Pharmacogenetics: A Tool in Cancer Therapy

Topic Information

Dear Colleagues,

Over the past years, the availability of high-throughput technologies has led to an important change in pharmacogenetics, improving the practice of precision medicine. The tumour genetic landscape influences treatment response in cancer patients. Multiple molecular mechanisms of resistance to therapies in solid or hematologic tumours have been discussed, highlighting the degree of tumours’ heterogeneity. Multiple approaches, using liquid biopsies, circulating tumour cells and tissue biopsies, can be helpful to monitor patients during therapy and understand drug resistance mechanisms. This knowledge has paved the way for the development of personalized medicine aimed at providing better clinical and therapeutic approaches. To this end, there is an urgent need for the identification of predictive biomarkers of response/resistance to treatments and toxicity, including new tools for genome analysis for the development of personalized medicine. We are pleased to invite you to contribute to our Topic entitled “Pharmacogenetics: A Tool in Cancer Therapy” aimed to collect contributions on the potential role of Pharmacogenetics in cancer treatment, also highlighting the strength as well as its limits in clinical translation. This Topic aims to investigate the different pharmacogenetics approaches useful to identify potential biomarkers in cancer therapy. In this Topic, original research articles and reviews are welcome.

Research areas may include (but are not limited to) the following:

• Genetic variability related to drug toxicity and efficacy in cancer;
• Genomic and proteomic profiling in cancer;
• ncRNA profiles to predict prognosis and outcome in cancer;
• Liquid biopsy in cancer;
• Methylation profiles to predict cancer prognosis and outcome;
• Multi-omics approaches to the study of cancer treatment response;
• Epigenetic changes as determinants of drug response and resistance in cancer;
• Novel genomic targets for drug development.

I/We look forward to receiving your contributions.

Dr. Stefania Crucitta
Dr. Gloria Ravegnini
Dr. Rossana Roncato
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Cancers cancers	4.5	8.0	2009	17.4 Days	CHF 2900
International Journal of Molecular Sciences ijms	4.9	8.1	2000	16.8 Days	CHF 2900
Journal of Personalized Medicine jpm	-	4.1	2011	17.4 Days	CHF 2600
Onco onco	-	-	2021	27.8 Days	CHF 1000
Pharmaceuticals pharmaceuticals	4.3	6.1	2004	13.9 Days	CHF 2900

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Published Papers (9 papers)

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All Cancers IJMS JPM Onco Pharmaceuticals

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Open AccessArticle

MKX-AS1 Gene Expression Associated with Variation in Drug Response to Oxaliplatin and Clinical Outcomes in Colorectal Cancer Patients

by Ricardo D. Gonzalez, George W. Small, Adrian J. Green, Farida S. Akhtari, Alison A. Motsinger-Reif, Julia C. F. Quintanilha, Tammy M. Havener, David M. Reif, Howard L. McLeod and Tim Wiltshire

Pharmaceuticals 2023, 16(5), 757; https://doi.org/10.3390/ph16050757 - 17 May 2023

Cited by 2 | Viewed by 2493

Abstract

Oxaliplatin (OXAL) is a commonly used chemotherapy for treating colorectal cancer (CRC). A recent genome wide association study (GWAS) showed that a genetic variant (rs11006706) in the lncRNA gene MKX-AS1 and partnered sense gene MKX could impact the response of genetically varied cell [...] Read more.

Oxaliplatin (OXAL) is a commonly used chemotherapy for treating colorectal cancer (CRC). A recent genome wide association study (GWAS) showed that a genetic variant (rs11006706) in the lncRNA gene MKX-AS1 and partnered sense gene MKX could impact the response of genetically varied cell lines to OXAL treatment. This study found that the expression levels of MKX-AS1 and MKX in lymphocytes (LCLs) and CRC cell lines differed between the rs11006706 genotypes, indicating that this gene pair could play a role in OXAL response. Further analysis of patient survival data from the Cancer Genome Atlas (TCGA) and other sources showed that patients with high MKX-AS1 expression status had significantly worse overall survival (HR = 3.2; 95%CI = (1.17–9); p = 0.024) compared to cases with low MKX-AS1 expression status. Alternatively, high MKX expression status had significantly better overall survival (HR = 0.22; 95%CI = (0.07–0.7); p = 0.01) compared to cases with low MKX expression status. These results suggest an association between MKX-AS1 and MKX expression status that could be useful as a prognostic marker of response to OXAL and potential patient outcomes in CRC. Full article

(This article belongs to the Topic Pharmacogenetics: A Tool in Cancer Therapy)

