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12 pages, 1734 KiB

Open AccessArticle

miR-335-laden B Cell-Derived Extracellular Vesicles Promote SOX4-Dependent Apoptosis in Human Multiple Myeloma Cells

by Elisabetta Lombardi, Gonzalo Almanza, Kinga Kowal, Marco Valvasori, Francesco Agostini, Carla Vicinanza, Francesco Da Ros, Cristina Durante, Miriam Marangon, Mariagrazia Michieli, Maurizio Rupolo, Mario Mazzucato and Maurizio Zanetti

J. Pers. Med. 2021, 11(12), 1240; https://doi.org/10.3390/jpm11121240 - 23 Nov 2021

Cited by 3 | Viewed by 1993

Abstract

Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow. Despite novel therapies, MM still remains an incurable cancer and new strategies are needed. Increased expression of the transcription factor Sex-determining region Y-related high-mobility-group box transcription factor [...] Read more.

Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow. Despite novel therapies, MM still remains an incurable cancer and new strategies are needed. Increased expression of the transcription factor Sex-determining region Y-related high-mobility-group box transcription factor 4 (SOX4) has been correlated with tumor development and progression through a variety of distinct processes, including inhibition of apoptosis, increased cell invasion and metastasis, and induction and maintenance of cancer-initiating cells. The role of SOX4 in MM is largely unknown. Since SOX4 is a known target of miR-335, we used miR-335 to assess whether SOX4 modulation could promote apoptosis in MM cells. Using an MM cell model we show that miR-335 acts both on SOX4-related genes (AKT, PI3K) and hypoxia-inducible factor 1-alpha (Hif1-α). In addition, we show miR-335-laden extracellular vesicles induced in B cells (iEVs) are also effective in targeting SOX4, causing apoptosis. Collectively, we propose that miR-335-laden iEVs could be developed as a novel form of gene therapy in MM. Full article

(This article belongs to the Special Issue Pharmacogenomics of Oncology Therapies)

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19 pages, 1287 KiB

Open AccessArticle

Association between Genetic Variants and Cisplatin-Induced Nephrotoxicity: A Genome-Wide Approach and Validation Study

by Zulfan Zazuli, Corine de Jong, Wei Xu, Susanne J. H. Vijverberg, Rosalinde Masereeuw, Devalben Patel, Maryam Mirshams, Khaleeq Khan, Dangxiao Cheng, Bayardo Ordonez-Perez, Shaohui Huang, Anna Spreafico, Aaron R. Hansen, David P. Goldstein, John R. de Almeida, Scott V. Bratman, Andrew Hope, Jennifer J. Knox, Rebecca K. S. Wong, Gail E. Darling, Abhijat Kitchlu, Simone W. A. van Haarlem, Femke van der Meer, Anne S. R. van Lindert, Alexandra ten Heuvel, Jan Brouwer, Colin J. D. Ross, Bruce C. Carleton, Toine C. G. Egberts, Gerarda J. M. Herder, Vera H. M. Deneer, Anke H. Maitland-van der Zee and Geoffrey Liu Show full author list Hide full author list

J. Pers. Med. 2021, 11(11), 1233; https://doi.org/10.3390/jpm11111233 - 20 Nov 2021

Cited by 5 | Viewed by 2912

Abstract

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults [...] Read more.

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort (n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = −8.4, 95% CI −11.4–−5.4, p = 3.9 × 10⁻⁸) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3–6.7, p = 7.4 × 10⁻⁷) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = −1.5, 95% CI −5.3–2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8–3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies. Full article

(This article belongs to the Special Issue Pharmacogenomics of Oncology Therapies)

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17 pages, 2536 KiB

Open AccessArticle

DPYD Exome, mRNA Expression and Uracil Levels in Early Severe Toxicity to Fluoropyrimidines: An Extreme Phenotype Approach

by Priscila Villalvazo, Belén Marzal-Alfaro, Pilar García-Alfonso, José Luis Revuelta-Herrero, Fabienne Thomas, Sara López-Tarruella, Xandra García-González, Aitana Calvo, Malika Yakoubi, Sara Salvador-Martín, Flora López-López, Iker Aguilar, María Sanjurjo-Sáez, Miguel Martín and Luis Andrés López-Fernández

J. Pers. Med. 2021, 11(8), 792; https://doi.org/10.3390/jpm11080792 - 13 Aug 2021

Cited by 2 | Viewed by 2303

Abstract

Dihydropyrimidine dehydrogenase deficiency is a major cause of severe fluoropyrimidine-induced toxicity and could lead to interruption of chemotherapy or life-threatening adverse reactions. This study aimed to characterize the DPYD exon sequence, mRNA expression and in vivo DPD activity by plasma uracil concentration. It [...] Read more.

