DNA amplification in human gastric carcinomas

Mor, Orna; Ranzani, Guglielmina Nadia; Ravia, Yehoshua; Rotman, Galit; Gutman, Mordechai; Manor, A; Amadori, Dino; Houldsworth, Jane; Hollstein, Monica; Schwab, Manfred; Shiloh, Yosef

doi:10.1016/0165-4608(93)90217-a

Cited by 34 publications

(28 citation statements)

References 15 publications

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“…In line with the notion that FGFR2 is a driver oncogene when its locus is aberrantly amplifi ed, we selected human primary gastric tumors for the presence of FGFR2 copy number alterations and confi rmed them to be exquisitely responsive to the selective FGFR inhibitor NVP-BGJ398, whereas models with normal FGFR2 DNA copy number were insensitive to the drug (data not shown). In agreement with previous analyses of FGFR2 copy number alterations conducted by FISH ( 8,9 ) or Southern blot ( 11 ), we have found high level amplifi cations (copy number > 10) of FGFR2 by means of PCR in 5% of gastric tumors among a total of 147 specimens as well as in 1 of 22 esophageal tumors, which has not previously been reported, thus providing additional new opportunities for the therapeutic application of an FGFR inhibitor. Interestingly, we also identifi ed FGFR3 copy number gains in 3 of the bladder cancer cell lines that were inhibited by NVP-BGJ398 (log 2 ratio 1 for RT112 and RT112/84 and log 2 ratio 0.94 for RT4), which may account for the significantly high FGFR3 transcript expression in these cell lines (Supplementary Fig.…”

Section: Research Articlesupporting

confidence: 78%

“…Furthermore, high-resolution gene copy number analysis in lung cancer revealed FGFR1 amplifi cation preferentially in the squamous subtype ( 4,5 ). FGFR2 copy number gains, albeit with a low incidence, were reported in breast tumors ( 6,7 ) and in gastric cancer in particular in poorly differentiated adenocarcinomas (8)(9)(10)(11). Among the ligands, FGF19 , located in the common 11q13 amplicon, was recently identifi ed to be a driver gene in liver cancer in cooperation with its neighboring gene, cyclin D1 ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

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FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor

et al. 2012

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Patient stratifi cation biomarkers that enable the translation of cancer genetic knowledge into clinical use are essential for the successful and rapid development of emerging targeted anticancer therapeutics. Here, we describe the identifi cation of patient stratifi cation biomarkers for NVP-BGJ398, a novel and selective fi broblast growth factor receptor (FGFR) inhibitor. By intersecting genome-wide gene expression and genomic alteration data with cell line-sensitivity data across an annotated collection of cancer cell lines called the Cancer Cell Line Encyclopedia, we show that genetic alterations for FGFR family members predict for sensitivity to NVP-BGJ398. For the fi rst time, we report oncogenic FGFR1 amplifi cation in osteosarcoma as a potential patient selection biomarker. Furthermore, we show that cancer cell lines harboring FGF19 copy number gain at the 11q13 amplicon are sensitive to NVP-BGJ398 only when concomitant expression of β-klotho occurs. Thus, our fi ndings provide the rationale for the clinical development of FGFR inhibitors in selected patients with cancer harboring tumors with the identifi ed predictors of sensitivity. SIGNIFICANCE:The success of a personalized medicine approach using targeted therapies ultimately depends on being able to identify the patients who will benefi t the most from any given drug. To this end, we have integrated the molecular profi les for more than 500 cancer cell lines with sensitivity data for the novel anticancer drug NVP-BGJ398 and showed that FGFR genetic alterations are the most significant predictors for sensitivity. This work has ultimately endorsed the incorporation of specifi c patient selection biomakers in the clinical trials for NVP-BGJ398. Cancer Discov; 2(12); 1118-33.

