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Acute rejection ( AR) remains a concern for kidney transplantation. Cytokines are key mediators in the induction and effector phases of all immune and inflammatory responses. Single nucleotide polymorphisms ( SNPs) in cytokines and their receptors may relate to AR. We investigated the relation between AR and SNPs in the genes encoding for IL-2(-330G>T), IL-10(−592C>A and −1082G>A), TGF-β 1(915G>C), and IL-2 RB(rs228942 C>A and rs228953 C>T) in 325 renal transplant patients during the first year after transplantation. The overall incidence of AR was 15.4%. In multivariate analysis, only the use of induction therapy was correlated with AR (odds ratio 1.9; 95% confidence interval 1.1-3.7; p = 0.04). No statistically significant associations between the SNPs studied and AR were observed. SNPs in the investigated cytokines and their receptors were not associated with the risk of AR. Genotyping patients for these SNPs is unlikely to aid the clinician in adjusting the immunosuppressive therapy for individual patients. [ABSTRACT FROM AUTHOR]

Introduction: Cytochrome P450 (CYP) plays a key role in the metabolism of coumarin anticoagulants and nonsteroidal anti-inflammatory drugs (NSAIDs). Because CYP2C9 is a genetically polymorphic enzyme, genetic variability could play an important role in the potential interaction between NSAIDs and coumarins. We investigated whether NSAIDs were associated with overanticoagulation during therapy with coumarins and evaluated the effect of the CYP2C9 polymorphisms on this potential interaction. Methods: We conducted a population-based cohort study among patients of an anticoagulation clinic who were treated with acenocoumarol or phenprocoumon between April 1, 1991, and May 31, 2003, and whose CYP2C9 status was known. Patients were followed up until an international normalized ratio (INR) of 6.0 or greater was reached or until the end of treatment, death, or the end of the study. Proportional hazards regression analysis was used to estimate the risk of an INR of 6.0 or greater in relation to concomitant use of a coumarin anticoagulant and NSAIDs after adjustment for several potentially confounding factors. To study effect modification by CYP2C9 genotype, stratified analyses were performed for wild-type patients and patients with a variant genotype. Results: Of the 973 patients in the cohort, 415 had an INR of 6.0 or greater. Several NSAIDs increased the risk of overanticoagulation. The risk of overanticoagulation was 2.98 (95% confidence interval, 1.09–7.02) in coumarin-treated patients taking NSAIDs with a CYP2C9*2 allele and 10.8 (95% confidence interval, 2.57–34.6) in those with a CYP2C9*3 allele. Conclusions: Several NSAIDs were associated with overanticoagulation. For NSAIDs that are known CYP2C9 substrates, this risk was modified by allelic variants of CYP2C9. More frequent INR monitoring of patients taking NSAIDs is warranted. [Copyright &y& Elsevier]

Monoclonal antibodies that inhibit the programmed cell death protein 1 axis (anti-PD-1/PD-L1) are part of a new pharmacological strategy aimed at reinforcing the immune response to cancer. Despite the success in several cancer types, a significant percentage of patients do not benefit from treatment with these drugs due to intrinsic or acquired resistance or the occurrence of immune-related adverse reactions. Assessment of PD-L1 expression in tumor tissues is currently used to predict drug response in the clinics; however, there is a growing interest in identifying blood-based biomarkers that, owing to the minimally-invasive nature, can allow a dynamic monitoring of drug response in daily clinical practice. In the current review article, we discuss whether the assessment of PD-L1 mRNA and protein levels in circulating extracellular vesicles may have the potential to predict the likelihood of tumor response to anti-PD-1/PD-L1 antibodies. [ABSTRACT FROM AUTHOR]

Abstract Pharmacogenetic testing is increasingly implemented in routine diagnostics. However, quality control measures, in particular confirmation practices e.g. the use of two independent genotyping techniques, are subject of debate and there are no clear guidelines. The aim of the current paper is to discuss the current practice in confirmation testing in the field of pharmacogenetics and draw attention to this situation. DPYD genotyping is used as a case example to highlight the importance of assigning the correct genotype. Current confirmation practices in laboratories are explored through a survey. Substantial heterogeneity was observed with 54% of the laboratories applying different forms of confirmation practice. Finally, we evaluated over 10 years of genotyping results from two large genotyping facilities, which both use a second, independent genotyping technique. Discrepancies between tests were identified in 9 patients (0.01%), possibly due to allele dropout. We feel that a second, independent technique is useful for genetic tests with a high clinical impact, such as DPYD testing. Guidelines can help to align confirmatory laboratory practices for pharmacogenetics, which may need to be specified per gene and test. Highlights • The analytical validity of a pharmacogenetic test result is of utmost importance. • A measure to assure analytical validity is the use of a second confirmation method. • Heterogeneity in confirmation practice exists between laboratories. • Guidelines are key to align laboratory practices for pharmacogenetic testing. • Guidelines may need to be specified per gene and test. [ABSTRACT FROM AUTHOR]

