This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Antonescu, C. R. Articles by Besmer, P. Search for Related Content PubMed PubMed Citation Articles by Antonescu, C. R. Articles by Besmer, P.

Association of KIT Exon 9 Mutations with Nongastric Primary Site and Aggressive Behavior

KIT Mutation Analysis and Clinical Correlates of 120 Gastrointestinal Stromal Tumors¹

Departments of Pathology [C. R. A., L. S., S. J. T., J. M. W., M. L.], Surgery [M. F. B., R. P. D.], Medicine [R. M.], Human Genetics [M. R.], Biostatistics and Epidemiology [E. R.] of Memorial Sloan-Kettering Cancer Center, and Molecular Biology Program, Sloan-Kettering Institute [G. S., P. B.], New York, New York, 10021

Purpose: Activating mutations of the KIT juxtamembrane region are the most common genetic events in gastrointestinal stromal tumors (GISTs) and have been noted as independent prognostic factors. The impact of KIT mutation in other regions, such as the extracellular or kinase domains, is not well-defined and fewer than 30 cases have been published to date.

Experimental Design: One hundred twenty GISTs, confirmed by KIT immunoreactivity, were evaluated for the presence of KIT exon 9, 11, 13, and 17 mutations. The relation between the presence/type of KIT mutation and clinicopathological factors was analyzed using Fisher’s exact test and log-rank test.

Results: Forty-four % of the tumors were located in the stomach, 47% in the small bowel, 6% in the rectum, and 3% in the retroperitoneum. Overall, KIT mutations were detected in 78% of patients as follows: 67% in exon 11, 11% in exon 9, and none in exon 13 or 17. The types of KIT exon 11 mutations were heterogeneous and clustered in the classic "hot spot" at the 5' end of exon 11. Seven % of cases showed internal tandem duplications (ITD) at the 3' end of exon 11, in a region that we designate as a second hot spot for KIT mutations. Interestingly, these cases were associated with: female predominance, stomach location, occurrence in older patients, and favorable outcome. There were significant associations between exon 9 mutations and large tumor size (P < 0.001) and extragastric location (P = 0.02). Ten of these 13 patients with more than 1-year follow-up have developed recurrent disease.

Conclusions: Most KIT-expressing GISTs show KIT mutations that are preferentially located within the classic hot spot of exon 11. In addition, we found an association between a second hot spot at the 3'end of exon 11, characterized by ITDs, and a subgroup of clinically indolent gastric GISTs in older females. KIT exon 9 mutations seem to define a distinct subset of GISTs, located predominantly in the small bowel and associated with an unfavorable clinical course.

This article has been cited by other articles:

				N. P. Agaram, M. P. Laquaglia, B. Ustun, T. Guo, G. C. Wong, N. D. Socci, R. G. Maki, R. P. DeMatteo, P. Besmer, and C. R. Antonescu Molecular Characterization of Pediatric Gastrointestinal Stromal Tumors Clin. Cancer Res., May 15, 2008; 14(10): 3204 - 3215. [Abstract] [Full Text] [PDF]

				S. Tabone-Eglinger, F. Subra, H. El Sayadi, L. Alberti, E. Tabone, J.-P. Michot, N. Theou-Anton, A. Lemoine, J.-Y. Blay, and J.-F. Emile KIT Mutations Induce Intracellular Retention and Activation of an Immature Form of the KIT Protein in Gastrointestinal Stromal Tumors Clin. Cancer Res., April 15, 2008; 14(8): 2285 - 2294. [Abstract] [Full Text] [PDF]

				C. Braconi, R. Bracci, I. Bearzi, F. Bianchi, A. Costagliola, R. Catalani, A. Mandolesi, R. Ranaldi, E. Galizia, S. Cascinu, et al. KIT and PDGFR{alpha} mutations in 104 patients with gastrointestinal stromal tumors (GISTs): a population-based study Ann. Onc., April 1, 2008; 19(4): 706 - 710. [Abstract] [Full Text] [PDF]

				Y. Suehara, T. Kondo, K. Seki, T. Shibata, K. Fujii, M. Gotoh, T. Hasegawa, Y. Shimada, M. Sasako, T. Shimoda, et al. Pfetin as a Prognostic Biomarker of Gastrointestinal Stromal Tumors Revealed by Proteomics Clin. Cancer Res., March 15, 2008; 14(6): 1707 - 1717. [Abstract] [Full Text] [PDF]

				C. P. Raut and R. P. DeMatteo Prognostic Factors for Primary GIST: Prime Time for Personalized Therapy? Ann. Surg. Oncol., January 1, 2008; 15(1): 4 - 6. [Full Text] [PDF]

				N. P. Agaram, P. Besmer, G. C. Wong, T. Guo, N. D. Socci, R. G. Maki, D. DeSantis, M. F. Brennan, S. Singer, R. P. DeMatteo, et al. Pathologic and Molecular Heterogeneity in Imatinib-Stable or Imatinib-Responsive Gastrointestinal Stromal Tumors Clin. Cancer Res., January 1, 2007; 13(1): 170 - 181. [Abstract] [Full Text] [PDF]