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Section: Research Articlesupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor

et al. 2012

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“…For this analysis we utilized a DNA hybridization probe encoding a portion of the extracellular domain common to both the FGFR2/Bek and KGFR receptors. In RNA isolated from cell lines derived from gastric and colon carcinomas, FGFR2/KGFR mRNA was expressed at very high levels in KATO-III and SNU-16 (Figure 4a), consistent with the ampli®cation of the FGFR2 gene in these tumor cells (Hattori et al, 1990;Mor et al, 1993). Other gastric and colon carcinoma cells, with the exception of HA117, showed expression of FGFR2/KGFR similar to that of B5/589, a normal human mammary epithelial cell line which expresses KGFR.…”

Section: Expression Of Fgfrs In Human Tumor Cell Linessupporting

confidence: 62%

Ligand-independent activation of fibroblast growth factor receptor-2 by carboxyl terminal alterations

et al. 1997

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To assess the e ect(s) of the C-terminal domain on FGFR2 function, we engineered a series of mutant FGFR2 cDNAs encoding deletions in the C-terminus of the receptor and compared their growth properties in NIH3T3 ®broblasts. In contrast to FGFR2-WT, receptors with C-terminal truncations induced ligandindependent transformation of NIH3T3 cells and transfectants expressing these mutant receptors eciently formed colonies in semisolid medium. Introduction of point mutations (Y to F) into the C-terminus of FGFR2 at positions 813, 784 or 780 revealed that these mutant receptors also displayed activities similar to that of C-terminally truncated receptors. C-terminally altered FGF receptors did not show an increase in the basal level of receptor phosphorylation compared to that of FGFR2-WT suggesting that elevated receptor phosphorylation does not underlie the transforming activity of these receptors. Interestingly, expression of transforming FGFR2 derivatives, unlike H-Ras transformed cells, did not result in the activation of the mitogen-activated protein kinases (MAPKs), p42/ERK2 and p44/ERK1, indicating that this pathway is not constitutively active in FGFR2-transformed cells. Finally, we report the overexpression of FGFR2 mRNA and protein in several human tumor cell lines suggesting activation of the receptor in these tumors.

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“…6,7 A number of alterations, including gene amplification, chromosomal translocation, insertional mutations, altered transcriptional elongation rates, and a prolonged mRNA half-life, 7 affect MYC expression in various neoplasms. Gastric carcinoma studies using Southern blot [8][9][10] or comparative genetic hybridization (CGH) 11 revealed that Myc was amplified in a small fraction of gastric cancers. However, there have been very few comprehensive studies simultaneously examining protein expression and gene amplification of Myc in gastric cancer.…”

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confidence: 99%

Non-incidental coamplification of Myc and ERBB2, and Myc and EGFR, in gastric adenocarcinomas

et al. 2007

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This study was conducted to assess the frequencies of protein overexpression and gene amplification of Myc and to identify the mechanisms of Myc gene amplification, especially with regards to its possible coamplification with ERBB2 or EGFR in gastric adenocarcinomas. By immunohistochemical analysis of a total of 300 formalin-fixed and paraffin-embedded gastric adenocarcinomas, the nuclear overexpression of MYC was found in 47 tumors (16%). A fluorescence in situ hybridization (FISH) analysis revealed that nine (19%) of the 47 tumors with protein overexpression had cancer cells with high levels of Myc amplification, whereas only seven (6%) of the 122 tumors without protein overexpression showed high-level Myc gene amplification. Such Myc amplification was significantly correlated with positive nuclear protein overexpression. The coamplification of ERBB2 or EGFR with Myc that was found in six and four cases, respectively, is believed to be nonincidental because those frequencies were significantly higher than the individual frequencies observed for the total examined cases (ERBB2: 7%; EGFR: 4%). The high levels of gene amplification of these three genes, as visualized by FISH, could be broadly classified into two typical types, namely, 'multiple scattered signals' and 'large clustered signals'. Using two-color FISH, the coexistence of coamplified Myc and ERBB2, or Myc and EGFR, within single nuclei in various combinations of amplification types and copy numbers, could be ascertained in all nine cases, including one in which the synchronous 'multiple scattered type' coamplification of Myc and ERBB2 was observed. In three tumors, coamplification of ERBB2 and EGFR was found; however, ERBB2-and EGFR-amplified cell populations were separate and mutually exclusive. We propose that the nonincidental coamplification of Myc and either ERBB2 or EGFR occurred through translocation and subsequent rearrangement.

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DNA amplification in human gastric carcinomas

Cited by 34 publications

References 15 publications

FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor

FGFR Genetic Alterations Predict for Sensitivity to NVP-BGJ398, a Selective Pan-FGFR Inhibitor

Ligand-independent activation of fibroblast growth factor receptor-2 by carboxyl terminal alterations

Non-incidental coamplification of Myc and ERBB2, and Myc and EGFR, in gastric adenocarcinomas

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