Mutation analysis of gastrointestinal stromal tumors: increasing significance for risk assessment and effective targeted therapy.
Molecular characterization of gastrointestinal stromal tumors (GISTs) plays an increasing role not only for the patient's prognosis but also for treatment options and in the context of resistance to therapy. Several mutational subtypes in KIT or platelet-derived growth factor receptor-alpha (PDGFRalpha) have been identified to be correlated with a different clinical behavior of GISTs. In KIT exon 11, deletions in the proximal part are associated with a high metastatic risk, whereas duplications in the distal part lead to a less aggressive phenotype. GISTs of the small bowel with a duplication in KIT exon 9 are often high risk tumors. In contrast, PDGFRalpha exon 18 mutated GISTs tend to have a low malignant potential. The authors suggest to include these molecular data together with classical parameters such as mitotic count and tumor size into the risk assessment of GISTs. The first choice for treatment of GISTs is still the surgical resection. In advanced tumors, which cannot be R0 resected, the neoadjuvant treatment with the tyrosine kinase inhibitor imatinib is now well established. Furthermore, an adjuvant treatment of locally R0-resected intermediate and high risk tumors is evaluated in several international clinical trials. For metastatic disease, treatment with imatinib is still the first option, but with new upcoming substances, the molecular characterization of GISTs may become mandatory. Very recently, it has been shown that sunitinib may be especially effective in GISTs with KIT exon 9 mutation, whereas these tumors show only an intermediate response to imatinib. A European Organisation for Research and Treatment of Cancer clinical trial randomizing patients according to their mutational status is under preparation. Secondary resistance to imatinib treatment is increasing, at least partly due to secondary mutations in the tyrosine kinase domain of the KIT receptor. Once a lesion has been shown to carry such a mutation, the local excision may be useful, mean while still responding metastases are further controlled by continuing imatinib. Taken together, the molecular characterization of GISTs turns out to play a central role before and during the treatment with tyrosine kinase inhibitors, which have improved the treatment of GIST patients dramatically.
Wardelmann
Eva
E
Department of Pathology, University of Bonn Medical School, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. eva.wardelmann@ukb.uni-bonn.de
Büttner
Reinhard
R
Merkelbach-Bruse
Sabine
S
Schildhaus
Hans-Ulrich
HU
D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D012307:Risk Factors
D004273:DNA, Neoplasm; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha
Oncogene. 2001 Aug 16;20(36):5054-8
11526490
Ann Surg. 2000 Jan;231(1):51-8
10636102
Am J Surg Pathol. 2006 Apr;30(4):477-89
16625094
Gastroenterology. 2005 Feb;128(2):270-9
15685537
Blood. 2000 Aug 1;96(3):925-32
10910906
Hum Pathol. 2002 May;33(5):466-77
12094371
Am J Surg Pathol. 2005 Jan;29(1):52-68
15613856
Lab Invest. 2006 Jan;86(1):94-100
16258521
Science. 2003 Jan 31;299(5607):708-10
12522257
Hum Pathol. 2002 May;33(5):459-65
12094370
Lancet. 2004 Sep 25-Oct 1;364(9440):1127-34
15451219
Int J Surg Pathol. 2003 Apr;11(2):75-81
12754623
Virchows Arch. 2006 Mar;448(3):306-10
16244869
Clin Cancer Res. 2003 Aug 15;9(9):3329-37
12960119
J Clin Oncol. 2003 Dec 1;21(23):4342-9
14645423
Am J Pathol. 1998 May;152(5):1259-69
9588894
J Clin Oncol. 2005 Aug 10;23(23):5357-64
15928335
Histopathology. 2005 Feb;46(2):166-75
15693889
Science. 1998 Jan 23;279(5350):577-80
9438854
Am J Pathol. 2000 Oct;157(4):1091-5
11021812
J Gastroenterol Hepatol. 2003 Feb;18(2):147-51
12542597
Virchows Arch. 2005 Oct;447(4):772-7
16021514
Int J Cancer. 2003 Oct 10;106(6):887-95
12918066
Eur J Cancer. 2006 May;42(8):1093-103
16624552
Mod Pathol. 2003 Dec;16(12):1257-64
14681327
Clin Cancer Res. 2006 Mar 15;12(6):1743-9
16551858
Mod Pathol. 1998 Aug;11(8):728-34
9720500
Lancet Oncol. 2005 Apr;6(4):249-51
15811621
Semin Diagn Pathol. 2006 May;23(2):70-83
17193820
Am J Pathol. 2004 Jul;165(1):107-13
15215166
Eur J Cancer. 2004 Mar;40(5):689-95
15010069
J Biol Chem. 1999 May 7;274(19):13399-402
10224103
J Clin Oncol. 2005 Sep 1;23(25):6190-8
16135486
Mod Pathol. 2006 Nov;19(11):1480-6
16892012
Mod Pathol. 2000 Oct;13(10):1134-42
11048809
Lab Invest. 1999 Jan;79(1):59-65
9952111
Science. 2001 Aug 3;293(5531):876-80
11423618
Am J Pathol. 2000 Apr;156(4):1157-63
10751339
Am J Surg Pathol. 2004 Jul;28(7):889-94
15223958
J Pathol. 2001 Apr;193(4):505-10
11276010
Cancer Res. 2001 Nov 15;61(22):8118-21
11719439
Blood. 2003 Jul 1;102(1):276-83
12623848
Gastroenterology. 2003 Sep;125(3):660-7
12949711
Hum Pathol. 2002 May;33(5):478-83
12094372
Lab Invest. 2004 Jul;84(7):874-83
15146165
J Mol Diagn. 2004 Aug;6(3):197-204
15269295
Dtsch Med Wochenschr. 2004 Aug 20;129(34-35):1817-20
15314746
J Pharmacol Exp Ther. 2000 Oct;295(1):139-45
10991971
Am J Surg Pathol. 1999 Sep;23(9):1109-18
10478672
Hum Pathol. 1999 Oct;30(10):1213-20
10534170
Int J Surg Pathol. 2005 Oct;13(4):313-8
16273186
Semin Oncol. 2001 Oct;28(5 Suppl 17):19-26
11740803
Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):4089-95
15217944