				H.-Y. Huang, W.-W. Huang, C.-N. Lin, H.-L. Eng, S.-H. Li, C.-F. Li, D. Lu, S.-C. Yu, and C.-Y. Hsiung Immunohistochemical Expression of p16INK4A, Ki-67, and Mcm2 Proteins in Gastrointestinal Stromal Tumors: Prognostic Implications and Correlations with Risk Stratification of NIH Consensus Criteria Ann. Surg. Oncol., December 1, 2006; 13(12): 1633 - 1644. [Abstract] [Full Text] [PDF]

				S. Corbacioglu, M. Kilic, M.-A. Westhoff, D. Reinhardt, S. Fulda, and K.-M. Debatin Newly identified c-KIT receptor tyrosine kinase ITD in childhood AML induces ligand-independent growth and is responsive to a synergistic effect of imatinib and rapamycin Blood, November 15, 2006; 108(10): 3504 - 3513. [Abstract] [Full Text] [PDF]

				F. Rossi, I. Ehlers, V. Agosti, N. D. Socci, A. Viale, G. Sommer, Y. Yozgat, K. Manova, C. R. Antonescu, and P. Besmer Oncogenic Kit signaling and therapeutic intervention in a mouse model of gastrointestinal stromal tumor PNAS, August 22, 2006; 103(34): 12843 - 12848. [Abstract] [Full Text] [PDF]

				L Tornillo and L M Terracciano An update on molecular genetics of gastrointestinal stromal tumours. J. Clin. Pathol., June 1, 2006; 59(6): 557 - 563. [Abstract] [Full Text] [PDF]

				J. Cammenga, S. Horn, U. Bergholz, G. Sommer, P. Besmer, W. Fiedler, and C. Stocking Extracellular KIT receptor mutants, commonly found in core binding factor AML, are constitutively active and respond to imatinib mesylate Blood, December 1, 2005; 106(12): 3958 - 3961. [Abstract] [Full Text] [PDF]

				N. Theou, S. Gil, A. Devocelle, C. Julie, A. Lavergne-Slove, A. Beauchet, P. Callard, R. Farinotti, A. Le Cesne, A. Lemoine, et al. Multidrug Resistance Proteins in Gastrointestinal Stromal Tumors: Site-Dependent Expression and Initial Response to Imatinib Clin. Cancer Res., November 1, 2005; 11(21): 7593 - 7598. [Abstract] [Full Text] [PDF]

				C. L. Corless, A. Schroeder, D. Griffith, A. Town, L. McGreevey, P. Harrell, S. Shiraga, T. Bainbridge, J. Morich, and M. C. Heinrich PDGFRA Mutations in Gastrointestinal Stromal Tumors: Frequency, Spectrum and In Vitro Sensitivity to Imatinib J. Clin. Oncol., August 10, 2005; 23(23): 5357 - 5364. [Abstract] [Full Text] [PDF]

				M B Loughrey, C Mitchell, G B Mann, M Michael, and P M Waring Gastrointestinal stromal tumour treated with neoadjuvant imatinib J. Clin. Pathol., July 1, 2005; 58(7): 779 - 781. [Abstract] [Full Text] [PDF]

				S. L. Blair, W. B. Al-Refaie, J. Wang-Rodriguez, C. Behling, M.-W. Ali, and A. R. Moossa Gastrointestinal Stromal Tumors Express ras Oncogene: A Potential Role for Diagnosis and Treatment Arch Surg, June 1, 2005; 140(6): 543 - 548. [Abstract] [Full Text] [PDF]

				R Penzel, S Aulmann, M Moock, M Schwarzbach, R J Rieker, and G Mechtersheimer The location of KIT and PDGFRA gene mutations in gastrointestinal stromal tumours is site and phenotype associated J. Clin. Pathol., June 1, 2005; 58(6): 634 - 639. [Abstract] [Full Text] [PDF]

				C. R. Antonescu, P. Besmer, T. Guo, K. Arkun, G. Hom, B. Koryotowski, M. A. Leversha, P. D. Jeffrey, D. Desantis, S. Singer, et al. Acquired Resistance to Imatinib in Gastrointestinal Stromal Tumor Occurs Through Secondary Gene Mutation Clin. Cancer Res., June 1, 2005; 11(11): 4182 - 4190. [Abstract] [Full Text] [PDF]

				C. L. Corless, L. McGreevey, A. Town, A. Schroeder, T. Bainbridge, P. Harrell, J. A. Fletcher, and M. C. Heinrich KIT Gene Deletions at the Intron 10-Exon 11 Boundary in GI Stromal Tumors J. Mol. Diagn., November 1, 2004; 6(4): 366 - 370. [Abstract] [Full Text] [PDF]

				C. L. Corless, J. A. Fletcher, and M. C. Heinrich Biology of Gastrointestinal Stromal Tumors J. Clin. Oncol., September 15, 2004; 22(18): 3813 - 3825. [Abstract] [Full Text] [PDF]

				C. R. Antonescu, A. Viale, L. Sarran, S. J. Tschernyavsky, M. Gonen, N. H. Segal, R. G. Maki, N. D. Socci, R. P. DeMatteo, and P. Besmer Gene Expression in Gastrointestinal Stromal Tumors Is Distinguished by KIT Genotype and Anatomic Site Clin. Cancer Res., May 15, 2004; 10(10): 3282 - 3290. [Abstract] [Full Text] [PDF]