title: KIT codon 558 insertions in gastrointestinal stromal tumors. Analysis of 17 rare KIT mutants.
abstract: Gastrointestinal stromal tumors are the most common mesenchymal neoplasms of gastrointestinal tract often driven by oncogenic KIT exon 11 mutations. Although deletions and substitutions are most frequent KIT exon 11 mutations, duplications and insertions have been reported as well. In contrast to duplications, which cluster in 3'KIT exon 11, insertions affect 5'KIT, particularly codon 558. Clinicopathologic profile of gastrointestinal stromal tumors with insertions in codon 558 is not known. In this study, 17 gastrointestinal stromal tumors with codon 558 insertions are reported. Fifteen (88.2%) KIT codon 558 insertions consisted of 1694_1695insTCC leading to Lys558delinsAsnPro. However, 2 variant mutants Lys558delinsAsnGln and Lys558delinsAsnAsn were also identified. Based on analysis of inserted and flanking sequences, the insertions contain inverted DNA sequences of the opposite strand. Therefore, these insertions may develop due to a DNA strand switch during replication by DNA polymerases and by the effects of several different DNA repair processes. Patient median age was 61 years, and male-to-female ratio was 1:1.8. gastrointestinal stromal tumors were diagnosed in stomach (n = 4), small intestine (n = 7), and rectum (n = 3). Three tumors were disseminated and primary location could not be established. Fourteen tumors had spindle cell morphology, and epithelioid cell features were seen in 2 intestinal and 1 disseminated gastrointestinal stromal tumor. Based on size and mitotic activity, 2 (50%) of 4 gastric and 3 (48.9%) of 7 small intestinal gastrointestinal stromal tumors had more than 50% risk of metastases according to previous studies of gastrointestinal stromal tumor prognosis. All 3 rectal gastrointestinal stromal tumors were malignant. Metastases were verified in 8 (66.7%) of 12 patients with known clinical and follow-up data. In summary, KIT codon 558 insertions are rare mutations accounting for less than 1% of all KIT mutants. Gastrointestinal stromal tumors with these mutations appear to have predilection to female patients and intestinal location. Moreover, KIT codon 558 insertions might indicate an increased risk of malignant behavior for gastric gastrointestinal stromal tumors.
authors: Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA. lasota@afip.osd.mil
authors: Jerzy
authors: J
authors: Lasota
authors: Wojciech
authors: W
authors: Kuban
authors: Eva
authors: E
authors: Wardelmann
authors: Maria
authors: M
authors: Debiec-Rychter
authors: Sabine
authors: S
authors: Merkelbach-Bruse
authors: Raf
authors: R
authors: Sciot
authors: Janusz
authors: J
authors: Rys
authors: Sonja E
authors: SE
authors: Steigen
authors: Katarzyna
authors: K
authors: Iwanik
authors: Joseph A
authors: JA
authors: Holden
authors: Anna
authors: A
authors: Jerzak Vel Dobosz
authors: Hans-Ulrich
authors: HU
authors: Schildhaus
authors: Markku
authors: M
authors: Miettinen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D003062:Codon; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics / Q000473:pathology; D008297:Male; D008637:Mesenchymoma / Q000235:genetics* / Q000556:secondary; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D012004:Rectal Neoplasms / Q000235:genetics / Q000473:pathology; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D003062:Codon; D004273:DNA, Neoplasm; D019009:Proto-Oncogene Proteins c-kit