The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity
Abstract Background Despite a growing number of publications highlighting the potential impact on the therapy outcome, rare genetic variants (minor allele frequency < 1%) in genes associated to drug adsorption, distribution, metabolism, and elimination are poorly studied. Previously, rare germlin...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-11-01
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| Series: | Human Genomics |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40246-023-00546-9 |
| _version_ | 1827764274975473664 |
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| author | Elena De Mattia Jerry Polesel Marco Silvestri Rossana Roncato Lucia Scarabel Stefano Calza Michele Spina Fabio Puglisi Giuseppe Toffoli Erika Cecchin |
| author_facet | Elena De Mattia Jerry Polesel Marco Silvestri Rossana Roncato Lucia Scarabel Stefano Calza Michele Spina Fabio Puglisi Giuseppe Toffoli Erika Cecchin |
| author_sort | Elena De Mattia |
| collection | DOAJ |
| description | Abstract Background Despite a growing number of publications highlighting the potential impact on the therapy outcome, rare genetic variants (minor allele frequency < 1%) in genes associated to drug adsorption, distribution, metabolism, and elimination are poorly studied. Previously, rare germline DPYD missense variants were shown to identify a subset of fluoropyrimidine-treated patients at high risk for severe toxicity. Here, we investigate the impact of rare genetic variants in a panel of 54 other fluoropyrimidine-related genes on the risk of severe toxicity. Methods The coding sequence and untranslated regions of 54 genes related to fluoropyrimidine pharmacokinetics/pharmacodynamics were analyzed by next-generation sequencing in 120 patients developing grade 3–5 toxicity (NCI-CTC vs3.0) and 104 matched controls. Sequence Kernel Association Test (SKAT) analysis was used to select genes with a burden of genetic variants significantly associated with risk of severe toxicity. The statistical association of common and rare genetic variants in selected genes was further investigated. The functional impact of genetic variants was assessed using two different in silico prediction tools (Predict2SNP; ADME Prediction Framework). Results SKAT analysis highlighted DPYS and PPARD as genes with a genetic mutational burden significantly associated with risk of severe fluoropyrimidine-related toxicity (Bonferroni adjusted P = 0.024 and P = 0.039, respectively). Looking more closely at allele frequency, the burden of rare DPYS variants was significantly higher in patients with toxicity compared with controls (P = 0.047, Mann–Whitney test). Carrying at least one rare DPYS variant was associated with an approximately fourfold higher risk of severe cumulative (OR = 4.08, P = 0.030) and acute (OR = 4.21, P = 0.082) toxicity. The burden of PPARD rare genetic variants was not significantly related to toxicity. Some common variants with predictive value in DPYS and PPARD were also identified: DPYS rs143004875-T and PPARD rs2016520-T variants predicted an increased risk of severe cumulative (P = 0.002 and P = 0.001, respectively) and acute (P = 0.005 and P = 0.0001, respectively) toxicity. Conclusion This work demonstrated that the rare mutational burden of DPYS, a gene strictly cooperating with DPYD in the catabolic pathway of fluoropyrimidines, is a promising pharmacogenetic marker for precision dosing of fluoropyrimidines. Additionally, some common genetic polymorphisms in DPYS and PPARD were identified as promising predictive markers that warrant further investigation. |
| first_indexed | 2024-03-11T11:02:02Z |
| format | Article |
| id | doaj.art-43e97f65f43942da9fd70a4799972bf0 |
| institution | Directory Open Access Journal |
| issn | 1479-7364 |
| language | English |
| last_indexed | 2024-03-11T11:02:02Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Human Genomics |
| spelling | doaj.art-43e97f65f43942da9fd70a4799972bf02023-11-12T12:24:10ZengBMCHuman Genomics1479-73642023-11-0117111510.1186/s40246-023-00546-9The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicityElena De Mattia0Jerry Polesel1Marco Silvestri2Rossana Roncato3Lucia Scarabel4Stefano Calza5Michele Spina6Fabio Puglisi7Giuseppe Toffoli8Erika Cecchin9Experimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCSUnit of Cancer Epidemiology, Centro Di Riferimento Oncologico Di Aviano (CRO) IRCCSDepartment of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori di MilanoExperimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCSExperimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCSDepartment of Molecular and Translational Medicine, University of BresciaDepartment of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCSSDepartment of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCSSExperimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCSExperimental and Clinical Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCSAbstract Background Despite a growing number of publications highlighting the potential impact on the therapy outcome, rare genetic variants (minor allele frequency < 1%) in genes associated to drug adsorption, distribution, metabolism, and elimination are poorly studied. Previously, rare germline DPYD missense variants were shown to identify a subset of fluoropyrimidine-treated patients at high risk for severe toxicity. Here, we investigate the impact of rare genetic variants in a panel of 54 other fluoropyrimidine-related genes on the risk of severe toxicity. Methods The coding sequence and untranslated regions of 54 genes related to fluoropyrimidine pharmacokinetics/pharmacodynamics were analyzed by next-generation sequencing in 120 patients developing grade 3–5 toxicity (NCI-CTC vs3.0) and 104 matched controls. Sequence Kernel Association Test (SKAT) analysis was used to select genes with a burden of genetic variants significantly associated with risk of severe toxicity. The statistical association of common and rare genetic variants in selected genes was further investigated. The functional impact of genetic variants was assessed using two different in silico prediction tools (Predict2SNP; ADME Prediction Framework). Results SKAT analysis highlighted DPYS and PPARD as genes with a genetic mutational burden significantly associated with risk of severe fluoropyrimidine-related toxicity (Bonferroni adjusted P = 0.024 and P = 0.039, respectively). Looking more closely at allele frequency, the burden of rare DPYS variants was significantly higher in patients with toxicity compared with controls (P = 0.047, Mann–Whitney test). Carrying at least one rare DPYS variant was associated with an approximately fourfold higher risk of severe cumulative (OR = 4.08, P = 0.030) and acute (OR = 4.21, P = 0.082) toxicity. The burden of PPARD rare genetic variants was not significantly related to toxicity. Some common variants with predictive value in DPYS and PPARD were also identified: DPYS rs143004875-T and PPARD rs2016520-T variants predicted an increased risk of severe cumulative (P = 0.002 and P = 0.001, respectively) and acute (P = 0.005 and P = 0.0001, respectively) toxicity. Conclusion This work demonstrated that the rare mutational burden of DPYS, a gene strictly cooperating with DPYD in the catabolic pathway of fluoropyrimidines, is a promising pharmacogenetic marker for precision dosing of fluoropyrimidines. Additionally, some common genetic polymorphisms in DPYS and PPARD were identified as promising predictive markers that warrant further investigation.https://doi.org/10.1186/s40246-023-00546-9DPYSRare variantFluoropyrimidineToxicityNext-generation sequencingClinical implementation |
| spellingShingle | Elena De Mattia Jerry Polesel Marco Silvestri Rossana Roncato Lucia Scarabel Stefano Calza Michele Spina Fabio Puglisi Giuseppe Toffoli Erika Cecchin The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity Human Genomics DPYS Rare variant Fluoropyrimidine Toxicity Next-generation sequencing Clinical implementation |
| title | The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity |
| title_full | The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity |
| title_fullStr | The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity |
| title_full_unstemmed | The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity |
| title_short | The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity |
| title_sort | burden of rare variants in dpys gene is a novel predictor of the risk of developing severe fluoropyrimidine related toxicity |
| topic | DPYS Rare variant Fluoropyrimidine Toxicity Next-generation sequencing Clinical implementation |
| url | https://doi.org/10.1186/s40246-023-00546-9 |
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