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

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.

Figure 1

Immunohistochemical staining of LMTK3 with the anti-LMTK3 mouse monoclonal antibody (Santa Cruz Biotechnology). Specimens were processed as described in Materials and Methods. A, LMTK3 protein expression in breast cancer samples were utilized as positive controls (x200; Leica ICC50). Negative controls were performed by omission of the primary antibody (not shown). B, LMTK3 protein expression in adjuvant gastric cancer samples from USC cohort (x200; Leica ICC50).

Figure 2

Schema of the relationship between LMTK3 and ERs in breast cancer and gastric cancer. ERα and ERβ have opposing effects in each other. ERα is predominantly expressed in breast cancer, while ERβ is predominant expression in gastric cancer. LMTK3 phosphorylates ERα and protects it from proteosomal degradation in breast cancer. It is proposed that LMTK3 may phosphorylate ERβ, in a similar mechanism shown for ERα in breast cancer, leading to its activation. Abbreviations; ERα, estrogen receptor α; ERβ, estrogen receptor β; LMTK3, lemur tyrosine kinase-3; P, phosphate.