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19 pages, 2533 KiB  

Open AccessArticle

RYK Gene Expression Associated with Drug Response Variation of Temozolomide and Clinical Outcomes in Glioma Patients

by Ricardo D. Gonzalez, George W. Small, Adrian J. Green, Farida S. Akhtari, Tammy M. Havener, Julia C. F. Quintanilha, Amber B. Cipriani, David M. Reif, Howard L. McLeod, Alison A. Motsinger-Reif and Tim Wiltshire

Pharmaceuticals 2023, 16(5), 726; https://doi.org/10.3390/ph16050726 - 10 May 2023

Cited by 1 | Viewed by 2661

Abstract

Temozolomide (TMZ) chemotherapy is an important tool in the treatment of glioma brain tumors. However, variable patient response and chemo-resistance remain exceptionally challenging. Our previous genome-wide association study (GWAS) identified a suggestively significant association of SNP rs4470517 in the RYK (receptor-like kinase) gene [...] Read more.

Temozolomide (TMZ) chemotherapy is an important tool in the treatment of glioma brain tumors. However, variable patient response and chemo-resistance remain exceptionally challenging. Our previous genome-wide association study (GWAS) identified a suggestively significant association of SNP rs4470517 in the RYK (receptor-like kinase) gene with TMZ drug response. Functional validation of RYK using lymphocytes and glioma cell lines resulted in gene expression analysis indicating differences in expression status between genotypes of the cell lines and TMZ dose response. We conducted univariate and multivariate Cox regression analyses using publicly available TCGA and GEO datasets to investigate the impact of RYK gene expression status on glioma patient overall (OS) and progression-free survival (PFS). Our results indicated that in IDH mutant gliomas, RYK expression and tumor grade were significant predictors of survival. In IDH wildtype glioblastomas (GBM), MGMT status was the only significant predictor. Despite this result, we revealed a potential benefit of RYK expression in IDH wildtype GBM patients. We found that a combination of RYK expression and MGMT status could serve as an additional biomarker for improved survival. Overall, our findings suggest that RYK expression may serve as an important prognostic or predictor of TMZ response and survival for glioma patients. Full article

(This article belongs to the Topic Pharmacogenetics: A Tool in Cancer Therapy)

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25 pages, 929 KiB  

Open AccessSystematic Review

Influence of Single-Nucleotide Polymorphisms on Clinical Outcomes of Capecitabine-Based Chemotherapy in Colorectal Cancer Patients: A Systematic Review

by Yasmin Cura, Cristina Pérez-Ramírez, Almudena Sánchez-Martín, Cristina Membrive-Jimenez, María Isabel Valverde-Merino, Encarnación González-Flores and Alberto Jiménez Morales

Cancers 2023, 15(6), 1821; https://doi.org/10.3390/cancers15061821 - 17 Mar 2023

Cited by 12 | Viewed by 3081

Abstract

The aim of this systematic review was to provide a comprehensive overview of the literature published in the last decade on the association of single-nucleotide polymorphisms in genes involved in the pharmacodynamic and pharmacokinetic pathways of capecitabine with treatment outcomes among colorectal cancer [...] Read more.

The aim of this systematic review was to provide a comprehensive overview of the literature published in the last decade on the association of single-nucleotide polymorphisms in genes involved in the pharmacodynamic and pharmacokinetic pathways of capecitabine with treatment outcomes among colorectal cancer patients. A systematic search of the literature published in the last 10 years was carried out in two databases (Medline and Scopus) using keywords related to the objective. Quality assessment of the studies included was performed using an assessment tool derived from the Strengthening the Reporting of Genetic Association (STREGA) statement. Thirteen studies were included in this systematic review. Genes involved in bioactivation, metabolism, transport, mechanism of action of capecitabine, DNA repair, and folate cycle were associated with toxicity. Meanwhile, genes related to DNA repair were associated with therapy effectiveness. This systematic review reveals that several SNPs other than the four DPYD variants that are screened in clinical practice could have an impact on treatment outcomes. These findings suggest the identification of future predictive biomarkers of effectiveness and toxicity in colorectal cancer patients treated with capecitabine. However, the evidence is sparse and requires further validation. Full article

(This article belongs to the Topic Pharmacogenetics: A Tool in Cancer Therapy)

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12 pages, 1843 KiB  

Open AccessArticle

Identification of Potential Treatments for Acute Lymphoblastic Leukemia through Integrated Genomic Network Analysis

by Zulfan Zazuli, Lalu Muhammad Irham, Wirawan Adikusuma and Nur Melani Sari

Pharmaceuticals 2022, 15(12), 1562; https://doi.org/10.3390/ph15121562 - 14 Dec 2022

Cited by 4 | Viewed by 2332

Abstract

The advancement of high-throughput sequencing and genomic analysis revealed that acute lymphoblastic leukemia (ALL) is a genetically heterogeneous disease. The abundance of such genetic data in ALL can also be utilized to identify potential targets for drug discovery and even drug repurposing. We [...] Read more.