Dihydropyrimidine dehydrogenase deficiency is a major cause of severe fluoropyrimidine-induced toxicity and could lead to interruption of chemotherapy or life-threatening adverse reactions. This study aimed to characterize the DPYD exon sequence, mRNA expression and in vivo DPD activity by plasma uracil concentration. It was carried out in two groups of patients with extreme phenotypes (toxicity versus control) newly treated with a fluoropyrimidine, during the first three cycles of treatment. A novel nonsense gene variant (c.2197insA) was most likely responsible for fluoropyrimidine-induced toxicity in one patient, while neither DPYD mRNA expression nor plasma uracil concentration was globally associated with early toxicity. Our present work may help improve pharmacogenetic testing to avoid severe and undesirable adverse reactions to fluoropyrimidine treatment and it also supports the idea of looking beyond DPYD. Full article

(This article belongs to the Special Issue Pharmacogenomics of Oncology Therapies)

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Review

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17 pages, 566 KiB

Open AccessReview

Role of Long Non-Coding RNA Polymorphisms in Cancer Chemotherapeutic Response

by Zheng Zhang, Meng Gu, Zhongze Gu and Yan-Ru Lou

J. Pers. Med. 2021, 11(6), 513; https://doi.org/10.3390/jpm11060513 - 04 Jun 2021

Cited by 6 | Viewed by 2799

Abstract

Genetic polymorphisms are defined as the presence of two or more different alleles in the same locus, with a frequency higher than 1% in the population. Since the discovery of long non-coding RNAs (lncRNAs), which refer to a non-coding RNA with a length [...] Read more.

Genetic polymorphisms are defined as the presence of two or more different alleles in the same locus, with a frequency higher than 1% in the population. Since the discovery of long non-coding RNAs (lncRNAs), which refer to a non-coding RNA with a length of more than 200 nucleotides, their biological roles have been increasingly revealed in recent years. They regulate many cellular processes, from pluripotency to cancer. Interestingly, abnormal expression or dysfunction of lncRNAs is closely related to the occurrence of human diseases, including cancer and degenerative neurological diseases. Particularly, their polymorphisms have been found to be associated with altered drug response and/or drug toxicity in cancer treatment. However, molecular mechanisms are not yet fully elucidated, which are expected to be discovered by detailed studies of RNA–protein, RNA–DNA, and RNA–lipid interactions. In conclusion, lncRNAs polymorphisms may become biomarkers for predicting the response to chemotherapy in cancer patients. Here we review and discuss how gene polymorphisms of lncRNAs affect cancer chemotherapeutic response. This knowledge may pave the way to personalized oncology treatments. Full article

(This article belongs to the Special Issue Pharmacogenomics of Oncology Therapies)

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23 pages, 1599 KiB

Open AccessReview

Generating a Precision Endoxifen Prediction Algorithm to Advance Personalized Tamoxifen Treatment in Patients with Breast Cancer

by Thomas Helland, Sarah Alsomairy, Chenchia Lin, Håvard Søiland, Gunnar Mellgren and Daniel Louis Hertz

J. Pers. Med. 2021, 11(3), 201; https://doi.org/10.3390/jpm11030201 - 13 Mar 2021

Cited by 13 | Viewed by 3127

Abstract

Tamoxifen is an endocrine treatment for hormone receptor positive breast cancer. The effectiveness of tamoxifen may be compromised in patients with metabolic resistance, who have insufficient metabolic generation of the active metabolites endoxifen and 4-hydroxy-tamoxifen. This has been challenging to validate due to [...] Read more.

