An Association Between <i>RRM1</i> Haplotype and Gemcitabine-Induced Neutropenia in Breast Cancer Patients

Rha, Sun Young; Jeung, Hei Cheul; Choi, Yujung; Yang, Woo Ick; Yoo, Jin Ho; Kim, Byung Soo; Roh, Jae Kyung; Chung, Hyun Cheol

doi:10.1634/theoncologist.12-6-622

Cited by 50 publications

(39 citation statements)

References 16 publications

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“…It should be noted that the validation material used in this study was not completely independent of the screening because the remaining non-extreme patients were used for the validation in addition to an independent patient cohort. Several studies have previously associated toxicity and response with variants of candidate genes involved in metabolism and transport of gemcitabine such as CDA, dCK, SLC28A1, SLC28A3 as well as target molecules RRM1, RRM2 and RRM2b (19)(20)(21)(22)(23)(24). In a recent metaanalysis, the genetic variant A79C in the CDA gene was associated with severe anemia, but without being able to show an effect related to neutropenia, thrombocytopenia, or response (25).…”

Section: Discussionmentioning

confidence: 99%

Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities

Gréen

Hasmats

Kupershmidt

et al. 2016

Clinical Cancer Research

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Purpose: Chemotherapies are associated with significant interindividual variability in therapeutic effect and adverse drug reactions. In lung cancer, the use of gemcitabine and carboplatin induces grade 3 or 4 myelosuppression in about a quarter of the patients, while an equal fraction of patients is basically unaffected in terms of myelosuppressive side effects. We therefore set out to identify genetic markers for gemcitabine/carboplatin-induced myelosuppression.Experimental Design: We exome sequenced 32 patients that suffered extremely high neutropenia and thrombocytopenia (grade 3 or 4 after first chemotherapy cycle) or were virtually unaffected (grade 0 or 1). The genetic differences/polymorphism between the groups were compared using six different bioinformatics strategies: (i) whole-exome nonsynonymous single-nucleotide variants association analysis, (ii) deviation from Hardy-Weinberg equilibrium, (iii) analysis of genes selected by a priori biologic knowledge, (iv) analysis of genes selected from gene expression meta-analysis of toxicity datasets, (v) Ingenuity Pathway Analysis, and (vi) FunCoup network enrichment analysis.Results: A total of 53 genetic variants that differed among these groups were validated in an additional 291 patients and were correlated to the patients' myelosuppression. In the validation, we identified rs1453542 in OR4D6 (P ¼ 0.0008; OR, 5.2; 95% CI, 1.8-18) as a marker for gemcitabine/carboplatin-induced neutropenia and rs5925720 in DDX53 (P ¼ 0.0015; OR, 0.36; 95% CI, 0.17-0.71) as a marker for thrombocytopenia. Patients homozygous for the minor allele of rs1453542 had a higher risk of neutropenia, and for rs5925720 the minor allele was associated with a lower risk for thrombocytopenia.Conclusions: We have identified two new genetic markers with the potential to predict myelosuppression induced by gemcitabine/carboplatin chemotherapy. Clin Cancer Res; 22(2); 366-73.Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities

Gréen

Hasmats

Kupershmidt

et al. 2016

Clinical Cancer Research

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“…19,27,29 No significant associations were detected for both RRM1 G2464A and A2455G polymorphisms and RRM1 gene expression. These results are in agreement with a previous study showing no significant association between mRNA levels of wild-type and polymorphic types in RRM1 G2464A alone (P ¼ 0.301), or a combination of several types of RRM1, including RRM1 A2455G, in 62 human cancer cell lines were used, including six lung cancer cell lines.…”

Section: Expression Of Drug-related Genes In Nsclcmentioning

confidence: 94%

“…28 In the same study, the RRM1 G2464A polymorphism demonstrated an association with gemcitabine sensitivity, 30 while together with the A2455G polymorphism was associated with neutropenia after gemcitabine treatment in breast cancer patients. 29 Therefore, further functional studies evaluating coexpressing genes, as well as prospective clinical trial for its application as a predictive biomarker are needed.…”

