Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site Journal Article

Authors: Antonescu, C. R.; Viale, A.; Sarran, L.; Tschernyavsky, S. J.; Gonen, M.; Segal, N. H.; Maki, R. G.; Socci, N. D.; DeMatteo, R. P.; Besmer, P.
Article Title: Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site
Abstract: Purpose: Gastrointestinal stromal tumors (GISTs) are specific KIT expressing and KIT-signaling driven mesenchymal tumors of the human digestive tract, many of which have KIT-activating mutations. Previous studies have found a relatively homogeneous gene expression profile in GIST, as compared with other histological types of sarcomas. Transcriptional heterogeneity within clinically or molecularly defined subsets of GISTs has not been previously reported. We tested the hypothesis that the gene expression profile in GIST:; might be related to KIT genotype and possibly to other clinicopathological factors. Experimental Design: An HG-U133A Affymetrix chip (22,000 genes) platform was used to determine the variability of gene expression in 28 KIT-expressing GIST samples from 24 patients. A control group of six intra-abdominal leiomyosarcomas was also included for comparison. Statistical analyses (t tests) were performed to identify discriminatory gene lists among various GIST subgroups. The levels of expression of various GIST subsets were also linked to a modified version of the growth factor/KIT signaling pathway to analyze differences at various steps in signal transduction. Results: Genes involved in KIT signaling were differentially expressed among wild-type and mutant GISTs. High gene expression of potential drug targets, such as VEGF, MCSF, and BCL2 in the wild-type group, and Mesothelin in exon 9 GISTs were found. There was a striking difference in gene expression between stomach and small bowel GISTs. This finding was validated in four separate tumors, two gastric and two intestinal, from a patient with familial GIST with a germ-line KIT W557R substitution. Conclusions: GISTs have heterogeneous gene expression depending on KIT genotype and tumor location, which is seen at both the genomic level and the KIT signaling pathway in particular. These findings may explain their variable clinical behavior and response to therapy.
Keywords: immunohistochemistry; signal transduction; vasculotropin; clinical article; human tissue; vascular endothelial growth factor a; unclassified drug; gene mutation; exon; mutation; exons; drug targeting; gene; gastrointestinal stromal tumor; tumor localization; proto-oncogene proteins c-kit; protein bcl 2; gene expression; protein; genetic variability; genotype; cell line, tumor; gastrointestinal neoplasms; gene expression regulation; gene expression regulation, neoplastic; oligonucleotide array sequence analysis; nucleotide sequence; dna mutational analysis; nucleic acid hybridization; leiomyosarcoma; image processing, computer-assisted; intestine, small; stomach; colony stimulating factor 1; mesothelin; receptors, platelet-derived growth factor; growth substances; kit gene; humans; human; priority journal; article
Journal Title: Clinical Cancer Research
Volume: 10
Issue: 10
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2004-05-15
Start Page: 3282
End Page: 3290
Language: English
DOI: 10.1158/1078-0432.ccr-03-0715
PROVIDER: scopus
PUBMED: 15161681
Notes: Clin. Cancer Res. -- Cited By (since 1996):131 -- Export Date: 16 June 2014 -- CODEN: CCREF -- Molecular Sequence Numbers: GENBANK: AB020707, AB028641, AF091352, AF111344, AF116771, AI935720, AK000550, AK027071, BC000196, BC000740, H79306, H95344, L20490, L37882, M19267, M76453, M81104, NM_000426, NM_000586, NM_001904, NM_001924, NM_002649, NM_002975, NM_003282, NM_003505, NM_003573, NM_003752, NM_003753, NM_003802, NM_003919, NM_004988, NM_005657, NM_005823, NM_006121, NM_006516, NM_006851, NM_006932, NM_013982, NM_014061, NM_014575, NM_015722, NM_020994, NM_021098, U13700, U15174, U31466, U49245, X03795, Z23002, Z23022; -- Source: Scopus
Altmetric Score
MSK Authors
  1. Ronald P DeMatteo
    602 DeMatteo
  2. Neil Howard Segal
    107 Segal
  3. Mithat Gonen
    716 Gonen
  4. Cristina R Antonescu
    612 Antonescu
  5. Robert Maki
    211 Maki
  6. Agnes Viale
    205 Viale
  7. Nicholas D Socci
    188 Socci
  8. Peter Besmer
    84 Besmer
  9. Lisa Ann Marie Sarran
    10 Sarran