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Clinical significance of UGT1A1 polymorphism and expression of ERCC1, BRCA1, TYMS, RRM1, TUBB3, STMN1 and TOP2A in gastric cancer

BMC Gastroenterology volume 17, Article number: 2 (2017) Cite this article

Abstract

Background

Individualized therapeutic regimen is a recently intensively pursued approach for targeting diseases, in which the search for biomarkers was considered the first and most important. Thus, the goal of this study was to investigate whether the UGT1A1, ERCC1, BRCA1, TYMS, RRM1, TUBB3, STMN1 and TOP2A genes are underlying biomarkers for gastric cancer, which, to our knowledge, has not been performed.

Methods

Ninety-eight tissue specimens were collected from gastric cancer patients between May 2012 and March 2015. A multiplex branched DNA liquidchip technology was used for measuring the mRNA expressions of ERCC1, BRCA1, TYMS, RRM1, TUBB3, STMN1 and TOP2A. Direct sequencing was performed for determination of UGT1A1 polymorphisms. Furthermore, correlations between gene expressions, polymorphisms and clinicopathological characteristics were investigated.

Results

The expressions of TYMS, TUBB3 and STMN1 were significantly associated with the clinicopathological characteristics of age, gender and family history of gastric cancer, but not with differentiation, growth patterns, metastasis and TNM staging in patients with gastric cancer. No clinical characteristics were correlated with the expressions of ERCC1, BRCA1, RRM1 and TOP2A. Additionally, patients carrying G allele at −211 of UGT1A1 were predisposed to developing tubular adenocarcinoma, while individuals carrying 6TAA or G allele respectively at *28 or −3156 of UGT1A1 tended to have a local invasion.

Conclusions

The UGT1A1 polymorphism may be useful to screen the risk population of gastric cancer, while TYMS, TUBB3 and STMN1 may be potential biomarkers for prognosis and chemotherapy guidance.

Peer Review reports

Background

Gastric cancer is the second most common malignancy and the third most common cause of cancer-related death in China, with an estimated 423,500 newly diagnosed cases and 298,500 deaths in 2012 [1]. Radical surgery followed by adjuvant chemotherapy is the mostly used strategy for management of gastric cancer. Nevertheless, the overall 5-year survival rate is still below 50% [2], which may result from the insensitivity and/or tolerance to chemotherapy in some gastric cancer patients. Consequently, screening effective biomarkers has become a hot topic in the field of gastric cancer in order to develop individualized therapies and make patients obtain more beneficial effects.

Recently, several studies have suggested that the expressions of excision repair cross complementing 1 (ERCC1), breast cancer susceptibility gene breast cancer 1 (BRCA1), thymidylate synthetase (TYMS), ribonucleotide reductase M1 (RRM1), β-tubulin III (TUBB3), stathmin1 (STMN1) and topoisomerase IIα (TOP2A) genes are differential in cancer tissues and are closely associated with the clinicopathological characteristics of patients (such as clinical staging or lymphatic metastasis), which make them suitable to act as possible biomarkers to evaluate the therapeutic response and survival rates of cancer patients [3–8]. Although mounting evidence also indicates their important roles in gastric cancer [9–15], no study, to our knowledge, has been conducted to simultaneously detect their expressions in the samples of gastric cancer like other cancers [3–8].

In addition, genetic polymorphisms also possess important clinical values in predicting a susceptibility to cancer and the ability of an individual to respond to therapeutic agents. For example, UDP-glucuronosyltransferases (UGTs) are important enzymes responsible for glucuronidation of serum bilirubin, which is a natural antioxidant. The inter-individual variation in enzyme activity of UGT1A1 isozyme due to the polymorphisms at positions −3156 (G > A), 211 (G/A) and TATA Box (6TAA/7TAA) leads to the lack of bilirubin and the development of cancer [16, 17]. UGTs also can transform toxic components (chemotherapy drugs) to less or nontoxic hydro-soluble forms, resulting in the failure or resistance of chemotherapy [18]. Although there have reports to investigate the relationship between UGT1A1 polymorphisms and chemotherapy drug (irinotecan) toxicity or response [19–21], no studies have been performed to explore the association of UGT1A1 polymorphisms with clinicopathological features, which was the goal of our study.

