title: Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene.
abstract: Thyroid cancer is the most common endocrine cancer, and targeted approaches to treat it pose considerable interest. In this study, we report the discovery of ALK gene mutations in thyroid cancer that may rationalize clinical evaluation of anaplastic lymphoma kinase (ALK) inhibitors in this setting. In undifferentiated anaplastic thyroid cancer (ATC), we identified two novel point mutations, C3592T and G3602A, in exon 23 of the ALK gene, with a prevalence of 11.11%, but found no mutations in the matched normal tissues or in well-differentiated thyroid cancers. These two mutations, resulting in L1198F and G1201E amino acid changes, respectively, both reside within the ALK tyrosine kinase domain where they dramatically increased tyrosine kinase activities. Similarly, these mutations heightened the ability of ALK to activate the phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein (MAP) kinase pathways in established mouse cells. Further investigations showed that these two ALK mutants strongly promoted cell focus formation, anchorage-independent growth, and cell invasion. Similar oncogenic properties were observed in the neuroblastoma-associated ALK mutants K1062M and F1174L but not in wild-type ALK. Overall, our results reveal two novel gain-of-function mutations of ALK in certain ATCs, and they suggest efforts to clinically evaluate the use of ALK kinase inhibitors to treat patients who harbor ATCs with these mutations.
authors: Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors: Avaniyapuram Kannan
authors: AK
authors: Murugan
authors: Mingzhao
authors: M
authors: Xing
references: Oncogene. 2003 Jan 30;22(4):517-27
references: 12555065
references: Am J Pathol. 2005 Jul;167(1):213-22
references: 15972965
references: Genes Chromosomes Cancer. 2003 May;37(1):98-105
references: 12661011
references: Oncogene. 2004 Aug 12;23(36):6071-82
references: 15208656
references: Cancer Lett. 2010 Dec 28;299(2):81-94
references: 20934803
references: J Clin Endocrinol Metab. 2008 Aug;93(8):3106-16
references: 18492751
references: Biochem J. 2008 Dec 1;416(2):153-9
references: 18990089
references: J Clin Endocrinol Metab. 2008 Nov;93(11):4331-41
references: 18713817
references: Mol Cell Endocrinol. 2010 May 28;321(1):20-8
references: 19897009
references: Thyroid. 2010 Jul;20(7):697-706
references: 20578891
references: Biochem J. 2009 May 27;420(3):345-61
references: 19459784
references: Science. 1994 Mar 4;263(5151):1281-4
references: 8122112
references: Oncogene. 2008 May 15;27(22):3194-200
references: 18071309
references: N Engl J Med. 2010 Oct 28;363(18):1693-703
references: 20979469
references: Eur J Cancer. 2010 Sep;46(13):2357-68
references: 20451371
references: Mod Pathol. 2008 May;21 Suppl 2:S37-43
references: 18437172
references: FASEB J. 1997 Oct;11(12):965-72
references: 9337149
references: Nature. 2008 Oct 16;455(7215):930-5
references: 18724359
references: Nature. 2008 Oct 16;455(7215):975-8
references: 18923525
references: Nature. 2008 Oct 16;455(7215):971-4
references: 18923524
references: N Engl J Med. 2010 Oct 28;363(18):1727-33
references: 20979472
references: Int J Oncol. 2008 Jan;32(1):101-11
references: 18097548
references: Int J Cancer. 2002 Jul 1;100(1):49-56
references: 12115586
references: Nat Rev Cancer. 2008 Jan;8(1):11-23
references: 18097461
references: Nature. 2008 Oct 16;455(7215):967-70
references: 18923523
references: Biochem J. 2010 Sep 15;430(3):425-37
references: 20632993
references: Nature. 2007 Aug 2;448(7153):561-6
references: 17625570
references: Cell Cycle. 2009 Jul 1;8(13):2122-4
references: 19411838
references: Endocrinol Metab Clin North Am. 2008 Jun;37(2):525-38, xi
references: 18502341