PD-0016 KSR1 gene polymorphism in mcrc patients treated with first-line folfiri and bevacizumab

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Genetic variants of kinases suppressors of ras (KSR1) to predict survival in patients with ER-alpha positive metastatic breast cancer

Background In addition to its activating role of MAPK pathway, the protein kinase suppressor of ras 1 (KSR1) has been identified as a novel modulator of estrogen receptor alpha (ERα), as silencing of KSR1 in ERα+ breast cancer (BC) cells lines resulted in dowregulation of ERα transcriptional activity in the presence of oestradiol. Our previously data revealed the existence of single nucleotide polymorphisms (SNPs) in EGFR and ERα pathway genes that may predict clinical outcome in ERα positive metastatic BC (mBC) patients. With respect to those findings we aimed to evaluate the clinical implication of KSR1 SNPs on survival in patients with primary ERα+ mBC treated with tamoxifen. Methods Tumoral DNA was obtained from 222 patients treated with tamoxifen withERα+ invasive BC who had undergone surgery between 1981 and 2003 (median age 56 [28-90]). Three relevant KSR1 SNPs were selected based on public literature resources and databases, including 2 SNPs localised in the regulating 3’untranslated region (rs224190, rs 1075952) and 1 non-synonymous SNP localised in the coding exon 7 region (rs2293180). All SNP were analysed using DNA sequencing with OS and DFS as primary endpoint. Results The overall median follow-up was 6.4 years.In univariate analysis the rs2241906 SNP was significantly associated with DFS and OS and patients with the TT genotypedemonstrated shorter DFS (2.1 vs. 7.1 months, p=0.005) and OS ( 2.6 vs. 8.4 months p=0.002) than patients with the x/C genotypes. The associations remained significant in the multivariate analysis adjusting age, lymph node status and HER2 status (HR (95%CI): 4.81 (2.00-11.59) and 5.74 (2.29-14.43), for DFS and OS, respectively). The same significant correlation was retrieved with the SNP rs1075952 in linkage disequilibrium with rs2241906 that was used as a control. No relationship was shown between rs2293180 and survival. Conclusions Our findings demonstrated that KSR1 polymorphisms could arise as a potential marker to predict survival in patients with mBC treated with tamoxifen. The putative role of KSR1 as a modulator of ERα activity could functionally explain our results yielding insight for further studies

Association of gender-related tumor recurrence with a polymorphic variant of LMTK3 in stage II and III colon cancer

Background: Recent evidence suggests that Lemur Tyrosine Kinase 3 (LMTK3) activates estrogen receptor alpha (ERα) 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), ERβ expression has been shown to be predominant with low levels of ERα also expressed. ERα stimulates cell proliferation, while ERβ negatively regulates the estrogen-dependent activity of ERα. 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 ERα-dependent loop mechanism with higher estrogen levels in females exerting the effect on ERβ. Larger prospective trials are warranted to confirm these findings, and in vitro and in vivo studies are needed to identify the underlying biological mechanism

Prognostic value of lemur tyrosine kinase-3 (LMTK3) polymorphism in Japanese (J) patients (PTS) with localized gastric adenocarcinoma (GAC)

Background LMTK3 is an estrogen receptor α (ERα) regulator. Recent studies show that [rs808419(r8) and rs9989661(r9)] and LMTK3 expression are prognostic in breast and colon cancers. Our group demonstrated that r9AA is associated with shorter time to recurrence in Caucasian(C) and Hispanic(H) females(F) with GAC. We investigated the significance of LMTK3 polymorphism in J PTS with GAC. Methods Blood or tissue samples of 169 J PTS who had surgery with/without adjuvant chemotherapy (ACT) were analyzed. Genomic DNA was extracted using the QIAmp kit; all samples were analyzed using PCR-based direct DNA-sequencing. The endpoints of the study were disease-free survival (DFS) and overall survival (OS). Kaplan-Meier curves and log-rank test were used for univariate analysis. Multivariate analysis was performed to test the interaction between polymorphism and gender adjusting for other variables. Results 60 F and 109 males were enrolled in this study, 17% stage(s) IB, 31% s II, 36% s III, 17% s IV (AJCC-6). The median age was 67(31-88). 65% of PTS received S-1 based ACT. Median follow-up was 4 years(ys). Prognosis was worse in men with r9 AA than AG/GG, at 1 year 67% (95% CI 40-83%) with AA vs 99% (95% CI 91-99%) of AG/GG were alive (p= 0.039). Median survival was not reached in the AG/GG group; in the AA group median DFS and OS was 1yr (p= 0.03) and 2ys (p= 0.039) respectively. In the multivariate analysis adjusting for s, age, and ACT, males carrying AA had increased risk of disease recurrence (HR 3.84 95%CI 1.86-7.92, p< 0.001) and dying (HR 3.47 95%CI 1.58-7.62 p=0.002) compared to those with AG/GG (HR=1, reference). Conclusions r9 AA was associated with significantly worse DFS and OS in J male with GAC. These results confirm our previous findings that LMTK3 is an independent prognostic factor for localized GAC; interestingly the relationship between gender and prognostic significance is the opposite in J vs. C/H. The gender disparity can be due to the differences in the etiology (histological subtypes), management strategies, allele frequency, and degree of estrogen exposure in the two populations. Additional studies are warranted to identify the underlying biological mechanism

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