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1.
Sci Transl Med ; 13(603)2021 07 21.
Article in English | MEDLINE | ID: mdl-34290055

ABSTRACT

Pharmacogenomics is a key component of personalized medicine that promises safer and more effective drug treatment by individualizing drug choice and dose based on genetic profiles. In clinical practice, genetic biomarkers are used to categorize patients into *-alleles to predict CYP450 enzyme activity and adjust drug dosages accordingly. However, this approach leaves a large part of variability in drug response unexplained. Here, we present a proof-of-concept approach that uses continuous-scale (instead of categorical) assignments to predict enzyme activity. We used full CYP2D6 gene sequences obtained with long-read amplicon-based sequencing and cytochrome P450 (CYP) 2D6-mediated tamoxifen metabolism data from a prospective study of 561 patients with breast cancer to train a neural network. The model explained 79% of interindividual variability in CYP2D6 activity compared to 54% with the conventional *-allele approach, assigned enzyme activities to known alleles with previously reported effects, and predicted the activity of previously uncharacterized combinations of variants. The results were replicated in an independent cohort of tamoxifen-treated patients (model R 2 adjusted = 0.66 versus *-allele R 2 adjusted = 0.35) and a cohort of patients treated with the CYP2D6 substrate venlafaxine (model R 2 adjusted = 0.64 versus *-allele R 2 adjusted = 0.55). Human embryonic kidney cells were used to confirm the effect of five genetic variants on metabolism of the CYP2D6 substrate bufuralol in vitro. These results demonstrate the advantage of a continuous scale and a completely phased genotype for prediction of CYP2D6 enzyme activity and could potentially enable more accurate prediction of individual drug response.


Subject(s)
Cytochrome P-450 CYP2D6 , Pharmaceutical Preparations , Alleles , Cytochrome P-450 CYP2D6/genetics , Genotype , Humans , Prospective Studies , Tamoxifen
2.
Pharmacogenet Genomics ; 25(6): 279-88, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25815774

ABSTRACT

BACKGROUND AND AIM: Pharmacogenetic studies continue to search for pretreatment predictors of chemotherapeutic efficacy and toxicity in metastatic colorectal cancer. Both genome-wide association studies and candidate gene studies have yielded potential genetic markers for chemosensitivity. We conducted a clinical association study, validating the effect of specific genetic markers cited in recently published papers on the efficacy of the oral 5-fluoro-uracil prodrug capecitabine. PATIENTS AND METHODS: Germline DNA was collected for 268 metastatic colorectal cancer patients from the CAIRO trial, a multicenter phase III trial, randomizing between combined or sequential first-line treatment with capecitabine, irinotecan, and oxaliplatin. Genotyping was performed for eight single-nucleotide polymorphisms (SNPs), using high-resolution melting curves. Four SNPs are located in the MTRR gene, and another four SNPs showed significant association with 5-fluoro-uracil cytotoxicity in a recent in-vitro genome-wide association study. The primary endpoint was progression-free survival (PFS); secondary endpoints were objective response and overall survival. RESULTS: In patients receiving capecitabine monotherapy, rs4702484, located in ADCY2 and close to MTRR, was associated with slightly reduced PFS for homozygous wild-type patients (CC 6.2 vs. CT 8.0 months; P=0.018). For the other selected genetic markers, we found no association with PFS, overall survival, or radiologic response upon treatment with capecitabine, either in the total study population or in the capecitabine monotherapy subgroup. CONCLUSION: With the exception of rs4702484, we found no evidence of an effect on capecitabine chemosensitivity for any of the studied SNPs. More specifically, variants in methionine synthase reductase (MTRR) are not likely associated with capecitabine efficacy.


Subject(s)
Adenylyl Cyclases/genetics , Biomarkers, Tumor/genetics , Capecitabine/administration & dosage , Colorectal Neoplasms/genetics , Ferredoxin-NADP Reductase/genetics , Adult , Aged , Aged, 80 and over , Clinical Trials, Phase III as Topic , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Disease-Free Survival , Female , Genetic Association Studies , Genotype , Humans , Male , Middle Aged , Neoplasm Metastasis , Pharmacogenetics , Randomized Controlled Trials as Topic
3.
Breast Cancer Res Treat ; 144(3): 599-606, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24590773

