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Association of gender-related tumor recurrence with a polymorphic variant of LMTK3 in stage II and III colon cancer
conference contribution
posted on 2023-06-10, 01:44 authored by Wu Zhang, Armin Gerger, Melissa Janae Labonte, Dongyun Yang, Pierre Oliver Bohanes, Yan Ning, Thomas Winder, Peter M D Wilson, Leonor Benhaim, Rita El-Khoueiry, Anthony B El-Khoueiry, Syma Iqbal, Georgios GiamasGeorgios Giamas, Justin Stebbing, Heinz-Josef LenzBackground: Recent evidence suggests that Lemur Tyrosine Kinase 3 (LMTK3) activates estrogen receptor alpha (ERa) transcriptional activity in breast cancer. The mutant variants of two single nucleotide polymorphisms (SNPs) in LMTK3 (rs8108419 and rs9989661) were independently associated with reduced time to tumor recurrence (TTR), suggesting these SNPs were functionally significant. In colon cancer (CC), ERß expression has been shown to be predominant with low levels of ERa also expressed. ERa stimulates cell proliferation, while ERß negatively regulates the estrogen-dependent activity of ERa. Based on these previous findings, we hypothesized that LMTK3 rs808419 and rs9989661 may predict TTR in stage II and III CC. Methods: Either blood or FFPE tissue specimens were obtained from 234 patients (107 females and 127 males; median age 59 yrs (range 22–78 yrs)) with stage II (105 pts) or III (129 pts) CC at the University of Southern California. The median follow-up was 4.4 years. LMTK3 rs8108419 and rs9989661 were determined by PCR-RFLP. The primary endpoint of the study was TTR. This study was conducted adhering to the reporting recommendations for tumor marker prognostic studies (REMARK). Results: The minor allele of LMTK3 rs9989661 (C; frequency=30.5%) showed significantly longer median TTR (5.9 vs 12.2+ yrs; HR: 0.41, 95%CI: 0.15-1.18, log-rank p=0.086; univariate analysis) in female CC patients. After Cox proportional hazards model adjustment for stage and type of adjuvant chemotherapy, this result remained significant (HR: 0.25, 95%CI: 0.077-0.778, Wald test p=0.017). No significant association was found between TTR and LMTK3 rs9989661 in men and rs8108419 in both genders. Conclusions: This is the first report demonstrating LMTK3 rs9989661 associations with gender-related TTR in CC. We hypothesize that there is an ERa-dependent loop mechanism with higher estrogen levels in females exerting the effect on ERß. Larger prospective trials are warranted to confirm these findings, and in vitro and in vivo studies are needed to identify the underlying biological mechanism.
History
Publication status
- Published
Journal
Journal of Clinical OncologyISSN
0732-183XPublisher
American Society of Clinical OncologyExternal DOI
Issue
4Volume
30Page range
454-454Event type
conferenceDepartment affiliated with
- Biochemistry Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2021-11-12Usage metrics
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