Tamoxifen is an endocrine treatment for hormone receptor positive breast cancer. The effectiveness of tamoxifen may be compromised in patients with metabolic resistance, who have insufficient metabolic generation of the active metabolites endoxifen and 4-hydroxy-tamoxifen. This has been challenging to validate due to the lack of measured metabolite concentrations in tamoxifen clinical trials. CYP2D6 activity is the primary determinant of endoxifen concentration. Inconclusive results from studies investigating whether CYP2D6 genotype is associated with tamoxifen efficacy may be due to the imprecision in using CYP2D6 genotype as a surrogate of endoxifen concentration without incorporating the influence of other genetic and clinical variables. This review summarizes the evidence that active metabolite concentrations determine tamoxifen efficacy. We then introduce a novel approach to validate this relationship by generating a precision endoxifen prediction algorithm and comprehensively review the factors that must be incorporated into the algorithm, including genetics of CYP2D6 and other pharmacogenes. A precision endoxifen algorithm could be used to validate metabolic resistance in existing tamoxifen clinical trial cohorts and could then be used to select personalized tamoxifen doses to ensure all patients achieve adequate endoxifen concentrations and maximum benefit from tamoxifen treatment. Full article

(This article belongs to the Special Issue Pharmacogenomics of Oncology Therapies)

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24 pages, 1560 KiB

Open AccessReview

A Genotyping/Phenotyping Approach with Careful Clinical Monitoring to Manage the Fluoropyrimidines-Based Therapy: Clinical Cases and Systematic Review of the Literature

by Valeria Conti, Emanuela De Bellis, Valentina Manzo, Francesco Sabbatino, Francesco Iannello, Fabrizio Dal Piaz, Viviana Izzo, Bruno Charlier, Berenice Stefanelli, Martina Torsiello, Teresa Iannaccone, Albino Coglianese, Francesca Colucci, Stefano Pepe and Amelia Filippelli

J. Pers. Med. 2020, 10(3), 113; https://doi.org/10.3390/jpm10030113 - 03 Sep 2020

Cited by 6 | Viewed by 3863

Abstract

Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. FP pharmacogenetics, including four DPYD polymorphisms (DPYD-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the DPYD-PGx should [...] Read more.

Fluoropyrimidines (FP) are mainly metabolised by dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene. FP pharmacogenetics, including four DPYD polymorphisms (DPYD-PGx), is recommended to tailor the FP-based chemotherapy. These polymorphisms increase the risk of severe toxicity; thus, the DPYD-PGx should be performed prior to starting FP. Other factors influence FP safety, therefore phenotyping methods, such as the measurement of 5-fluorouracil (5-FU) clearance and DPD activity, could complement the DPYD-PGx. We describe a case series of patients in whom we performed DPYD-PGx (by real-time PCR), 5-FU clearance and a dihydrouracil/uracil ratio (as the phenotyping analysis) and a continuous clinical monitoring. Patients who had already experienced severe toxicity were then identified as carriers of DPYD variants. The plasmatic dihydrouracil/uracil ratio (by high-performance liquid chromatography (HPLC)) ranged between 1.77 and 7.38. 5-FU clearance (by ultra-HPLC with tandem mass spectrometry) was measured in 3/11 patients. In one of them, it reduced after the 5-FU dosage was halved; in the other case, it remained high despite a drastic dosage reduction. Moreover, we performed a systematic review on genotyping/phenotyping combinations used as predictive factors of FP safety. Measuring the plasmatic 5-FU clearance and/or dihydrouracil/uracil (UH2/U) ratio could improve the predictive potential of DPYD-PGx. The upfront DPYD-PGx combined with clinical monitoring and feasible phenotyping method is essential to optimising FP-based chemotherapy. Full article

(This article belongs to the Special Issue Pharmacogenomics of Oncology Therapies)

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18 pages, 2683 KiB

Open AccessReview

Pharmacogenomics to Predict Tumor Therapy Response: A Focus on ATP-Binding Cassette Transporters and Cytochromes P450

by Viktor Hlaváč, Petr Holý and Pavel Souček

J. Pers. Med. 2020, 10(3), 108; https://doi.org/10.3390/jpm10030108 - 28 Aug 2020

Cited by 13 | Viewed by 4575

Abstract

Pharmacogenomics is an evolving tool of precision medicine. Recently, due to the introduction of next-generation sequencing and projects generating “Big Data”, a plethora of new genetic variants in pharmacogenes have been discovered. Cancer resistance is a major complication often preventing successful anticancer treatments. [...] Read more.