The present study aims to detect the UGT1A1 polymorphisms and expressions of ERCC1, BRCA1, TYMS, RRM1, TUBB3, STMN1 and TOP2A in the tumor tissues from gastric cancer patients and explore their relationships with the clinicopathological characteristics, hoping to provide guidance for targeted cancer therapies individually.

Methods

Tissue samples

A total of 98 tissue specimens were collected from gastric cancer patients in our hospital between May 2012 and March 2015. The samples were formalin-fixed paraffin-embedded (FFPE) or fresh frozen after radical surgery. All of them were histologically confirmed by two independent, experienced pathologists. All patients had complete medical records and no patient received neoadjuvant treatments prior to the primary surgery. All patients gave written informed consents for sample retention, analysis for research purposes and paper publication. The study protocol was approved by the ethics committee of Chengdu Military General Hospital of PLA, China.

Detection of mRNA expression levels

A multiplex branched DNA liquidchip (MBL) technology (Guangzhou SurExam Bio-Tech Co., Ltd., China) was used for quantitative determination of all the genes at the mRNA level in the tissue samples simultaneously as previously reported [3, 22, 23]. Briefly, the tissue samples were lysed in buffer at 56 °C for 2 h. The lysed product was transferred to a 96-well plate in which blocking reagent, capture beads and target gene-specific probe sets were included, and then incubated at 55 °C overnight on a shaker, followed by adding the hybridization mixture. Signals for bound target mRNA were amplified with streptavidin‑phycoerythrin at 50 °C for 30 min. The fluorescence value of each sample was recognized and analyzed by the Luminex 200 system (Luminex, Austin, TX, USA) to represent the mRNA expression level of each gene. The expression level of each gene was divided into low expression (<25%), middle expression (25 ~ 75%) and high expression (>75%) by comparing to the cut‑off value of each gene which was provided by Guangzhou Surexam Medical Test Center [24].

UGT1A1 polymorphism analysis

DNA was extracted from tissue samples using a phenol-chloroform method. Single nucleotide polymorphisms for the TATA box of the promoter (UGT1A1*28, 6TAA/7TAA) and exon 1 (−211 G/A) were simultaneously determined with the PCR primer sequences as follows: 5’-ATTAACTTGGTGTATCGATTGG-3’ and 5’-AAGCATAGCAGAGTCCTTTTTTA-3’[25], while the PCR primer sequences for the phenobarbital responsive enhancer module region of the promoter (−3156 G/A) were 5’-CTGGGGATAAACATGGGATG-3’ and 5’- CACCACCACTTCTGGAACCT-3’ [26]. Direct sequencing was performed using the ABIPRISM310 Genetic Analyzer (Applied Biosystems, Foster City, CA) according to standard protocols.

Statistical analysis

Statistical analyses were conducted using the SPSS v.19.0 statistical software (SPSS, Chicago, IL, USA). Statistically significant differences were evaluated by the chi-square test for categorical variables and t-test for continuous variables. P value of < 0.05 was considered statistically significant.

Results

Patient characteristics

The patient characteristics are summarized in Table 1 (raw data see Additional file 1). Of the 98 patients, 76 (77.6%) were males and 22 (22.4%) were females. Ages of patients ranged from 32 to 77 years, with a mean of 56.92 ± 10.15 years. Thus, patients were stratified into two age groups (age > 57 years and age < 57 years). Histologically, all 98 lesions were classified into tubular adenocarcinoma (n = 75) and non-tubular adenocarcinoma (including mucinous adenocarcinoma, n = 21; and other types, n = 2). Further, samples with tubular adenocarcinoma was respectively shown to be well, moderately or poorly differentiated in 1, 21 and 53 patients, while the mucinous adenocarcinoma included poor differentiation and un-differentiation in 6 and 15 patients, respectively. Metastasis, including lymph node and distant involvement, was present in 55 (56.1%) patients. Approximately 81% (79/98) of the patients were diagnosed with a three- or four-level invasion depth. According to the 2002 AJCC TNM staging criteria [27], patients were classified as stage I (18, 18.4%), II (29, 29.6%), III (39, 39.8%) and IV (12, 12.2%) tumor. Thirty-two patients had the history of alcohol intake and most of the patients (93%) did not have the family history of gastric cancer.