The advancement of high-throughput sequencing and genomic analysis revealed that acute lymphoblastic leukemia (ALL) is a genetically heterogeneous disease. The abundance of such genetic data in ALL can also be utilized to identify potential targets for drug discovery and even drug repurposing. We aimed to determine potential genes for drug development and further guide the identification of candidate drugs repurposed for treating ALL through integrated genomic network analysis. Genetic variants associated with ALL were retrieved from the GWAS Catalog. We further applied a genomic-driven drug repurposing approach based on the six functional annotations to prioritize crucial biological ALL-related genes based on the scoring system. Lastly, we identified the potential drugs in which the mechanisms overlapped with the therapeutic targets and prioritized the candidate drugs using Connectivity Map (CMap) analysis. Forty-two genes were considered biological ALL-risk genes with ARID5B topping the list. Based on potentially druggable genes that we identified, palbociclib, sirolimus, and tacrolimus were under clinical trial for ALL. Additionally, chlorprothixene, sirolimus, dihydroergocristine, papaverine, and tamoxifen are the top five drug repositioning candidates for ALL according to the CMap score with dasatinib as a comparator. In conclusion, this study determines the practicability and the potential of integrated genomic network analysis in driving drug discovery in ALL. Full article

(This article belongs to the Topic Pharmacogenetics: A Tool in Cancer Therapy)

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11 pages, 615 KiB  

Open AccessCase Report

Concomitant Administration of Capecitabine and Folate Supplements: Need to Encourage Medication Reconciliation

by Berenice Stefanelli, Carmine Sellitto, Emanuela De Bellis, Martina Torsiello, Nicola Bertini, Angelo Maria Pezzullo, Graziamaria Corbi, Francesco Sabbatino, Stefano Pepe, Angela Tesse, Valeria Conti and Amelia Filippelli

Pharmaceuticals 2022, 15(11), 1388; https://doi.org/10.3390/ph15111388 - 10 Nov 2022

Cited by 4 | Viewed by 2527

Abstract

Hand-Foot syndrome (HFS) and diarrhoea are dose-limiting Adverse Drug Reactions (ADRs) of capecitabine-based chemotherapy. Four polymorphisms in the dihydropyrimidine dehydrogenase (DPYD) gene, encoding the DPD enzyme responsible for the metabolism of fluoropyrimidines, such as capecitabine, are strongly associated with severe ADRs, [...] Read more.

Hand-Foot syndrome (HFS) and diarrhoea are dose-limiting Adverse Drug Reactions (ADRs) of capecitabine-based chemotherapy. Four polymorphisms in the dihydropyrimidine dehydrogenase (DPYD) gene, encoding the DPD enzyme responsible for the metabolism of fluoropyrimidines, such as capecitabine, are strongly associated with severe ADRs, and their screening should be performed before starting treatment. Moreover, capecitabine-related toxicity may worsen due to drug-drug and drug-supplement interactions. Here we investigated factors responsible for severe HFS and diarrhoea presented by two patients, non-carriers of the recommended DPYD single nucleotide polymorphisms (SNPs) but carriers of other genetic variants suggested to increase the risk of capecitabine-related ADRs. Through careful therapy recognition, we demonstrated that, unbeknownst to the oncologists, the patients were taking folic acid during the treatment with capecitabine at a dosage higher than 2000 mg/m², which is the maximum tolerated dose when folate is administered. To resolve the ADRs, the therapy had to be drastically changed. In one case, dose reduction of capecitabine and discontinuation of lipid-lowering agents were carried out. In the other case, discontinuation of capecitabine and folic acid and capecitabine re-administration were performed after a month. Genetic and environmental factors should be considered good predictors of severe capecitabine-related toxicity. Medication reconciliation should be encouraged to avoid the harmful consequences of inappropriate treatments. Full article

(This article belongs to the Topic Pharmacogenetics: A Tool in Cancer Therapy)

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14 pages, 3565 KiB  

Open AccessArticle

The Expression Patterns of Human Cancer-Testis Genes Are Induced through Epigenetic Drugs in Colon Cancer Cells

by Mikhlid H. Almutairi, Turki M. Alrubie, Bader O. Almutairi, Abdullah M. Alamri, Abdulwahed F. Alrefaei, Maha M. Arafah, Mohammad Alanazi and Abdelhabib Semlali

Pharmaceuticals 2022, 15(11), 1319; https://doi.org/10.3390/ph15111319 - 26 Oct 2022

Cited by 7 | Viewed by 2363

Abstract

Background: The expression of human germline genes is restricted to the germ cells of the gonads, which produce sperm and eggs. The germline genes involved in testis development and potentially activated in cancer cells are known as cancer-testis (CT) genes. These genes are [...] Read more.

