Expression of CYP3A4 as a predictor of response to chemotherapy in peripheral T-cell lymphomas

Rodríguez‐Antona, Cristina; Leskelä, Susanna; Zając, Magdalena; Cuadros, Marta; Alvés, Javier; Moneo, Maria Victoria; Martín, Carmen; Cigudosa, Juan C.; Carnero, Amancio; Robledo, Mercedes; Benı́tez, Javier; Martı́nez-Delgado, Beatriz

doi:10.1182/blood-2007-02-075036

Cited by 44 publications

(43 citation statements)

References 25 publications

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“…Interestingly, all patients with metastasis carried at least more than two unfavorable alleles, suggesting that the genes which were initially selected to be related with the metabolism of doxorubicin and cisplatin might also influence the development of metastasis. For all associated genes in this study we have identified publications suggesting that the expression of these five genes are linked to metastasis formation (20,22,27,30,31). We were able to identify a group of patients with very poor outcome, which may benefit from alternative or novel treatment strategies.…”

Section: Discussionmentioning

confidence: 99%

A First Step toward Personalized Medicine in Osteosarcoma: Pharmacogenetics as Predictive Marker of Outcome after Chemotherapy-Based Treatment

Hagleitner

Coenen

Gelderblom

et al. 2015

Clinical Cancer Research

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Purpose: Overall survival in patients with osteosarcoma is only 60%. Poor response to chemotherapy is the dominant risk factor for poor survival. Pharmacogenetic research can offer possibilities to optimize treatment and improve outcome. We applied a pathway-based approach to evaluate the cumulative effect of genes involved in the metabolism of cisplatin and doxorubicin in relationship to clinical outcome.Experimental Design: We included 126 patients with osteosarcoma. To comprehensively assess common genetic variation in the 54 genes selected, linkage disequilibrium (LD; r 2 ¼ 0.8)-based tag-single nucleotide polymorphisms (SNP) strategy was used. A final set of 384 SNPs was typed using Illumina Beadarray platform. SNPs significantly associated with 5-year progression-free survival (PFS) were replicated in another 64 patients with osteosarcoma. Results:We identified five variants in FasL, MSH2, ABCC5, CASP3, and CYP3A4 that were associated with 5-year PFS. Risk stratification based on the combined effects of the risk alleles showed a significant improvement of 5-year PFS. Patients that carried no or only one risk allele had a 5-year PFS of 100% compared with a 5-year PFS of 84.4% for carriers of two or three risk alleles, 66.7% PFS if a patient carried four to five alleles, and a 5-year PFS of 41.8% for patients with >5 risk alleles (P < 0.001).Conclusions: We identified several genes that showed association with PFS in patients with osteosarcoma. These pharmacogenetic risk factors might be useful to predict treatment outcome and to stratify patients immediately after diagnosis and offer the possibility to improve treatment and outcome. Clin Cancer Res; 21(15); 3436-41. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

A First Step toward Personalized Medicine in Osteosarcoma: Pharmacogenetics as Predictive Marker of Outcome after Chemotherapy-Based Treatment

Hagleitner

Coenen

Gelderblom

et al. 2015

Clinical Cancer Research

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“…Rodríguez-Antona et al (23) found that a high tumoral expression of CYP3A4 was significantly associated with a lower complete remission rate in peripheral T-cell lymphomas (PTCL). They concluded that a high CYP3A4 tumoral expression could be useful to predict poor response to the standard PTCL chemotherapy, but it does not affect survival.…”

Section: Discussionmentioning

confidence: 99%

Expression profiling and long lasting responses to chemotherapy in metastatic gastric cancer

Nigro

Monteverde²,

Riba³

et al. 2010

Int J Oncol

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Abstract. Current palliative chemotherapy (CT) regimens achieve clinical benefits in less than 50% of patients treated for metastatic gastric cancers, and long-term survivals are anecdotical. Genetic polymorphisms and differences at the level of transcription in genes involved in biological processes of drug metabolism, DNA repair and drug resistance can explain the observed individual differences in response to drugs, in survival and in different susceptibility to the toxic effects of CT. The possibility to classify patients on the basis of genetic signatures could help in choosing the CT regimen. We present herein an analysis of genetic and expression profiling of three patients affected by metastatic gastric cancer, treated with CT and alive, disease-free, at 66-82 months. Four patients with typical clinical outcome represented the control group. Expression profiling from paraffin-embedded tumor tissues was performed on an ad hoc set of genes involved in drug metabolism and resistance, DNA repair, cell cycle regulation and growth factors signalling. Genetic polymorphism analysis on DNA extracted from peripheral blood was done by pyrosequencing of genetic markers predictive of drug response. Expression analysis in long-term survivors revealed a significant upregulation of PTEN, TP63, GADD45a and MAPK1 genes. We found also an upregulation of CYP1A1, CYP3A4 and ERBB4 genes. EGF was found to be down-regulated in long-term survivors. ERCC1 C8092A polymorphism seems to be associated with survival in our set of patients. The present study shed light on a set of genes, which could have a predictive role in survival of patients with metastatic gastric tumors.

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“…Frozen samples from peripheral T-cell lymphomas were collected through the Spanish National Cancer Centre (Madrid, Spain) tumor bank network from pathology departments of different hospitals in Spain (20). The main characteristics of this human material and cell lines used for mRNA quantification are shown in Supplementary Table S1.…”

Section: Methodsmentioning

confidence: 99%

Hematologic β-Tubulin VI Isoform Exhibits Genetic Variability That Influences Paclitaxel Toxicity

et al. 2012

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Cellular microtubules composed of a-b-tubulin heterodimers that are essential for cell shape, division, and intracellular transport are valid targets for anticancer therapy. However, not all the conserved but differentially expressed members of the b-tubulin gene superfamily have been investigated for their role in these settings. In this study, we examined roles for the hematologic isoform b-tubulin VI and functional genetic variants in the gene. b-tubulin VI was highly expressed in blood cells with a substantial interindividual variability (seven-fold variation in mRNA). We characterized DNA missense variations leading to Q43P, T274M, and R307H, and a rare nonsense variant, Y55X. Because variations in the hematologic target of microtubule-binding drugs might alter their myelosuppressive action, we tested their effect in cell lines stably expressing the different b-tubulin VI full-length variants, finding that the T274M change significantly decreased sensitivity to paclitaxel-induced tubulin polymerization. Furthermore, patients treated with paclitaxel and carrying b-tubulin VI T274M exhibited a significantly lower thrombocytopenia than wild-type homozygous patients (P ¼ 0.031). Together, our findings define b-tubulin VI as a hematologic isotype with significant genetic variation in humans that may affect the myelosuppresive action of microtubule-binding drugs. A polymorphism found in a tubulin isoform expressed only in hemapoietic cells may contribute to the patient variation in myelosuppression that occurs after treatment with microtubule-binding drugs. Cancer Res; 72(18); 4744-52. Ó2012 AACR.

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Expression of CYP3A4 as a predictor of response to chemotherapy in peripheral T-cell lymphomas

Cited by 44 publications

References 25 publications

A First Step toward Personalized Medicine in Osteosarcoma: Pharmacogenetics as Predictive Marker of Outcome after Chemotherapy-Based Treatment

A First Step toward Personalized Medicine in Osteosarcoma: Pharmacogenetics as Predictive Marker of Outcome after Chemotherapy-Based Treatment

Expression profiling and long lasting responses to chemotherapy in metastatic gastric cancer

Hematologic β-Tubulin VI Isoform Exhibits Genetic Variability That Influences Paclitaxel Toxicity

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