title: Presence of homozygous KIT exon 11 mutations is strongly associated with malignant clinical behavior in gastrointestinal stromal tumors.
abstract: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of gastrointestinal tract. GISTs range from benign indolent neoplasms to highly malignant sarcomas. Gain-of-function mutations of tyrosine kinase receptors, KIT or PDGFRA, have been identified in most GISTs. In this study, we report 36 GIST patients whose tumors had homozygous KIT exon 11 mutations detected by direct sequencing of PCR products. Loss of heterozygosity in KIT locus and other chromosome 4 loci were documented in majority of these tumors. However, fluorescence in situ hybridization with KIT locus-specific probe and chromosome 4 centromeric enumeration probe showed no evidence of KIT hemizygosity in a majority of analyzed cases. These findings are consistent with duplication of chromosome 4 with KIT mutant allele. Homozygous KIT exon 11 mutations were found in 33 primary tumors and 7 metastatic lesions. In two cases, shift from heterozygosity to homozygosity was documented during tumor progression being present in metastases, but not in primary tumors. Among primary GISTs, there were 16 gastric, 18 intestinal and 2 from unknown locations. An average primary tumor size was 12 cm and average mitotic activity 32/50 HPFs. Out of 32 tumors 29 (90.6%) with complete clinicopathologic data were diagnosed as sarcomas with more than 50% risk of metastatic disease, and 26 of 29 patients with follow-up had metastases or died of disease. An average survival time among pre-imatinib patients, who died of the disease was 33.4 months. Based on these findings, we conclude that presence of homozygous KIT exon 11 mutations is associated with malignant course of disease and should be considered an adverse prognostic marker in GISTs.
authors.affiliation: Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA. lasota@afip.osd.mil
authors.forename: Jerzy
authors.initials: J
authors.lastname: Lasota
authors.forename: Anna Jerzak
authors.initials: AJ
authors.lastname: vel Dobosz
authors.forename: Bartosz
authors.initials: B
authors.lastname: Wasag
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wozniak
authors.forename: Ewa
authors.initials: E
authors.lastname: Kraszewska
authors.forename: Wanda
authors.initials: W
authors.lastname: Michej
authors.forename: Konrad
authors.initials: K
authors.lastname: Ptaszynski
authors.forename: Piotr
authors.initials: P
authors.lastname: Rutkowski
authors.forename: Maarit
authors.initials: M
authors.lastname: Sarlomo-Rikala
authors.forename: Sonja E
authors.initials: SE
authors.lastname: Steigen
authors.forename: Regine
authors.initials: R
authors.lastname: Schneider-Stock
authors.forename: Jerzy
authors.initials: J
authors.lastname: Stachura
authors.forename: Maria
authors.initials: M
authors.lastname: Chosia
authors.forename: Gabriel
authors.initials: G
authors.lastname: Ogun
authors.forename: Wlodzimierz
authors.initials: W
authors.lastname: Ruka
authors.forename: Janusz A
authors.initials: JA
authors.lastname: Siedlecki
authors.forename: Markku
authors.initials: M
authors.lastname: Miettinen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D005091:Exons; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006720:Homozygote; D006801:Humans; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics*; D010879:Piperazines / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use; D018570:Risk Assessment
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit