Prognostic role of lemur tyrosine kinase-3 germline polymorphisms in adjuvant gastric cancer in Japan and the United States

Takeru Wakatsuki, Melissa J LaBonte, Pierre O Bohanes, Wu Zhang, Dongyun Yang, Mizutomo Azuma, Afsaneh Barzi, Yan Ning, Fotios Loupakis, Siamak Saadat, Nico Volz, Sebastian Stintzing, Rita El-Khoueiry, Wasaburo Koizumi, Masahiko Watanabe, Manish Shah, Justin Stebbing, Georgios Giamas, Heinz-Josef Lenz, Melissa LaBonte Wilson

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Abstract

Lemur tyrosine kinase-3 (LMTK3) was recently identified as an estrogen receptor (ER)-α modulator related to endocrine therapy resistance, and its polymorphisms rs9989661 (T>C) T/T genotype and rs8108419 (G>A) G/G or A/G genotype predicted improved outcomes in breast cancer. Because different predominant ER distributions link to breast and gastric cancer and little is known of the prognostic role of LMTK3 in gastric cancer, this study was carried out to clarify the prognostic role of these polymorphisms in gastric cancer. One-hundred and sixty-nine Japanese and 137 U.S. patients with localized gastric adenocarcinoma were enrolled. Genomic DNA was extracted from blood or tissue, and all samples were analyzed by PCR-based direct DNA sequencing. Overall, these polymorphisms were not associated with survival in both cohorts. When gender was considered, in multivariate analysis, harboring rs9989661 T/T genotype was associated with disease-free survival [HR, 4.37; 95% confidence interval (CI), 2.08-9.18; P < 0.0001] and overall survival (OS; HR, 3.69; 95% CI, 1.65-8.24; P = 0.0014) in the Japanese males and time to recurrence (HR, 7.29; 95% CI, 1.07-49.80; P = 0.043) in the U.S. females. Meanwhile, harboring rs8108419 G/G genotype was associated with OS in the Japanese females (HR, 3.04; 95% CI, 1.08-8.56; P = 0.035) and the U.S. males (HR, 3.39; 95% CI, 1.31-8.80; P = 0.012). The prognostic role of these polymorphisms may be negative in gastric cancer. These findings suggest that the estrogen pathway may play a prognostic role in patients with gastric cancer but this may be dependent on the regional differences both in physiology and genetic alterations of gastric cancer.

Original languageEnglish
Pages (from-to)2261-72
Number of pages12
JournalMolecular Cancer Therapeutics
Volume12
Issue number10
DOIs
Publication statusPublished - Oct 2013

Bibliographical note

©2013 AACR.

Keywords

  • Adult
  • Aged
  • Disease-Free Survival
  • Estrogen Receptor alpha
  • Female
  • Genetic Association Studies
  • Humans
  • Japan
  • Male
  • Membrane Proteins
  • Middle Aged
  • Prognosis
  • Protein-Serine-Threonine Kinases
  • Stomach Neoplasms
  • Tumor Markers, Biological
  • United States

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    Wakatsuki, T., LaBonte, M. J., Bohanes, P. O., Zhang, W., Yang, D., Azuma, M., Barzi, A., Ning, Y., Loupakis, F., Saadat, S., Volz, N., Stintzing, S., El-Khoueiry, R., Koizumi, W., Watanabe, M., Shah, M., Stebbing, J., Giamas, G., Lenz, H-J., & LaBonte Wilson, M. (2013). Prognostic role of lemur tyrosine kinase-3 germline polymorphisms in adjuvant gastric cancer in Japan and the United States. Molecular Cancer Therapeutics, 12(10), 2261-72. https://doi.org/10.1158/1535-7163.MCT-12-1134