Use of genetic variants of LMTK3 to predict tumor recurrence in female localized gastric adenocarcinoma

Background: Previous study suggests that high basal Lemur Tyrosine Kinase 3 (LMTK3) expression was associated with advanced stage of primary breast cancers as well as decreased overall and disease-free survival. LMTK3 was also found overexpressed in gastric cancer. Our previous data showed the mutant variants of two single nucleotide polymorphisms (SNPs) in LMTK3 (rs8108419 and rs9989661) were independently associated with reduced time to tumor recurrence (TTR) in colon cancer (CC). We hypothesized that LMTK3 rs808419 and rs9989661 may predict TTR in a cohort of localized gastric cancer patients. Methods: Either blood or FFPE tissue specimens obtained from 137 localized (stage Ib-IV) GA patients (54 females and 83 males) were included in this study. All patients were treated with surgery alone or surgery and adjuvant (radio)-chemotherapy at the University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC), the Los Angeles County/University of Southern California Medical Center, or the Memorial Sloan-Kettering Cancer Center from 1992 to 2008. The median follow-up was 3.3 years. LMTK3 rs8108419 and rs9989661 were determined by PCR-RFLP. The primary endpoint of the study was TTR. Results: LMTK3 rs9989661 was significantly associated with TTR in females GA patients. Female patients with minor C allele (TC or CC) (n=25) of LMTK3 rs9989661 showed significantly longer median TTR=7.0 (95%CI: 2.1-8.3+) years compared to those harboring homozygous TT genotype. (n=28), TTR=1.7 (95%CI: 0.7-7.0+) years.( log-rank p=0.025; univariate analysis). After Cox proportional hazards model adjustment for stage and type of adjuvant chemotherapy, this result remained significant (HR: 0.14, 95%CI: 0.02-0.94, multivariate Wald p value = 0.043 in the dominant model). No significant association was found between TTR and LMTK3 rs9989661 in men and rs8108419 in both genders. Conclusions: This pilot study demonstrating LMTK3 rs9989661 may be potential molecular marker to predict TTR in female localized GA. Larger prospective trials are warranted to confirm these findings, and in vitro and in vivo studies are needed to identify the underlying biological mechanism.