Table 1 Characteristics of 98 gastric cancer patients
Full size table

Gene expression and their relationships with clinical characteristics

There were no significant associations between all 12 clinicopathological characteristics and the expressions of ERCC1, BRCA1, RRM1 and TOP2A. The expressions of TYMS (Table 2), TUBB3 and STMN1 (Table 3) were found to be correlated with age, in which patients with age < 57 years exhibited lower expressions of TYMS (P = 0.044), TUBB3 (P = 0.024) and STMN1 (P = 0.042). Furthermore, lower expression of TUBB3 was observed in female patients (P = 0.026) and patients having a family history of gastric cancer (P = 0.025) (Table 3). Similar to ERCC1, BRCA1, RRM1 and TOP2A, no correlations were also seen between clinicopathological characteristics of differentiation, growth patterns, metastasis and TNM staging, and the expression levels of TYMS, TUBB3 and STMN1 (Tables 2 and 3).

Table 2 Relationships between gene expression and clinical characteristics
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Table 3 Relationships between gene expression and clinical characteristics (Continued Table 2)
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UGT1A1 polymorphisms and their relationships with clinical characteristics

There were no significant differences in the genotype distribution between patients with different gender, age, family history, alcohol history, differentiation degree, growth patterns, metastasis and TNM staging (Table 4). The genotype frequencies for the UGT1A1 polymorphism at position −211 were associated with the histological type, in which patients with GG genotype showed a predisposition to developing tubular adenocarcinoma. In addition, polymorphisms at positions *28 and −3156 were correlated with the depth of invasion (both P = 0.023) where patients carrying 6TAA or G allele tended to have a local invasion. Combined effects for UGT1A1*28, UGT1A1-211 and UGT1A1-3156 were also performed and the results only indicated the association with the histological type (P = 0.043) (Table 5).

Table 4 UGT1A11 polymorphisms and their relationships with clinical characteristics
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Table 5 UGT1A11 polymorphisms and their relationships with clinical characteristics (Continued Table 4)
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Discussion

Individualized therapeutic regimen is a recently intensively pursued approach for targeting diseases at the molecular level, in which the search for biomarkers was considered the first and most important [28, 29]. Therefore, the present study was to investigate whether the genes ERCC1, BRCA1, TYMS, RRM1, TUBB3, STMN1 and TOP2A are underlying biomarkers for patients with gastric cancer, which, to our knowledge, has not been performed. However, our results showed that only the expression levels of TYMS, TUBB3 and STMN1 were significantly associated with the clinical characteristics of age, gender and family history of gastric cancer, but not with differentiation degree, growth patterns, metastasis and TNM staging in patients with gastric cancer. No clinical characteristics were correlated with the expressions of ERCC1, BRCA1, RRM1 and TOP2A. These findings seemed not to be fully in accordance with the studies of other cancers [3–8], suggesting the difference among different cancers.

TUBB3 is one of the major components of microtubules (a basic constructive unit of spindle) to be involved in cell division, thus promoting the possibility of malignant growth and metastases [30]. As expected, TUBB3 is shown to be higher expressed in various cancers than that in healthy control, including gastric cancer (31.6 ± 17.8 ng/mL vs. 16.9 ± 3.8 ng/mL, p < 0.001) [31]. To reduce the expression of TUBB3 and improve survival of cancer patients, several anti-microtubule chemotherapeutic agents (i.e. paclitaxel, capecitabine, carboplatin) were suggested and the studies demonstrated that the patients were more sensitive to these treatments when TUBB3 mRNA expression was low enough [31–34]. In this study, we found TUBB3 was relatively lower expressed in the females (P = 0.026), patients with age < 57 years (P = 0.024) and family history of gastric cancer (P = 0.025), suggesting the above anti-microtubule chemotherapeutic agents should be recommended for these patients to obtain more benefits.