Background: The expression of human germline genes is restricted to the germ cells of the gonads, which produce sperm and eggs. The germline genes involved in testis development and potentially activated in cancer cells are known as cancer-testis (CT) genes. These genes are potential therapeutic targets and biomarkers, as well as drivers of the oncogenic process. CT genes can be reactivated by treatment with drugs that demethylate DNA. The majority of the existing literature on CT gene activation focuses on X-chromosome-produced CT genes. We tested the hypothesis that epigenetic landscape changes, such as DNA methylation, can alter several CT gene expression profiles in cancer and germ cells. Methods: Colon cancer (CC) cell lines were treated with the DNA methyltransferase inhibitor (DNMTi) 5-aza-2’-deoxycytidine, or with the histone deacetylase inhibitor (HDACi) trichostatin A (TSA). The effects of these epigenetic treatments on the transcriptional activation of previously published CT genes (CTAG1A, SCP2D1, TKTL2, LYZL6, TEX33, and ACTRT1) and testis-specific genes (NUTM1, ASB17, ZSWIM2, ADAM2, and C10orf82) were investigated. Results: We found that treatment of CC cell lines with 5-aza-2’-deoxycytidine or TSA correlated with activation of X-encoded CT genes and non-X-encoded CT genes in somatic (non-germline) cells. Conclusion: These findings confirm that a subset of CT genes can be regulated by hypomethylating drugs and subsequently provide a potential therapeutic target for cancer. Full article

(This article belongs to the Topic Pharmacogenetics: A Tool in Cancer Therapy)

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19 pages, 366 KiB  

Open AccessReview

Impact of Genetic Polymorphisms and Biomarkers on the Effectiveness and Toxicity of Treatment of Chronic Myeloid Leukemia and Acute Myeloid Leukemia

by Carolina Alarcón-Payer, María Del Mar Sánchez Suárez, Alicia Martín Roldán, José Manuel Puerta Puerta and Alberto Jiménez Morales

J. Pers. Med. 2022, 12(10), 1607; https://doi.org/10.3390/jpm12101607 - 29 Sep 2022

Cited by 5 | Viewed by 2852

Abstract

Most malignant hematological diseases are generally a consequence of acquired mutations or rearrangements in cell replication processes. Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease that results from acquired genetic and epigenetic alterations in hematopoietic progenitor cells. Despite the advances [...] Read more.

Most malignant hematological diseases are generally a consequence of acquired mutations or rearrangements in cell replication processes. Acute myeloid leukemia (AML) is a clinically and molecularly heterogeneous disease that results from acquired genetic and epigenetic alterations in hematopoietic progenitor cells. Despite the advances made in understanding the pathogenesis of this disease, the overall survival of patients remains very low due to the high relapse rate. Pharmacogenetics and massive sequencing studies have allowed the identification of new recurrent mutations with significant prognostic impact in AML; furthermore, it seems likely that whole genome sequencing will soon become a standard diagnostic test, which will allow the molecular diagnosis of patients. Therefore, it is necessary to develop molecular targets that open new therapeutic perspectives and allow individualized treatment of patients with this aggressive disease. Chronic myeloid leukemia (CML) is the first neoplastic disease for which a characteristic genetic alteration was described. It has, by definition, a genetic marker, the BCR::ABL1 rearrangement, as a consequence of the t9;22(q34;q11) translocation. Its study is essential for the diagnosis of this entity and also for monitoring the response to treatment. Drugs known as tyrosine kinase inhibitors (TKIs) that target the BCR::ABL1 protein (oral targeted therapy) are the conventional treatment of CML, representing a change of paradigm in the management of oncohematological patients. Full article

(This article belongs to the Topic Pharmacogenetics: A Tool in Cancer Therapy)

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14 pages, 3573 KiB  

Open AccessArticle

HIF-PH Encoded by EGLN1 Is a Potential Therapeutic Target for Chronic Lymphocytic Leukemia

by Wancheng Guo, Daomiao Liang, Peilong Wang, Le Yin, Huifang Zhang, Cheng Xing, Zineng Huang, Yinghua Wu, Heng Li, Zhao Cheng, Xiaojuan Xiao, Jing Liu, Zhihua Wang and Hongling Peng

Pharmaceuticals 2022, 15(6), 734; https://doi.org/10.3390/ph15060734 - 10 Jun 2022

Cited by 3 | Viewed by 3381

Abstract

Owing to the recent emergence of drug resistance to Bruton’s tyrosine kinase inhibitors (BTK) in chronic lymphocytic leukemia (CLL) treatment, it is crucial to identify alternative therapeutic targets. Therefore, we aimed to identify therapeutic options for CLL besides BTK. We identified that HIF1A [...] Read more.

