prognostic relevance.
*Institute of Pathology, University of Cologne Medical Center, Cologne †Gerhard-Domagk-Institute of Pathology, University of Münster Medical Center, Münster ‡Department of General and Abdominal Surgery, University of Mainz Medical Center, Mainz §Division of Surgical Oncology and Thoracic Surgery, University of Mannheim Medical Center, Mannheim ∥Department of Hematology, Oncology and Palliative Care, Sarcoma Center Berlin-Brandenburg, HELIOS Klinikum Bad Saarow, Bad Saarow, Germany.
Helen
H
Künstlinger
Sebastian
S
Huss
Sabine
S
Merkelbach-Bruse
Elke
E
Binot
Michaela Angelika
MA
Kleine
Heike
H
Loeser
Jens
J
Mittler
Wolfgang
W
Hartmann
Peter
P
Hohenberger
Peter
P
Reichardt
Reinhard
R
Büttner
Eva
E
Wardelmann
Hans-Ulrich
HU
Schildhaus
D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides / Q000627:therapeutic use; D016009:Chi-Square Distribution; D004252:DNA Mutational Analysis / Q000379:methods*; D005091:Exons; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009691:Nucleic Acid Denaturation; D010641:Phenotype; D010879:Piperazines / Q000627:therapeutic use; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use; D012042:Registries; D015203:Reproducibility of Results; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit