TY - JOUR
T1 - Prognostic role of lemur tyrosine kinase-3 germline polymorphisms in adjuvant gastric cancer in Japan and the United States
AU - Wakatsuki, Takeru
AU - LaBonte, Melissa J
AU - Bohanes, Pierre O
AU - Zhang, Wu
AU - Yang, Dongyun
AU - Azuma, Mizutomo
AU - Barzi, Afsaneh
AU - Ning, Yan
AU - Loupakis, Fotios
AU - Saadat, Siamak
AU - Volz, Nico
AU - Stintzing, Sebastian
AU - El-Khoueiry, Rita
AU - Koizumi, Wasaburo
AU - Watanabe, Masahiko
AU - Shah, Manish
AU - Stebbing, Justin
AU - Giamas, Georgios
AU - Lenz, Heinz-Josef
AU - LaBonte Wilson, Melissa
N1 - ©2013 AACR.
PY - 2013/10
Y1 - 2013/10
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Disease-Free Survival
KW - Estrogen Receptor alpha
KW - Female
KW - Genetic Association Studies
KW - Humans
KW - Japan
KW - Male
KW - Membrane Proteins
KW - Middle Aged
KW - Prognosis
KW - Protein-Serine-Threonine Kinases
KW - Stomach Neoplasms
KW - Tumor Markers, Biological
KW - United States
U2 - 10.1158/1535-7163.MCT-12-1134
DO - 10.1158/1535-7163.MCT-12-1134
M3 - Article
C2 - 23918832
SN - 1535-7163
VL - 12
SP - 2261
EP - 2272
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 10
ER -