Modern Pathology

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c-kit Mutations in Gastrointestinal Stromal Tumors Occur Preferentially in the Spindle Rather Than in the Epithelioid Cell Variant

Eva Wardelmann, Iris Neidt, Erhard Bierhoff, Nicola Speidel, Christoph Manegold, Hans-Peter Fischer, Ulrich Pfeifer and Torsten Pietsch

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FIGURE 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

FIGURE 1.

A–H, morphological and immunohistochemical features of a spindle cell (A, C, E, G) and an epithelioid (B, D, F, H) gastrointestinal stromal tumor. A, the spindle cells are arranged in storiform and herringbone patterns and have blunt-ended nuclei. B, the epithelioid cells are arranged in organoid clusters and have round nuclei and abundant cytoplasm. Both subtypes express CD34 (C and D), bcl-2 (E and F), and the Kit receptor (G and H). Magnifications, 240times.

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FIGURE 2.

Predicted amino acid sequences in Exons 9, 11, and 13. Numbers shown above the wild-type amino acid sequence indicate codons. Point mutations and changed amino acids are indicated in an empty square, insertions in a black square. Deleted amino acids are shown by dashes (—).

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FIGURE 3.

Single-strand conformational polymorphism analysis and sequence of Exon 11 in GISTs. Case 1 carries a 3-bp deletion corresponding to the deletion of Asp-579. The point mutation in Case 6 leads to the replacement of Val-559 by Asp. In Case 7, Trp-557 and Lys-558 are deleted; in Case 11, a deletion of 9 bp and concurrent insertion of 3 bp leads to the replacement of Gln-556, Trp-557, Lys-558, and Val-559 by His and Thr. In Case 10, two amino acids (Gln and Leu) are inserted at Codon 577.

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FIGURE 4.

Single-strand conformational polymorphism analysis and sequence analysis of Exons 9 and 13 in gastrointestinal stromal tumors. Case 41: Exon 9 shows a duplication of six nucleotides encoding for Ala-502 and Tyr-503. Case 47: In Exon 13, the mutation of A to G leads to the substitution of Lys-642 by Glu.

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FIGURE 5.

A review of mutations in Exon 11 in 150 cases published until now. On the right side, number of cases per mutation is indicated; under ref., authors are symbolized as follows: *Ernst et al. (4), +Hirota et al. (9), <Lasota et al. (14), =Miettinen et al. (24), ⁁Moskaluk et al. (28), Ñakahara et al. 1998 (29), $Sakurai et al. 1999 (31), §Taniguchi et al. 1999 (28), and >Wardelmann et al. 2002. The predominant type of mutation is a simple deletion of 1 to 15 amino acids.

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FIGURE 6.

Frequency of mutations per codon published until now (including our own cases). Each square symbolizes one case with an amino acid change or loss in this codon. A clustering of mutations is observed in the region between Codons 553 and 561 (128/150 cases, i.e., 85.3%).

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