Pharmacogenomics is an evolving tool of precision medicine. Recently, due to the introduction of next-generation sequencing and projects generating “Big Data”, a plethora of new genetic variants in pharmacogenes have been discovered. Cancer resistance is a major complication often preventing successful anticancer treatments. Pharmacogenomics of both somatic mutations in tumor cells and germline variants may help optimize targeted treatments and improve the response to conventional oncological therapy. In addition, integrative approaches combining copy number variations and long noncoding RNA profiling with germline and somatic variations seem to be a promising approach as well. In pharmacology, expression and enzyme activity are traditionally the more studied aspects of ATP-binding cassette transporters and cytochromes P450. In this review, we briefly introduce the field of pharmacogenomics and the advancements driven by next-generation sequencing and outline the possible roles of genetic variation in the two large pharmacogene superfamilies. Although the evidence needs further substantiation, somatic and copy number variants as well as rare variants and common polymorphisms in these genes could all affect response to cancer therapy. Regulation by long noncoding RNAs has also been shown to play a role. However, in all these areas, more comprehensive studies on larger sets of patients are needed. Full article

(This article belongs to the Special Issue Pharmacogenomics of Oncology Therapies)

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12 pages, 2899 KiB

Open AccessReview

Diagnostic and Prognostic Significance of MiR-150 in Colorectal Cancer: A Systematic Review and Meta-Analysis

by Daniel Sur, Claudia Burz, Shanthi Sabarimurugan and Alexandru Irimie

J. Pers. Med. 2020, 10(3), 99; https://doi.org/10.3390/jpm10030099 - 24 Aug 2020

Cited by 9 | Viewed by 2821

Abstract

Although treatment options have improved, the survival and quality of life of colorectal cancer (CRC) patients remain dismal. Therefore, significant biomarker prediction may help to improve colorectal cancer patient’s prognosis profile. MiRNAs have come as an option because of their essential role in [...] Read more.

Although treatment options have improved, the survival and quality of life of colorectal cancer (CRC) patients remain dismal. Therefore, significant biomarker prediction may help to improve colorectal cancer patient’s prognosis profile. MiRNAs have come as an option because of their essential role in cancer initiation and progression by regulating several molecular processes. MiR-150 has different roles in cancer, but its function in CRC is still ambiguous. We undertook a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) research criteria by interrogating several databases in order to assess the diagnostic accuracy and prognostic value of miR-150. Additionally, clinicalgov.org was scanned for possible trials. The literature was screened from inception to February 2020. A total of 12 out of 70 full-text articles were included in the meta-analysis. Among these, nine studies were included for diagnostic accuracy, and the remaining three were considered for prognostic significance of miR-150. With our results, miR-150 is an appropriate diagnostic biomarker, especially in serum and plasma, while the prognostic value of miR-150 was not statistically significant. The present study findings suggest that miR-150 has high specificity and sensitivity values as a potential diagnostic biomarker in colorectal cancer patients. Full article

(This article belongs to the Special Issue Pharmacogenomics of Oncology Therapies)

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20 pages, 315 KiB

Open AccessReview

Pharmacogenomics, Pharmacokinetics and Circulating Proteins As Biomarkers for Bevacizumab Treatment Optimization in Patients with Cancer: A Review

by Apostolos Papachristos and Gregory B. Sivolapenko

J. Pers. Med. 2020, 10(3), 79; https://doi.org/10.3390/jpm10030079 - 04 Aug 2020

Cited by 10 | Viewed by 3485

Abstract

Bevacizumab is a monoclonal antibody that targets VEGF-A and inhibits tumor angiogenesis. Bevacizumab is approved for the treatment of various cancer, including metastatic colorectal cancer (mCRC), ovarian cancer, lung cancer, and others. Thus, it is widely used in oncology, but contrary to other [...] Read more.

Bevacizumab is a monoclonal antibody that targets VEGF-A and inhibits tumor angiogenesis. Bevacizumab is approved for the treatment of various cancer, including metastatic colorectal cancer (mCRC), ovarian cancer, lung cancer, and others. Thus, it is widely used in oncology, but contrary to other therapeutic classes, there is still a lack of validating predictive factors for treatment outcomes with these agents. In recent years, the research for factors predictive of anti-VEGF treatments and especially bevacizumab response has been one of the most competitive translational research fields. Herein, we review and present the available literature of the clinical use of biomarkers, pharmacogenomics (PG), and therapeutic drug monitoring (TDM) approaches that can be used for the optimization of bevacizumab use in the era of precision medicine. Full article

(This article belongs to the Special Issue Pharmacogenomics of Oncology Therapies)

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