Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene

Avaniyapuram Kannan Murugan, Michael Mingzhao Xing

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)4403-4411
Number of pages9
JournalCancer Research
Volume71
Issue number13
DOIs
StatePublished - Jul 1 2011

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Mutation
Genes
Thyroid Neoplasms
Protein-Tyrosine Kinases
Endocrine Gland Neoplasms
anaplastic lymphoma kinase
Anaplastic Thyroid Carcinoma
Phosphatidylinositol 3-Kinase
Mitogen-Activated Protein Kinases
Neuroblastoma
Point Mutation
Exons
Phosphotransferases
Amino Acids
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene. / Murugan, Avaniyapuram Kannan; Xing, Michael Mingzhao.

In: Cancer Research, Vol. 71, No. 13, 01.07.2011, p. 4403-4411.

Research output: Contribution to journalArticle

Murugan, Avaniyapuram Kannan ; Xing, Michael Mingzhao. / Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene. In: Cancer Research. 2011 ; Vol. 71, No. 13. pp. 4403-4411.
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