Ribonucleotide reductase M1 gene promoter activity, polymorphisms, population frequencies, and clinical relevance

Bepler, Gerold; Zheng, Zhong; Gautam, Anirudh; Sharma, Shivani; Cantor, Alan; Sharma, Anupama; Cress, W. Douglas; Kim, Young Chul; Rosell, Rafael; McBride, Colleen M.; Robinson, Lary A.; Sommers, Eric; Haura, Eric B.

doi:10.1016/j.lungcan.2004.07.043

Cited by 76 publications

(78 citation statements)

References 12 publications

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“…The other subunit of RNR is encoded by the RRM1 gene, whose mRNA levels correlate with shorter survival in gemcitabine/ cisplatin-treated advanced NSCLC patients (43)(44)(45)(46). Interestingly, RRM2 is also associated with resistance to a variety of chemotherapeutic agents, including gemcitabine (47,48).…”

Section: Discussionmentioning

confidence: 99%

Survival prediction of stage I lung adenocarcinomas by expression of 10 genes

Bianchi¹,

Nuciforo²,

Vecchi³

et al. 2007

J. Clin. Invest.

102

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Adenocarcinoma is the predominant histological subtype of lung cancer, the leading cause of cancer deaths in the world. At stage I, the tumor is cured by surgery alone in about 60% of cases. Markers are needed to stratify patients by prognostic outcomes and may help in devising more effective therapies for poor prognosis patients. To achieve this goal, we used an integrated strategy combining meta-analysis of published lung cancer microarray data with expression profiling from an experimental model. The resulting 80-gene model was tested on an independent cohort of patients using RT-PCR, resulting in a 10-gene predictive model that exhibited a prognostic accuracy of approximately 75% in stage I lung adenocarcinoma when tested on 2 additional independent cohorts. Thus, we have identified a predictive signature of limited size that can be analyzed by RT-PCR, a technology that is easy to implement in clinical laboratories.

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Section: Discussionmentioning

confidence: 99%

Survival prediction of stage I lung adenocarcinomas by expression of 10 genes

Bianchi¹,

Nuciforo²,

Vecchi³

et al. 2007

J. Clin. Invest.

102

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“…When the association between these SNPs and gemcitabine IC 50 was examined, only cell lines with RRM1 2232G4A showed a tendency to be more chemosensitive to gemcitabine, although none of the differences reached a statistically significant level. Bepler et al (2005) analysed the RRM1 promoter for polymorphism, and discovered two SNPs, RRM1 À37C4A and À524T4C. There was a strong linkage between these SNPs, and À37CC in combination with À524TT was the most frequently observed allelotype, accounting for 42.4% of the ethnically diverse population of 1129.…”

Section: Pharmacogenomics Of Gemcitabinementioning

confidence: 99%

Pharmacogenomics of gemcitabine: can genetic studies lead to tailor-made therapy?

Kiyosawa²,

2007

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Gemcitabine is a deoxycytidine analogue that has a broad spectrum of antitumour activity in many solid tumours including pancreatic cancer. We have recently carried out a pharmacogenomic study in cancer patients treated with gemcitabine, and found that one genetic polymorphism of an enzyme involved in gemcitabine metabolism can cause interindividual variations in the pharmacokinetics and toxicity of this agent. In this paper, we review recent genetic studies of gemcitabine, and discuss the possibility of individualised cancer chemotherapy based on a pharmacogenomic approach.

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“…Among patients with surgically resected NSCLC, Bepler et al determined that the allelotype with the highest predicted promoter activity was associated with the best patient outcomes (14). However, in gemcitabine-treated NSCLC cells, we can hypothesize that lower predicted promoter activity would be associated with better responses to therapy.…”

mentioning

confidence: 93%

Efficacy of Gemcitabine in Patients with Non–Small Cell Lung Cancer According to Promoter Polymorphisms of the Ribonucleotide Reductase M1 Gene

Kim

Jeong

Kim

et al. 2008

Clinical Cancer Research

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Purpose: High ribonucleotide reductase M1 (RRM1) expression in resected lung cancers has been associated with better clinical outcomes. However, gemcitabine-treated patients with high tumoral RRM1 expression generally evidence poor prognoses due to the decreased efficacy of gemcitabine therapy. This study was designed in accordance with the hypothesis that polymorphisms (-37 and -524) of the RRM1 promoter gene sequence, which regulate RRM1expression, could influence the efficacy and prognosis of lung cancer patients treated with gemcitabine-based chemotherapy. Experimental Design: A retrospective dataset of 97 patients with advanced non^small cell lung cancer treated with gemcitabine regimens as a first-line treatment was studied in this work. The allelotyping of RRM1 promoter polymorphisms was conducted via real-time PCR using genomic DNA obtained from peripheral WBC. Results: The RRM1 promoter allelotype was RR37CC-R524TT in 58 patients, RR37AC-RR524CT in 29 patients, and other allelotypes in 10 patients. The response rate for gemcitabinecontaining chemotherapy was 49.5 %. The response rate was significantly higher in the RR37AC-RR524CT group (65.5%) compared with the group containing other allelotypes (42.6%; P = 0.039). Overall survival and progression-free survival did not differ significantly by allelotype. Conclusions: We detected significant differences in response rates to gemcitabine-based chemotherapy according to the allelotypes of the RRM1 promoter sequence, which could be determined using the germline DNA. Further functional and clinical studies will be required before this can be used as a predictive marker.

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Ribonucleotide reductase M1 gene promoter activity, polymorphisms, population frequencies, and clinical relevance

Cited by 76 publications

References 12 publications

Survival prediction of stage I lung adenocarcinomas by expression of 10 genes

Survival prediction of stage I lung adenocarcinomas by expression of 10 genes

Pharmacogenomics of gemcitabine: can genetic studies lead to tailor-made therapy?

Efficacy of Gemcitabine in Patients with Non–Small Cell Lung Cancer According to Promoter Polymorphisms of the Ribonucleotide Reductase M1 Gene

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