Owing to the recent emergence of drug resistance to Bruton’s tyrosine kinase inhibitors (BTK) in chronic lymphocytic leukemia (CLL) treatment, it is crucial to identify alternative therapeutic targets. Therefore, we aimed to identify therapeutic options for CLL besides BTK. We identified that HIF1A expression was higher in CLL patients than in controls, which may suggest good prognosis. We used a lentiviral knockdown of EGLN1 (encoding hypoxia-inducible factor prolyl hydroxylase [HIF-PH]) and found that the growth of MEC-1 cells slowed in the knockdown group. Treatment of CLL cell lines MEC-1 and HG3 with the HIF-PH inhibitor molidustat showed that molidustat could induce apoptosis in a concentration-dependent manner in CLL cells and had low cytotoxicity at this concentration. CXCR4, HIF1A, SLC2AI, and VEGF, the downstream molecules of the HIF pathway, were upregulated after molidustat treatment. Western blotting results indicated that molidustat increased HIF1A expression in CLL cell lines and cells from CLL patients, and sequencing/quantitative PCR analysis demonstrated that the ribosome biogenesis pathway was inhibited in MEC-1 cells after molidustat treatment. We further identified synergistic cytotoxicity of molidustat in combination with ibrutinib on the MEC-1 and HG3 cell lines at certain concentrations. Therefore, molidustat is a potential therapeutic option for CLL. Full article

(This article belongs to the Topic Pharmacogenetics: A Tool in Cancer Therapy)

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18 pages, 1056 KiB  

Open AccessArticle

Genome-Wide Analyses of Nephrotoxicity in Platinum-Treated Cancer Patients Identify Association with Genetic Variant in RBMS3 and Acute Kidney Injury

by Marije J. Klumpers, Ward De Witte, Giovanna Gattuso, Elisabetta Schiavello, Monica Terenziani, Maura Massimino, Corrie E. M. Gidding, Sita H. Vermeulen, Chantal M. Driessen, Carla M. Van Herpen, Esther Van Meerten, Henk-Jan Guchelaar, Marieke J. H. Coenen and D. Maroeska W. M. Te Loo

J. Pers. Med. 2022, 12(6), 892; https://doi.org/10.3390/jpm12060892 - 28 May 2022

Cited by 4 | Viewed by 2937

Abstract

Nephrotoxicity is a common and dose-limiting side effect of platinum compounds, which often manifests as acute kidney injury or hypomagnesemia. This study aimed to investigate the genetic risk loci for platinum-induced nephrotoxicity. Platinum-treated brain tumor and head–neck tumor patients were genotyped with genome-wide [...] Read more.

Nephrotoxicity is a common and dose-limiting side effect of platinum compounds, which often manifests as acute kidney injury or hypomagnesemia. This study aimed to investigate the genetic risk loci for platinum-induced nephrotoxicity. Platinum-treated brain tumor and head–neck tumor patients were genotyped with genome-wide coverage. The data regarding the patient and treatment characteristics and the laboratory results reflecting the nephrotoxicity during and after the platinum treatment were collected from the medical records. Linear and logistic regression analyses were performed to investigate the associations between the genetic variants and the acute kidney injury and hypomagnesemia phenotypes. A cohort of 195 platinum-treated patients was included, and 9,799,032 DNA variants passed the quality control. An association was identified between RBMS3 rs10663797 and acute kidney injury (coefficient −0.10 (95% confidence interval −0.13–−0.06), p-value 2.72 × 10⁻⁸). The patients who carried an AC deletion at this locus had statistically significantly lower glomerular filtration rates after platinum treatment. Previously reported associations, such as BACH2 rs4388268, could not be replicated in this study’s cohort. No statistically significant associations were identified for platinum-induced hypomagnesemia. The genetic variant in RBMS3 was not previously linked to nephrotoxicity or related traits. The validation of this study’s results in independent cohorts is needed to confirm this novel association. Full article

(This article belongs to the Topic Pharmacogenetics: A Tool in Cancer Therapy)

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