ABSTRACT

Musculoskeletal adverse events (MSAEs) and vasomotor symptoms (VMSs) are known side-effects of aromatase inhibitors, and may be related to genetic variations of the aromatase gene (CYP19A1). We investigated the relationship between these specific AEs and single nucleotide polymorphisms (SNPs) in the CYP19A1 gene in postmenopausal, hormone receptor-positive early breast cancer (BC) patients treated with adjuvant exemestane for 5 years. Dutch patients who were randomized to receive 5 years of exemestane in the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial were included. A tagging-SNP approach was performed, covering 80 % of variations of the CYP19A1 gene with 30 SNPs. Logistic regression analyses were used to assess the risk of reporting VMSs or MSAEs in relation to genotypes within selected SNPs. Of 737 included patients, 281 patients reported at least one MSAE (n = 210) or VMS (n = 163). Homozygous AA genotype of rs934635 was associated with a significantly higher odds of MSAEs (multivariate odds ratio (OR) 4.66, p = 0.008) and VMSs (multivariate OR 2.78, p = 0.044). Regarding both rs1694189 and rs7176005, the homozygous variant genotypes (TT) were associated with a higher odds of VMSs, but not MSAEs (OR 1.758, p = 0.025 and OR 6.361, p = 0.021, respectively). Our exploratory analysis demonstrated that some CYP19A1 gene variations may be associated with MSAEs and/or VMSs. Specifically, patients with the homozygous variant rs934635 genotype reported more MSAEs and VMSs. Although further confirmatory studies are warranted, genomic profiling can help identify patients at an increased risk of reporting these specific AEs, potentiating further personalized BC treatment.


Subject(s)
Aromatase Inhibitors/administration & dosage , Aromatase Inhibitors/adverse effects , Aromatase/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Germ-Line Mutation , Polymorphism, Single Nucleotide , Adult , Aged , Aged, 80 and over , Breast Neoplasms/pathology , Combined Modality Therapy , Female , Genotype , Humans , Middle Aged , Neoplasm Grading , Neoplasm Staging , Netherlands , Odds Ratio , Postmenopause , Risk Factors , Treatment Outcome
4.
Clin Chem Lab Med ; 50(2): 279-84, 2011 Oct 21.
Article in English | MEDLINE | ID: mdl-22022982

ABSTRACT

BACKGROUND: Several studies report difficulties in genotyping HNF1ß rs757210 using TaqMan probes. This is possibly due to the tri-allelic nature of this single nucleotide polymorphism (SNP). The aim of the present research was to develop alternative methods for genotyping rs757210. METHODS: Pyrosequencing and high resolution melting analysis of small amplicons (HRM) were developed and tested in panels of type 2 diabetes mellitus patients (n=258) and healthy blood donors (n=183). Results were confirmed by Sanger sequencing. RESULTS: With pyrosequencing, allele frequencies for the A, G and C allele of 0.42, 0.56, 0.02 and 0.37, 0.62, 0.01 were established in the panel of type 2 diabetes mellitus patients and healthy blood donors, respectively. Similar results were found using the more routinely available HRM method. Results for pyrosequencing and HRM were in 99.6% concordance. CONCLUSIONS: Pyrosequencing and HRM can be used to genotype the tri-allelic SNP rs757210 in the HNF1ß gene and have the advantage over the commercially available TaqMan analysis that they can determine the rare C-allele variant.


Subject(s)
Alleles , Genotyping Techniques , Hepatocyte Nuclear Factor 1-beta/genetics , Polymorphism, Single Nucleotide , Female , Hot Temperature , Humans , Male
5.
Jpn J Clin Oncol ; 41(10): 1168-76, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21840870

ABSTRACT

OBJECTIVE: Suboptimal treatment of chemotherapy-induced nausea and vomiting and unsatisfactory response to antiemetic drugs cause impairment of cancer patient's daily functioning. This study was aimed to investigate the association of selected germline polymorphisms with ondansetron and metoclopramide response in Indonesian cancer patients treated with highly emetogenic chemotherapy. METHODS: We enrolled 202 chemotherapy naïve patients treated with cisplatin at a dosage of ≥50 mg/m(2) as monotherapy or as combined chemotherapy. Ondansetron 8 mg and dexamethasone 8 mg intravenously were the standard antiemetic therapy for prevention of acute chemotherapy-induced nausea and vomiting. Metoclopramide 10 mg orally, three times per day as fixed prescription, was given until 5 days after chemotherapy to prevent delayed chemotherapy-induced nausea and vomiting. Primary and secondary outcomes were the occurrence of chemotherapy-induced nausea and vomiting in the acute and delayed phase. The following single-nucleotide polymorphisms were determined in ABCB1: rs1045642, rs2032582 and rs1128503; in 5-HT3B-R: rs45460698, rs4938058 and rs7943062; and in CYP2D6: rs16947 (CYP2D6 2), rs3892097 (CYP2D6 4) and rs1065852 (CYP2D6 10) using Taqman assays. RESULTS: During the acute phase, 21.8 and 30.2% patients experienced Grade 3 and 4 nausea and vomiting, respectively, whereas 38.6% patients experienced nausea and/or vomiting in the delayed phase. Carriers of the CTG haplotype of the ABCB1 gene experienced Grade 3 and 4 chemotherapy-induced nausea and vomiting more often than other haplotypes in the delayed phase (P< 0.05). No associations were found with the 5-HT3B receptor haplotypes and CYP2D6-predicted phenotypes. CONCLUSIONS: Our study shows that in Indonesian cancer patients treated with highly cytostatic emetogenic, carriership of the CTG haplotype of the ABCB1 gene is related to an increased risk of delayed chemotherapy-induced nausea and vomiting.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Antiemetics/pharmacology , Antineoplastic Agents/adverse effects , Cytochrome P-450 CYP2D6/genetics , Metoclopramide/pharmacology , Nausea/genetics , Ondansetron/pharmacology , Receptors, Serotonin, 5-HT3/genetics , Vomiting/genetics , ATP Binding Cassette Transporter, Subfamily B , Antiemetics/pharmacokinetics , Cisplatin/adverse effects , Female , Haplotypes/genetics , Humans , Indonesia , Male , Metoclopramide/pharmacokinetics , Middle Aged , Nausea/chemically induced , Neoplasms/drug therapy , Ondansetron/pharmacokinetics , Polymorphism, Single Nucleotide , Vomiting/chemically induced
6.
Pharmacogenet Genomics ; 21(8): 461-8, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21633322