STMN1 encodes a regulatory protein that participates in assembly and disassembly of the mitotic spindle, facilitating the achievement of mitosis process and uncontrolled proliferation of malignant tumor cells [35]. Hence, STMN1 should be also highly expressed in gastric cancer, which has been demonstrated by the study of Kang et al. who report an up-regulated expression of STMN1 in 80 and 56% primary gastric adenocarcinomas at protein and mRNA levels, respectively [36]. Knock-down of STMN1 using siRNA inhibits the proliferation, migration and invasion of gastric cancer cells and slows the growth of xenografts in nude mice [37–39]. Although STMN1 over-expression has been reported to be positively correlated with lymph node metastasis and TNM staging [36, 37, 40], no association was proved in our study, which may be attributed to small sample size and different detection methods. Moreover, studies imply that cancer patients with low expression of STMN1 mRNA will have a favorable clinical efficacy after being treated with Taxol regimens [41, 42]. Silencing STMN1 enhances the sensitivity of gastric cancer cells to docetaxel, with the resistance index reducing to 3.41 [13]. In this study, we found STMN1 was relatively lower expressed in the patients with age < 57 years (P = 0.042), suggesting Taxol and docetaxel may be a more appropriate treatment for patients aged < 57 years.

TYMS is a central enzyme in the folate metabolic pathway, which catalyzes the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate, thereby maintaining the dTMP (thymidine-5-prime monophosphate) pool critical for DNA replication and repair. Tumor cells with higher TYMS expression exhibited higher proliferative and metastatic activities due to its accelerated effect on the DNA replication [43, 44]. Thus, scholars suggest TYMS may be a potential biomarker for gastric cancer and response rates for the antifolate cytotoxic chemotherapy (i.e. raltitrexed, fluoropyrimidine) may be higher in patients with low expression of TYMS [45, 46].

Moreover, we also investigated whether the genetic variation in UGT1A1 gene was related with the clinical characteristics of gastric cancer, which, to our knowledge, has also not been performed. The results showed that patients carrying G allele at −211 were predisposed to developing tubular adenocarcinoma, while patients carrying 6TAA or G allele respectively at *28 and −3156 tended to have a local invasion. Our results are similar to previous studies because the -211GG, −211GA, *28 6TAA/6TAA, *28 6TAA/7TAA, −3156 GG or −3156 GA contribute to high expression of UGT1A1 gene, which causes high levels of glucuronidation and then reduces serum bilirubin levels. Lower bilirubin did not exert protective effects against cancer development and progression by inhibiting cellular damage induced by oxidative stress [26, 47]. Therefore, bilirubin levels should be moderately elevated to improve the overall survival of these patients [48].

Our study had some limitations. Firstly, this was a single institutional study and sample size was not enough large, which may result in different conclusions with previous studies. Secondly, the gene expression was only detected using the multiplex branched DNA liquidchip technology, but not confirmed by immunohistochemistry with normal stomach tissues or para-carcinoma tissues as control. However, we believe our study may be important because the expression level (low, middle, high) detected by the MBL technology may be more effective to guide the prognosis and individualized chemotherapy as previously described [3–8]. The studies about comparison with normal stomach tissues or para-carcinoma tissues only indicate the upregulation or downregulation, but not further classify the degree. Furthermore, the expression of 7 genes in comparison with normal stomach or adjacent normal has been independently investigated previously [9–15]. Thirdly, gastric cancer samples were only categorized according to the WHO’s, but not by the Lauren’s histological classification system in our hospital. However, recent studies indicate there is a high concordance between two systems [49, 50]. Fourthly, chemotherapy and follow up results had not been collected completely, although they have been performed in our center. This resulted in the lack of analysis on cost effectiveness ratio, which may be the most concern for patients. Nevertheless, we believe the average cost effectiveness ratio may be lower because our detection can guide the individualized chemotherapy arrangement, which may be beneficial to 1) improve the efficacy and prolong life; 2) reduce the side effect due to the inappropriate chemotherapy drugs, and enhance the quality of life; 3) prevent a waste of money due to the repeated attempts of chemotherapy drugs/scheme. In summary, further investigation is still essential to confirm the biomarker role of TYMS, TUBB3, STMN1 and UGT1A1 by a multicenter clinical study with large sample size, more classification systems, addition of control samples, immunohistochemistry confirmation and chemotherapy results.

