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Objective Currently , the targeted therapy is the first-choice treatment of advanced non-small cell lung cancer (NSCLC) in with epidermal growth factor receptor (EGFR) mutations, but few studies have been reported on the relationship between immunohistochemical markers and the EGFR mutation.The aim of this study is to analyze the relationship of the EGFR mutation with the ex-pressions of thymidylate synthetase (TS), excision repair cross-com-plementation group 1 ( ERCC1 ) , β-tubulin-III, and ribonucleofide reductase large subunit-l ( RRM1) in NSCLC. Methods We retro-spectively analyzed 336 cases of NSCLC treated in the Department of Medical Oncology , the Affiliated Hospital of Inner Mongolia Medical University, from June 2014 to December 2015 and examined 29 EGFR mutations.We divided the patients into a mutation and a non-mutation group, performed immunohistochemical staining of the TS, ERCC1,β-tubulin-III and RRM1 proteins and compared their expressions in the NSCLC tissue between the two groups . Results EGFR mutations were found in 138 ( 41.07%) of the 336 NSCLC patients but not in the other 198 ( 58.93%) .The expression of TS was significantly lower in the mutation than in the non-mutation group (9.42%vs 39.39%, P<0.05), and so was that of β-tubulin-III (44.2%vs 60.1%, P<0.05).EGFR mutations were correlated with decreased expressions of TS (r=-0.332, P<0.05) andβ-tubulin-III (r=-0.157, P<0.05).Multivariate regression analysis showed that the risk of EGFR mutations was 2.109 times higher in the fe-male patients than in the males (OR=2.109, 95%CI:1.268-3.509), 24.265 times higher in the adenocarcinoma than in the adeno-squamous carcinoma patients (OR=24.265, 95%CI:3.508-167.845), 15.2 times higher in the squamous carcinoma than in the ade-nocarcinoma patients (OR=15.200, 95%CI:4.480-51.569), 2.364 times higher in the lung biopsy specimens than in the surgically treated patients (OR=2.364, 95%CI:1.266-4.413), and 6.171 times higher in the patients with lowly expressed than in those with highly expressed TS (OR=6.171, 95%CI: 3.145-12.109). Conclusion The decreased expressions of TS and β-tubulin-Ⅲ in NSCLC indicate the mutation of the EGFR gene.
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Objective To investigate the correlation between TYMS gene mRNA expression level and EGFR mutation in stage Ⅲ A-N2 non-small-cell lung cancer tissue (NSCLC).Methods The branched DNA-liquidchip technology (bDNA-LCT) and mutant-enriched liquidchip (MEL) technology were used to detect the TYMS mRNA expression and EGFR mutations at exon 19 and 21 in NSCLC tissues from 30 patients with stages Ⅲ A-N2 NSCLC,and the results were analyzed.Results Among 30 cases,low TYMS mRNA expression was in 14 cases (46.7 ％),middle to low TYMS mRNA expression in 7 cases (23.3 ％),middle mRNA expression in 7 cases (23.3 ％),middle to high TYMS mRNA expression in 0 case and high TYMS mRNA expression in 2 cases (6.7％);12 cases of EGFR mutation were detected out with the mutation rate of 40.0％,including 6 cases of exon 19 deletion and 6 cases of exon 21 missense mutation.The TYMS mRNA expression level was correlated with the EGFR mutation.The EGFR mutation commonly occurred in the tumor tissue of the patients with TYMS mRNA low expression (Z=-2.604,P=0.009).Conclusion The TYMS mRNA expression in NSCLC tissue is correlated with the EGFR gene mutation,which can provide references for the drug selection aiming at the patients with different conditions.
