Thymidylate synthase (TS) gene expression in primary lung cancer patients: a large-scale study in Japanese population

Tanaka, Fumihiro; Wada, Hiromi; Fukui, Yousuke; Fukushima, Masakazu

doi:10.1093/annonc/mdq730

Cited by 36 publications

(30 citation statements)

References 35 publications

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“…The data from this study indicate significantly higher thymidylate synthase expression levels in squamous cell carcinomas than adenocarcinomas, consistent with prior studies (using both immunohistochemistry and direct mRNA measurement 15,25 ) regarding histology and thymidylate synthase. This study also identifies high thymidylate synthase expression in Table 3 Summary of EGFR and KRAS mutations in the adenosquamous specimens, including the microdissection cases adenosquamous tumors, showing more similarity to squamous cell specimens than adenocarcinomas.…”

Section: Discussionsupporting

confidence: 91%

Thymidylate synthase expression and molecular alterations in adenosquamous carcinoma of the lung

et al. 2013

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Thymidylate synthase expression is known to be higher in squamous cell carcinoma than in adenocarcinoma of the lung. It is thought that this is the reason for the poor efficacy of pemetrexed in squamous cell carcinoma. However, there is limited data on thymidylate synthase expression in adenosquamous carcinoma, a distinct subtype of lung cancer containing both squamous and glandular differentiation. Furthermore, molecular alterations like epidermal growth factor receptor and Kirsten rat sarcoma 2 viral oncogene homolog mutations, which are seen in adenocarcinomas, are not well understood in mixed histology tumors such as adenosquamous carcinoma. In our study, we sought to better characterize adenosquamous tumors of the lung. Using immunohistochemistry to evaluate thymidylate synthase protein levels, we found that the expression of thymidylate synthase in these mixed tumors roughly parallel that of squamous cell carcinoma, instead of falling in between squamous cell and adenocarcinoma. Of note, in adenosquamous samples, the expression of thymidylate synthase was more closely correlated within the two components than would be expected by random chance alone. Also, we had a relatively high rate of epidermal growth factor receptor (11%) and Kirsten rat sarcoma 2 viral oncogene homolog (33%) mutations in these specimens, with the mutations showing convergence in both the glandular and squamous components upon microdissection. Our results indicate that adenosquamous carcinomas are not simple mixtures of their two histological components; they rather behave as their own entity, and it is important to further understand their behavior. Given the similarity of thymidylate synthase expression between squamous cell and adenosquamous carcinoma, and that thymidylate synthase is the main target of pemetrexed, we extrapolate that pemetrexed may also have inferior clinical activity in adenosquamous carcinoma.

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Section: Discussionsupporting

confidence: 91%

Thymidylate synthase expression and molecular alterations in adenosquamous carcinoma of the lung

et al. 2013

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“…In the present study, TS expression was significantly increased in tumor tissues compared with the surrounding non-tumor lung tissues. This is consistent with the results of previous studies, regardless of the methodology used to measure TS (Higashiyama et al 2001;Shintani et al 2003;Tanaka et al 2011). The expression of DPD in lung cancer tissues was significantly higher than in non-tumor tissues in our study.…”

Section: Discussionsupporting

confidence: 93%

“…Our findings were consistent with RT-PCR results obtained in a large-scale study (Tanaka et al 2011), which also supports the validity of ELISA for measuring TS expression in clinical tissues.…”

Section: Discussionsupporting

confidence: 91%

“…They observed that TS gene expression in adenocarcinomas was significantly lower than in other types of carcinoma. Furthermore, they found that TS gene expression was significantly increased with decreased tumor cell differentiation (Tanaka et al 2011). In the present study, low TS expression levels were significantly associated with the features common for relatively slow growing adenocarcinoma, such as female sex, nonsmoker, well differentiated, and EGFR mutation.…”

Section: Discussionsupporting

confidence: 59%

“…Our data, together with those of previous studies, support the inhibition of DPD as a method to enhance the bioavailability and efficacy of 5-FU in lung cancer. Tanaka et al (2011) measured TS gene expression in laser-captured microdissected sections obtained from more than 2,500 primary lung cancers and their surrounding normal tissues using real-time RT-PCR. They observed that TS gene expression in adenocarcinomas was significantly lower than in other types of carcinoma.…”

Section: Discussionmentioning

confidence: 99%

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Higher Tissue Levels of Thymidylate Synthase Determined by ELISA Are Associated with Poor Prognosis of Patients with Lung Cancer

Shiina

Saito

Sakaizawa

et al. 2017

Tohoku J. Exp. Med.

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Thymidylate synthase (TS) is essential in thymidylate biosynthesis and DNA replication. Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme in pyrimidine catabolism and is important in catabolism of 5-fluorouracil (5-FU). The significance of TS and DPD expressed in lung cancer remains controversial. Here we analyzed the relationship between TS and DPD expression and clinicopathological features of lung cancer. Enzyme-linked immunosorbent assays (ELISAs) were used to measure TS and DPD levels in paired tumor and non-tumor lung tissues obtained from 168 patients (107 adenocarcinomas, 39 squamous cell carcinomas, and 22 others), who had operations at the Shinshu University Hospital from 2004 to 2007 and were followed up for a median of 57.0 months. TS and DPD expression levels were higher in tumor tissues, and TS expression levels were significantly lower in adenocarcinomas than those in other subtypes. In addition, patients with low TS levels survived longer compared with patents with high TS levels. By contrast, DPD expression levels were not correlated with overall patient survival. Importantly, patients with low TS and DPD levels exhibited significantly prolonged survival than those with high TS and DPD. Among the 168 patients, 59 patients were treated with tegafur-uracil (UFT), a DPD-inhibitory fluoropyrimidine, and the UFT-treated patients with high TS and high DPD levels showed worst prognosis. Our study demonstrates a significant correlation between low TS expression levels and long-term prognosis of patients with lung cancer. Thus, ELISA is a clinically useful method to measure TS and DPD expression in lung cancer tissues.

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Reply to association of EGFR mutation or ALK rearrangement with expression of DNA repair and synthesis genes in never‐smoker women with pulmonary adenocarcinoma

Ren

Zhou

2013

Cancer

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Thymidylate synthase (TS) gene expression in primary lung cancer patients: a large-scale study in Japanese population

Abstract: Lower TS expression in adenocarcinoma of the lung was confirmed in a large-scale study.

Cited by 36 publications

References 35 publications

Thymidylate synthase expression and molecular alterations in adenosquamous carcinoma of the lung

Thymidylate synthase expression and molecular alterations in adenosquamous carcinoma of the lung

Higher Tissue Levels of Thymidylate Synthase Determined by ELISA Are Associated with Poor Prognosis of Patients with Lung Cancer

Reply to association of EGFR mutation or ALK rearrangement with expression of DNA repair and synthesis genes in never‐smoker women with pulmonary adenocarcinoma

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