Conclusions

Our findings suggest UGT1A1 polymorphisms may be useful to screen the risk population of gastric cancer and schedule the appropriate pretreatment to improve the overall survival, while TYMS, TUBB3 and STMN1 may be potential biomarkers for prognosis and chemotherapy guidance.

Abbreviations

BRCA1:

Breast cancer susceptibility gene breast cancer 1

dTMP:

Thymidine-5-prime monophosphate

ERCC1:

Excision repair cross complementing 1

FFPE:

Formalin fixed paraffin embedded

MBL:

Multiplex branched DNA liquidchip

RRM1:

Ribonucleotide reductase M1

STMN1:

Stathmin1

TOP2A:

Topoisomerase IIα

TUBB3:

β-tubulin III

TYMS:

Thymidylate synthetase

UGTs:

UDP-glucuronosyltransferases

References

  1. Chen W, Zheng R, Zuo T, Zeng H, Zhang S, He J. National cancer incidence and mortality in China, 2012. Chin j cancer res. 2016;28:1–11.

  2. Smalley SR, Benedetti JK, Haller DG, Hundahl SA, Estes NC, Ajani JA, et al. Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J clin oncol. 2012;30:2327–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Han Y, Li G, Su C, Ren H, Chu X, Zhao Q, et al. Exploratory study on the correlation between 14 lung cancer-related gene expression and specific clinical characteristics of NSCLC patients. Mol clin oncol. 2013;1:887–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Han Y, Wang XB, Xiao N, Liu ZD. mRNA expression and clinical significance of ERCC1, BRCA1, RRM1, TYMS and TUBB3 in postoperative patients with non-small cell lung cancer. Asian pac j cancer prev. 2013;14:2987–90.

  5. Yu Y, Ding S, Liang Y, Zheng Y, Li W, Yang L, et al. Expression of ERCC1, TYMS, TUBB3, RRM1 and TOP2A in patients with esophageal squamous cell carcinoma: a hierarchical clustering analysis. Exp ther med. 2014;7:1578–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Wang H, Yang B, Geng T, Li B, Dai P, Chen C. Tissue-specific selection of optimal reference genes for expression analysis of anti-cancer drug-related genes in tumor samples using quantitative real-time RT-PCR. Exp mol pathol. 2015;98:375–81.

  7. Su C, Zhou S, Zhang L, Ren S, Xu J, Zhang J, et al. ERCC1, RRM1 and BRCA1 mRNA expression levels and clinical outcome of advanced non-small cell lung cancer. Med oncol. 2011;28:1411–7.

    Article  CAS  PubMed  Google Scholar 

  8. Zhao H, Zhang H, Du Y, Gu X. Prognostic significance of BRCA1, ERCC1, RRM1, and RRM2 in patients with advanced non-small cell lung cancer receiving chemotherapy. Tumour biol. 2014;35:12679–88.

    Article  CAS  PubMed  Google Scholar 

  9. Wei KK, Jiang L, Wei YY, Wang YF, Qian XK, Dai Q, et al. The prognostic value of ERCC1 expression in gastric cancer patients treated with platinum-based chemotherapy: a meta-analysis. Tumor biol. 2014;35:8721–31.

    Article  CAS  Google Scholar 

  10. Chen W, Wang J, Li X, Li J, Zhou L, Qiu T, et al. Prognostic significance of BRCA1 expression in gastric cancer. Med oncol. 2013;30:423.

  11. Claerhout S, Lim JY, Choi W, Park YY, Kim K, Kim SB, et al. Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer. Plos one. 2011;6:e24662.

  12. Huang J, Huabin HU, Xie Y, Tang Y, Liu W, Zhong M. Effect of TUBB3, TS and ERCC1 mRNA expression on chemoresponse and clinical outcome of advanced gastric cancer by multiplex branched-DNA liquid chip technology. J cent south univ. 2013;38:582–9.

    CAS  Google Scholar 

  13. Meng ZJ, Tao K. Enhancement of chemosensitivity by stathmin-1 silencing in gastric cancer cells in situ and in vivo. Oncol res featuring preclinical clin cancer ther. 2015;23:35–41.