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10.3969/j.issn.1007-3969.2013.04.009
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ObjectiveTo investigate the distribution of thethymidylate synthase (TS) gene polymorphisms inChinese femaleHan-nationality breast cancer patients,including tandemrepeat polymorphisms in the enhancer region ( ER), 6 bp deletion/insertion (del6/ins6) polymorphism in the 3′untranslated region (3′-UTR) and G→C single-nucleotide polymorphism (SNP). The association of TS gene polymorphism with pathological results was retrospectively analyzed.MethodsThis study included 83 breast cancer patients who received no preoperative chemotherapy. The polymorphisms of TS, ER and TS 3′2UTR were determined by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method.Results ( 1 ) Of the 83 patients, the frequencies of the TSER 3R/3 R, 2R/3 R and 2R/2R were 68.7％ ,27. 7％ and 3. 6％, respectively; (2) Due to existence of the G→C single nucleotide polymorphism,TSER genotypes were divided into 2R/2R, 2R/3C, 2R/3G, 3G/3G,3C/3C and 3G/3C,their frequencies were 3. 6％, 19. 3％, 8.4％, 19. 3％, 37. 3％ and 12. 1％, respectively; ( 3 ) Of the 83 patients, the frequencies of the TS 3′-UTR ins6/ias6、ins6/del6 and del6/del6 were 8.4％ 、50.6％ and 41.0％, respectively; (4) TSER polymorphisms were correlated with lymph node metastasis ( P = 0.019 ),Ki67 ( P = 0.022 ) and histological grade ( P = 0.042 ). The TS 3′-UTR polymorphisms were correlated with age ( P = 0.002) and histological grade (P = 0.042). G→C SNP were correlated with lymph node metastasis ( P = 0.021 ) and histological grade ( P = 0.028 ).ConclusionsChinese female Han-nationality breast cancer patients have more genotypes frequencies of the TSER 3R/3R and 3′-UTR del6/del6; The TS polymorphisms are correlated with pathological factors of breast cancer.
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Objective To establish human choriocarcinoma JeG-3 cell line resistant to floxuridine (FUDR)and describe the characteristics of this FUDR-resistant subline.The thymidylate synthase (TS) expression level in FUDR-resistant subline was also discussed.Methods The FUDR-resistant sub-line JeG-3/FUDRA was established by intermitted exposure to grads increased FUDR.Reversed microscope was used to observe the morphological changes in FUDR-resistant sub-line.Population doubling time was calculated and compared based on the growth curve of these two cell lines,cell cycles and chromosomal ploidy were assayed with flow cytometry methods.The chemo-luminescence assay was used to detect the hormone secretion by two kinds of cell lines.The resistant index (RI) was measured by cell counting kit-8 (CCK-8)assay.Quantitative RT-PCR was used to detect the mRNA expression level of TS and we also detected the TS mRNA expression level in different doses exposed subline.Results The RI of JeG-3/FUDRA was 31.62.Compared with the JeG-3 cell,the FUDR-resistant cell line had gross changes in morphological,cell growth,cell cycles and chromosomal numbers.The ability of human chorionic gonadotrop(hCG) and progesterone secretion was lower in JeG-3/FUDRA subline.The trend of TS mRNA expression was:while exposed to low concentration of FUDR,the TS mRNA expression level was downregulated,then followed the increasing dose of the drug,the expression level of TS mRNA ascended gradually.When the terminal concentration was reached,the expression level of TS mRNA in JeG-3/FUDRA subline was higher than that of JeG-3 cell line (P＜0.05).Conclusions We established the FUDR-resistant subline of JeG-3 successfully.The TS mRNA expression level is stage-related to the different concentration and different phase in FUDR exposure.Our data suggested that TS mRNA expression level may not be used as a biomarker to predict the chemosensitivity in FUDR-based chemotherapy.
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Objective: To investigate the effects of the tandem repeat polymorphisms in the enhancer region (ER) of thymidylate synthase (TS) gene and the 6-bp deletion/insertion (del6/ins6) polymorphism in the 3′ untranslated region (3′-UTR) of TS gene on the clinical outcomes of gastric cancer patients treated with 5-FU-based adjuvant chemotherapy. Methods: One hundred and sixteen patients with gastric cancer were treated with 5-FU-based adjuvant chemotherapy. The polymorphisms of TSER and TS 3′ -UTR in those patients were determined by polymerase chain reaction (PCR) method. Results: Of the 116 patients, the frequencies of the TSER 2R/2R, 2R/3R and 3R/3R were 7.8% (9/116), 31.9% (37/116), and 60.3% (70/116), respectively; the frequencies of the TS3′-UTR ins6/ins6, ins6/del6 and del6/del6 were 9.5% (11/116), 41.4% (48/116) and 49.1% (57/116), respectively. The median survival period in ins6/ins6 carriers was significantly shorter than that of del6/del6 (P = 0.017) or ins6/del6 (P = 0.022) carriers. There was no significant difference in median relapse-free survival period between different TSER carriers (P > 0.05). COX multivariate analysis showed that the ins6/ins6 carriers had increased death risk (P <0.05) compared to the other two genotypes. The median no-recurrence survival period had no statistical difference between them. Conclusion: The polymorphism of TS 3 UTR ins6/del6 may be an independent factor for the prognosis of gastric cancer patients treated with 5-FU-based adjuvant chemotherapy.
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