Somatic KIT (c-Kit) and PDGFRA Mutation Analysis
Gastrointestinal stromal tumors (GIST), Melanoma, Systemic Mastocytosis

The KIT gene encodes the human homolog of the proto-oncogene c-Kit. Activating mutations of KIT have been reported for 75%-85% of gastrointestinal stromal tumors (GIST), most often in exons 9 and 111.  Tumors with mutations in exon 9 of KIT gene are associated with significantly shorter progression-free survival and overall survival compared to tumors with mutations in exon 112.  However, tumors expressing an exon 9 mutation in c-kit had improved progression-free survival when given a high dose regimen of imatinib, compared to those with an exon 9 mutation who received regular dosing2.   Secondary mutations in exons 13, 14, 17, and 18 have also been associated with acquired resistance after imatinib treatment.

Mutations in exon 12, 14 and 18 of the PDGFRA gene may also help predict responsiveness to imatinib and are estimated to be present in 5%-7% GISTs1.  Specifically, PDGFRA D842V mutation has been associated with resistance to imatinib1, whereas other mutations of PDGFRA have been associated with imatinib sensitivity1.

KIT mutations have also been reported in melanomas.  Particularly, ~15% of acral and ~20% of mucosal melanomas are estimated to have a KIT mutation.  Case reports and multiple phase II clinical trials have documented dramatic responses to imatinib in melanoma patients with KIT mutations3-8. For patients with aggressive systemic mastocytosis (SM), the D816V activating mutation of KIT has been reported in greater than 90% of cases and is included as a minor diagnostic criterion by the World Health Organization9. The D816V mutation has been associated with poor prognosis in SM and resistance to imatinib10. Imatinib is FDA approved as a therapeutic for aggressive systemic mastocytosis of unknown or negative status for the D816V mutation.

To open a printable assay summary in a new window, click the link below.

C-Kit-NGS and PDGFRA-NGS (Targeted analysis for 136 cancer hotspot mutations in exons 2, 9, 11, 13, 14, 17, and 18 of the KIT gene, 25 cancer hotspot mutations in the PDGFRA gene by next generation sequencing.)
(in portable document format (pdf) which requires Adobe® Acrobat® Reader™ to view or print; download latest version free)

  1. Heinrich et al. (2008) J. Clin. Onc. 26 :5360-5367
  2. Debiec-Rychter et al. (2006) Eur. J. Can. 42:1093-1103
  3. Lutzky et al. (2008) Pig. Cell. Melan. Res 21:492-3
  4. Quintas-Cardama et al. (2008) Nat. Clin. Pract. Oncol. 5:737-740
  5. Hodi et al. (2008) J. Clin. Oncol. 26 :2046-2051
  6. Guo J, et al. J Clin Oncol. 2011 Jul 20;29(21):2904-9
  7. Carvajal RD, et al. JAMA. 2011 Jun 8;305(22):2327-34
  8. Hodi FS, et al. J Clin Oncol. 2013 Sep 10;31(26):3182-90
  9. Johnson MR, et al. Mod Pathol. 2009 Jan;22(1):50-7
  10. Verstovsek S. Eur J Haematol. 2013 Feb;90(2):89-98.