    Article  Google Scholar 

  14. Takechi T, Koizumi K, Tsujimoto H, Fukushima M. Screening of differentially expressed genes in 5-fluorouracil-resistant human gastrointestinal tumor cells. J j cancer res. 2001;92:696–703.

    Article  CAS  Google Scholar 

  15. Wang Q, Liu X, Zhou J, Huang Y, Zhang S, Shen J, et al. Ribonucleotide reductase large subunit M1 predicts poor survival due to modulation of proliferative and invasive ability of gastric cancer. Plos one. 2013;8:e70191.

  16. Lacko M, Roelofs HM, Te Morsche RH, Voogd AC, Ophuis MBO, Peters WH, et al. Genetic polymorphism in the conjugating enzyme UGT1A1 and the risk of head and neck cancer. Int j cancer. 2010;127:2815–21.

    Article  CAS  PubMed  Google Scholar 

  17. Dura P, Salomon J, Te Morsche RH, Roelofs HM, Kristinsson JO, Wobbes T, et al. High enzyme activity UGT1A1 or low activity UGT1A8 and UGT2B4 genotypes increase esophageal cancer risk. Int j oncol. 2012;40:1789–96.

    CAS  PubMed  Google Scholar 

  18. Oguri T, Takahashi T, Miyazaki M, Isobe T, Kohno N, Mackenzie PI, et al. UGT1A10 is responsible for SN-38 glucuronidation and its expression in human lung cancers. Anticancer res. 2004;24:2893–6.

    CAS  PubMed  Google Scholar 

  19. Jo J, Lee J, Ryu M, Chang H, Kim M, Lee H, et al. Phase II and UGT1A1 genotype study of irinotecan dose escalation as salvage therapy for advanced gastric cancer. Br j cancer. 2012;106:1591–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gao J, Zhou J, Li Y, Peng Z, Li Y, Wang X, et al. Associations between UGT1A1* 6/* 28 polymorphisms and irinotecan-induced severe toxicity in Chinese gastric or esophageal cancer patients. Med oncol. 2013;30:630.

  21. Wang W, Huang J, Tao Y, Lyu X, Yang L, Wu D, et al. Phase II and UGT1A1 polymorphism study of two different irinotecan dosages combined with cisplatin as first-line therapy for advanced gastric cancer. Chemotherapy. 2016;61:197–203.

    Article  PubMed  Google Scholar 

  22. Ren GJ, Zhao YY, Zhu YJ, Xiao Y, Xu JS, Shan B, et al. Tumor gene mutations and messenger RNA expression: correlation with clinical response to icotinib hydrochloride in non-small cell lung cancer. Chin med j (Beijing). 2011;124:19–25.

  23. Yang C, Zhou Q, He J, Yang H, Luo X, Xu J. Application of multiplex branched Dna liquidchip technology (Mbl) for optimal selection of chemotherapy in elderly patients. J geriatr oncol. 2014;5:S14.

    Article  Google Scholar 

  24. Sun S, Shi W, Wu Z, Zhang G, Yang BO, Jiao S. Prognostic significance of the mRNA expression of ERCC1, RRM1, TUBB3 and TYMS genes in patients with non-small cell lung cancer. Exp ther med. 2015;10:937–41.

  25. Inoue K, Sonobe M, Kawamura Y, Etoh T, Takagi M, Matsumura T, et al. Polymorphisms of the UDP-glucuronosyl transferase 1A genes are associated with adverse events in cancer patients receiving irinotecan-based chemotherapy. Tohoku j exp med. 2013;229:107–14.

    Article  CAS  PubMed  Google Scholar 

  26. Girard H, Butler LM, Villeneuve L, Millikan RC, Sinha R, Sandler RS, et al. UGT1A1 and UGT1A9 functional variants, meat intake, and colon cancer, among Caucasians and African-Americans. Mutat res fundam mol mech mutagen. 2008;644:56–63.

    Article  CAS  Google Scholar 

  27. Page DL, Fleming ID, Fritz AG, Balch CM, Haller DG, Morrow M. AJCC cancer staging manual. 6th ed. New York: Springer; 2002. p. 171–180.

  28. Baudhuin LM, Donato LJ, Uphoff TS. How novel molecular diagnostic technologies and biomarkers are revolutionizing genetic testing and patient care. Expert rev mol diagn. 2012;12:25–37.