ABSTRACT

OBJECTIVE: After the identification of type 2 diabetes mellitus (T2DM) risk alleles from genome-wide association studies, models have been developed to identify subjects at high risk to develop T2DM. We hypothesize that a panel of 20 repeatedly associated T2DM risk alleles influences response to sulfonylureas (SUs). METHODS: Two hundred and seven incident SU (tolbutamide, glibenclamide, glimepiride, gliclazide) users with T2DM were recruited from four primary care centers. A genetic risk score per patient was calculated based on the number of risk-alleles. With this score, patients were categorized into three predefined genetic risk groups. The effect of the genetic risk group on the achievement of stable SU dose, prescribed stable SU dose, and time to stable SU dose was analyzed. RESULTS: Carriers of more than 17 T2DM risk alleles had a 1.7-fold reduced likelihood to achieve stable SU dose (P=0.044). No significant effect of the number of T2DM risk alleles on prescribed dose was found. Carriers of more than 17 T2DM risk alleles showed a marginally significant increased time to stable dose (hazard ratio: 0.81; 95% confidence interval, 0.75-1.01, P=0.058). CONCLUSION: T2DM risk alleles are associated with response to SUs in primary care T2DM patients. This suggests that individualization of T2DM treatment according to genetic profile may be an opportunity to improve clinical outcome.


Subject(s)
Biomarkers, Pharmacological , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/genetics , Sulfonylurea Compounds/therapeutic use , Aged , Female , Genetic Association Studies , Genetic Variation , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk Factors , White People
7.
J Clin Oncol ; 27(26): 4406-12, 2009 Sep 10.
Article in English | MEDLINE | ID: mdl-19667267

ABSTRACT

PURPOSE: To identify genetic markers in the pharmacokinetic and pharmacodynamic pathways of sunitinib that predispose for development of toxicities: thrombocytopenia, leukopenia, mucosal inflammation, hand-foot syndrome, and any toxicity according to National Cancer Institute Common Toxicity Criteria higher than grade 2. PATIENTS AND METHODS: A multicenter pharmacogenetic association study was performed in 219 patients treated with single-agent sunitinib. A total of 31 single nucleotide polymorphisms in 12 candidate genes, together with several nongenetic variants, were analyzed for a possible association with toxicity. In addition, genetic haplotypes were developed and related to toxicity. RESULTS: The risk for leukopenia was increased when the G allele in CYP1A1 2455A/G (odds ratio [OR], 6.24; P = .029) or the T allele in FLT3 738T/C (OR, 2.8; P = .008) were present or CAG in the NR1I3 (5719C/T, 7738A/C, 7837T/G) haplotype (OR, 1.74; P = .041) was absent. Any toxicity higher than grade 2 prevalence was increased when the T allele of vascular endothelial growth factor receptor 2 1191C/T (OR, 2.39; P = .046) or a copy of TT in the ABCG2 (-15622C/T, 1143C/T) haplotype (OR, 2.63; P = .016) were present. The risk for mucosal inflammation was increased in the presence of the G allele in CYP1A1 2455A/G (OR, 4.03; P = .021) and the prevalence of hand-foot syndrome was increased when a copy of TTT in the ABCB1 (3435C/T, 1236C/T, 2677G/T) haplotype (OR, 2.56; P = .035) was present. CONCLUSION: This exploratory study suggests that polymorphisms in specific genes encoding for metabolizing enzymes, efflux transporters, and drug targets are associated with sunitinib-related toxicities. A better understanding of genetic and nongenetic determinants of sunitinib toxicity should help to optimize drug treatment in individual patients.


Subject(s)
Drug-Related Side Effects and Adverse Reactions/genetics , Indoles/adverse effects , Pharmacogenetics/methods , Pyrroles/adverse effects , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Constitutive Androstane Receptor , Cytochrome P-450 CYP1A1/genetics , Drug-Related Side Effects and Adverse Reactions/chemically induced , Female , Genetic Predisposition to Disease/genetics , Haplotypes , Humans , Indoles/pharmacokinetics , Leukopenia/chemically induced , Male , Middle Aged , Mucositis/chemically induced , Polymorphism, Single Nucleotide , Pyrroles/pharmacokinetics , Risk Factors , Sunitinib , Young Adult
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