Section: Expression Of Drug-related Genes In Nsclcmentioning

confidence: 99%

“…28 This SNP, together with the A2455G polymorphism was associated with clinical outcome after gemcitabine treatment in breast cancer patients, but no analyses on RRM1 expression levels in tissues were conducted in this study. 29 Examples on how pharmacogenetic characteristics might affect drug response are also offered by several studies on platinum compounds, which inhibit cell proliferation by damaging DNA through the formation of intra-and interstrand crosslinks. Drug resistance occurs mostly because of detoxification or efficient repair of damaged DNA by the members of the nucleotide excision repair system, including ERCC1.…”

Section: Introductionmentioning

confidence: 99%

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Expression of gemcitabine- and cisplatin-related genes in non-small-cell lung cancer

et al. 2009

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The aim of this study was to investigate the influence of histology and site of analysis (primary tumor versus lymph node) on the expression of genes involved in gemcitabine and cisplatin activity in non-small-cell lung cancer (NSCLC). Excision repair cross-complementing-1 (ERCC1), human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), 5 0 -nucleotidase (5 0 -NT), cytidine deaminase (CDA) and ribonucleotidereductase regulatory subunits (RRM1 and RRM2) were analyzed by quantitative-reverse transcription-PCR in 88 microdissected samples from 69 chemonaive patients. The results showed different patterns of expression for all studied genes, suggesting a possible stratification of the patients. No difference was observed between primary tumor and lymph node metastasis, as well as in adenocarcinoma and squamous-cell carcinoma specimens, while we found a correlation between the CDA-A79C polymorphism and gene expression levels. These data suggest a similar genetic susceptibility to gemcitabine-cisplatin regimens for squamous cell and adenocarcinoma and support the use of both lymph node and primary tumor for the expression profiling of NSCLC.

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“…Furthermore, RRM1 is the molecular target of gemcitabine, and its mRNA expression levels are related to the efficacy of gemcitabine therapy 7, 8. The RRM1 polymorphism – 37 C<A and haplotype – was shown to be associated with susceptibility to gemcitabine in cancer patients including lung cancer 9, 10. However, the relationship between the ribonucleotide reductase M1 ( RRM1 ) gene and susceptibility to lung cancer has not been well addressed.…”

Section: Introductionmentioning

confidence: 99%

RRM1 *151A>T, RRM1 ‐756T>C, and RRM1 ‐585T>Gis associated with increased susceptibility of lung cancer in Chinese patients

Zheng

Mao

et al. 2016

Cancer Medicine

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Ribonucleotide reductase M1 (RRM1) is a crucial gene in DNA repair. Recent studies have shown that RRM1 expression can be a powerful predictor of survival or chemotherapy sensitivity in patients presenting with carcinomas who are treated with adjuvant gemcitabine‐based chemotherapy including lung cancer. However, the relationship between the single nucleotide polymorphisms (SNP) of RRM1 and the susceptibility of lung cancer to chemotherapy has not been well addressed. We detected six tag SNPs of RRM1 genotypes in a cohort of 1007 patients with primary lung cancer and 1007 age‐ and sex‐matched population controls using SNaPshot detection technology. Logistic regression, odds ratios (OR), and 95% confidence intervals were calculated to estimate lung cancer risk associated with SNP genotypes and haplotypes, after adjusting for case–control matching factors. Compared with the T/T and A/T genotype of RRM1 *151A>T, the A/A genotype had an increased risk for overall lung cancer (adjusted OR, 1.33). Additionally, the T/T+T/C genotypes of RRM1 ‐756T>C were risk factors that increased the susceptibility to lung cancer (adjusted OR 1.54, as compared with the C/C genotype). While the T/T+G/T genotypes of RRM1 ‐585T>G behaved as protective factors to increase the susceptibility to lung cancer (adjusted OR 0.44, as compared with the C/C genotype). In summary, this is the first study to systematically identify the relationship between the polymorphisms of RRM1 and individual susceptibility to lung cancer. It is anticipated that the RRM1 *151A>T, RRM1 ‐756T>C, and RRM1 ‐585T>G polymorphisms will improve the predictive prognosis of lung cancer sensitivity.

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An Association Between RRM1 Haplotype and Gemcitabine-Induced Neutropenia in Breast Cancer Patients

Cited by 50 publications

References 16 publications

Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities

Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities

Expression of gemcitabine- and cisplatin-related genes in non-small-cell lung cancer

RRM1 *151A>T, RRM1 ‐756T>C, and RRM1 ‐585T>Gis associated with increased susceptibility of lung cancer in Chinese patients

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