  29. Ong FS, Das K, Wang J, Vakil H, Kuo JZ, Blackwell WL, et al. Personalized medicine and pharmacogenetic biomarkers: progress in molecular oncology testing. Expert rev mol diagn. 2012;12:593–602.

  30. McCarroll JA, Gan PP, Erlich RB, Liu M, Dwarte T, Sagnella SS, et al. TUBB3/βIII-tubulin acts through the PTEN/AKT signaling axis to promote tumorigenesis and anoikis resistance in non-small cell lung cancer. Cancer res. 2015;75:415–25.

    Article  CAS  PubMed  Google Scholar 

  31. Yu J, Gao J, Lu Z, Li Y, Shen L. Serum levels of TUBB3 correlate with clinical outcome in Chinese patients with advanced gastric cancer receiving first-line paclitaxel plus capecitabine. Med oncol. 2012;29:3029–34.

    Article  CAS  PubMed  Google Scholar 

  32. Gao S, Zhao X, Lin B, Hu Z, Yan L, Gao J. Clinical implications of REST and TUBB3 in ovarian cancer and its relationship to paclitaxel resistance. Tumour biol. 2012;33:1759–65.

    Article  CAS  PubMed  Google Scholar 

  33. Roque DM, Buza N, Glasgow M, Bellone S, Bortolomai I, Gasparrini S, et al. Class III β-tubulin overexpression within the tumor microenvironment is a prognostic biomarker for poor overall survival in ovarian cancer patients treated with neoadjuvant carboplatin/paclitaxel. Clin exp metastasis. 2014;31:101–10.

    Article  CAS  PubMed  Google Scholar 

  34. Hwang JE, Hong JY, Kim K, Kim SH, Choi WY, Kim MJ, et al. Class III β-tubulin is a predictive marker for taxane-based chemotherapy in recurrent and metastatic gastric cancer. BMC cancer. 2013;13:431.

  35. Karst AM, Levanon K, Duraisamy S, Liu JF, Hirsch MS, Hecht JL, et al. Stathmin 1, a marker of PI3K pathway activation and regulator of microtubule dynamics, is expressed in early pelvic serous carcinomas. Gynecol oncol. 2011;123:5–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kang W, Tong J, Chan A, Lung R, Chau SL, Wong Q, et al. Stathmin1 plays oncogenic role and is a target of microRNA-223 in gastric cancer. Plos one. 2012;7:e33919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jeon T, Han M, Lee Y, Lee Y, Kim G, Song G, et al. Overexpression of stathmin1 in the diffuse type of gastric cancer and its roles in proliferation and migration of gastric cancer cells. Br j cancer. 2010;102:710–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Akhtar J, Wang Z, Zhang ZP, Bi MM. Lentiviral-mediated RNA interference targeting stathmin1 gene in human gastric cancer cells inhibits proliferation in vitro and tumor growth in vivo. J transl med. 2013;11:212.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Akhtar J, Wang Z, Yu C, Zhang ZP. Effectiveness of local injection of lentivirus‐delivered stathmin1 and stathmin1 shRNA in human gastric cancer xenograft mouse. J gastroenterol hepatol. 2014;29:1685–91.

    Article  CAS  PubMed  Google Scholar 

  40. Ke B, Wu LL, Liu N, Zhang RP, Wang CL, Liang H. Overexpression of stathmin 1 is associated with poor prognosis of patients with gastric cancer. Tumour biol. 2013;34:3137–45.

  41. Meng XL, Su D, Wang L, Gao Y, Hu YJ, Yang HJ, et al. Low expression of stathmin in tumor predicts high response to neoadjuvant chemotherapy with docetaxel-containing regimens in locally advanced breast cancer. Genet test mol biomarkers. 2012;16:689–94.

  42. Lin X, Liao Y, Xie J, Liu S, Su L, Zou H. Op18/stathmin is involved in the resistance of taxol among different epithelial carcinoma cell lines. Cancer biother radiopharm. 2014;29:376–86.

    Article  CAS  PubMed  Google Scholar 

  43. Lu Y, Zhuo C, Cui B, Liu Z, Zhou P, Lu Y, et al. TYMS serves as a prognostic indicator to predict the lymph node metastasis in Chinese patients with colorectal cancer. Clin biochem. 2013;46:1478–83.

    Article  CAS  PubMed  Google Scholar 

  44. Burdelski C, Strauss C, Tsourlakis M, Kluth M, Hube-Magg C, Melling N, et al. Overexpression of thymidylate synthase (TYMS) is associated with aggressive tumor features and early PSA recurrence in prostate cancer. Oncotarget. 2015;6:8377–87.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Shen J, Wang H, Wei J, Yu L, Xie L, Qian X, et al. Thymidylate synthase mRNA levels in plasma and tumor as potential predictive biomarkers for raltitrexed sensitivity in gastric cancer. Int j cancer. 2012;131:E938–45.

    Article  CAS  PubMed  Google Scholar 

  46. Gao Y, Cui J, Xi H, Cai A, Shen W, Li J, et al. Association of thymidylate synthase expression and clinical outcomes of gastric cancer patients treated with fluoropyrimidine-based chemotherapy: a meta-analysis. Oncotargets ther. 2016;9:1339–50.

    Article  Google Scholar 

  47. Rao P, Suzuki R, Mizobuchi S, Yamaguchi T, Sasaguri S. Bilirubin exhibits a novel anti-cancer effect on human adenocarcinoma. Biochem biophys res commun. 2006;342:1279–83.

    Article  CAS  PubMed  Google Scholar 

  48. Li N, Xu M, Cai MY, Zhou F, Li CF, Wang BX, et al. Elevated serum bilirubin levels are associated with improved survival in patients with curatively resected non-small-cell lung cancer. Cancer epidemiol. 2015;39:763–8.

  49. Qiu M, Zhou Y, Zhang X, Wang Z, Wang F, Shao J, et al. Lauren classification combined with HER2 status is a better prognostic factor in Chinese gastric cancer patients. BMC cancer. 2014;14:823.

  50. Son HS, Shin YM, Park KK, Seo KW, Yoon KY, Jang HK, et al. Correlation between HER2 overexpression and clinicopathological characteristics in gastric cancer patients who have undergone curative resection. J gastric cancer. 2014;14:180–6.

    Article  PubMed  PubMed Central  Google Scholar 

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Availability of data and materials

All data supporting our findings were included within the present manuscript and its Additional file 1.

Authors’ contributions

YKC made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; GHZ, PHW, JZ, WG, YNS, LH, YZ, GDL, JQG and LZ were involved in drafting the manuscript or revising it critically for important intellectual content; YKC provided final approval of the version to be published. Each author participated sufficiently in the work to take public responsibility for appropriate portions of the content; and YKC agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All the authors had read and approved the final version of the manuscript.

Competing interests

The authors declare that they have no competing interests.

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Not applicable.

Ethics approval and consent to participate

The study protocol was approved by the ethics committee of Chengdu Military General Hospital of PLA, China. All patients gave written informed consents for sample retention and analysis for research purposes.

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Authors and Affiliations

  1. Department of Gastrointestinal Surgery, Center of General Surgery of P.L.A., Chengdu Army General Hospital, No.270 Rongdu avenue, Chengdu, 610083, Sichuan Province, China

    Yongkuan Cao, Guohu Zhang, Peihong Wang, Jun Zhou, Wei Gan, Yaning Song, Ling Huang, Ya Zhang, Guode Luo, Jiaqing Gong & Lin Zhang

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  1. Yongkuan Cao
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  2. Guohu Zhang
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  3. Peihong Wang
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  11. Lin Zhang
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Corresponding author

Correspondence to Yongkuan Cao.

Additional file

Additional file 1:

Raw data of patients. The general characteristics, gene expressions and polymorphisms of each patient are available. (XLS 54 kb)

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Cao, Y., Zhang, G., Wang, P. et al. Clinical significance of UGT1A1 polymorphism and expression of ERCC1, BRCA1, TYMS, RRM1, TUBB3, STMN1 and TOP2A in gastric cancer. BMC Gastroenterol 17, 2 (2017). https://doi.org/10.1186/s12876-016-0561-x

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Keywords

BMC Gastroenterology

ISSN: 1471-230X

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