Human scalp hair is an easily available but complex matrix for determination of cortisone and cortisol, and has been shown to reflect long-term glucocorticoid exposure. Hair glucocorticoid analysis has been used to detect hypo- and hypercortisolism. In this study, we describe the development and validation of a LC-MS/MS method for quantification of cortisone and cortisol in human scalp hair, and provide a novel approach for analysis and interpretation of the results. Improved sample preparation using pulverization and solid phase extraction allowed for low sample volumes (10 mg). Baseline chromatographic separation without matrix interference was achieved by reversed phase chromatography and MRM measurement in negative ion mode. Run-to-run time was 8 min. Mixed model analyses were performed to create individual patterns of cortisone and cortisol concentrations. Matrix matched calibration curves showed excellent linearity up to 100 pg (analyte)/mg (hair) for both cortisone and cortisol (R2>0.995). LLOQ was 1.5 and 1.0 pg/mg for cortisone and cortisol, respectively. Matrix effect was negligible for hair color (recoveries 95–105 %). Cortisone and cortisol concentrations decreased from proximal to distal hair segments, following a predictable, but subject-specific pattern, with less individual variation for cortisone than for cortisol. This improved LC-MS/MS method is able to accurately quantify cortisone and cortisol in human hair with minimum matrix interference. This new way of data analysis and interpretation including individual patterns of cortisone and cortisol will be of help with detection of pathological concentrations in both the high – and the low ranges of glucocorticoids. [ABSTRACT FROM AUTHOR]

Two cases show osimertinib/sotorasib combination could be effective in KRAS G12C-driven osimertinib resistance. [ABSTRACT FROM AUTHOR]

Objective: We sought to investigate maternal and child functional MDR1 C3435T polymorphism, periconception medication, folic acid use, and the risk of a congenital heart defect (CHD) in the offspring. Study Design: MDR1 3435C>T genotyping was performed in 283 case triads (mother, father, child) and 308 control triads. Information on periconception medication and folic acid use was obtained through questionnaires. Results: Mothers with MDR1 3435CT/TT genotype and using medication showed a significant association with the risk of a child with CHD (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.3–4.3) compared to mothers with MDR1 3435CC genotype not using medication. This risk increased without folic acid use (OR, 2.8; 95% CI, 1.2–6.4), and decreased in folic acid users (OR, 1.7; 95% CI, 0.8–3.7). Children carrying the MDR1 3435CT/TT genotype and periconceptionally exposed to medication without folic acid did not show significant risks. Conclusion: Mothers carrying the MDR1 3435T allele, using medication without folic acid, are at nearly 3-fold increased risk for CHD in the offspring. [ABSTRACT FROM AUTHOR]

A letter to the editor of Clinical Chemistry & Laboratory Medicine discusses the limitations and concerns regarding the use of uracil testing for pre-emptive dihydropyrimidine dehydrogenase (DPD) deficiency testing in fluoropyrimidine treatment. The authors argue that the exclusion of certain genetic variants in the genotyping panel used in the study hampers adequate comparison between genotyping and uracil testing. They also highlight the importance of proper identification of DPYD variant carriers and suggest that both genotyping and phenotyping should be used in combination for accurate testing. The authors urge medical societies and regulatory organizations to refrain from recommending fluoropyrimidine dosing strategies based on uracil levels alone. [Extracted from the article]

In this study we describe the development and validation of a liquid chromatography mass spectrometry method (LC-MS/MS) to quantify five tryptophan (TRP) metabolites within the kynurenine– and serotonin pathway and apply the method to serum samples of women in the first trimester of pregnancy. A secondary aim was to investigate the correlation between body mass index (BMI) and the five analytes. A LC-MS/MS was developed for the analysis of TRP, kynurenine (KYN), 5-hydroxytryptophan (5-HTP), hydroxytryptamine (5-HT), and 5-hydroxyindole acetic acid (5-HIAA). Serum samples (n=374) were analyzed of pregnant women (median gestational age: 8 ± 2 weeks) participating in a subcohort of the Rotterdam Periconceptional Cohort (Predict study). The LC-MS/MS method provided satisfactory separation of the five analytes (7 min run). For all analytes R2 was >0.995. Within- and between-run accuracies were 72–97% and 79–104%, and the precisions were all <15% except for the between-run precisions of the low QC-samples of 5-HTP and 5-HT (both 16%). Analyte concentrations were determined in serum samples of pregnant women (median (IQR)); TRP (µmol/L): 57.5 (13.4), KYN (µmol/L): 1.4 (0.4), 5-HTP (nmol/L): 4.1 (1.2), 5-HT (nmol/L): 615 (323.1), and 5-HIAA (nmol/L): 39.9 (17.0). BMI was negatively correlated with TRP, 5-HTP, and 5-HIAA (TRP: r=−0.18, p<0.001; 5-HTP: r=−0.13, p=0.02; natural log of 5-HIAA: r=−0.11, p=0.04), and positively with KYN (r=0.11, p=0.04). The LC-MS/MS method is able to accurately quantify kynurenine– and serotonin pathway metabolites in pregnant women, providing an opportunity to investigate the role of the TRP metabolism in the (patho)physiology of pregnancy. [ABSTRACT FROM AUTHOR]

To determine the safety, feasibility, pharmacokinetics, and cost of UGT1A1 genotype-guided dosing of irinotecan. In this prospective, multicentre, non-randomised study, patients intended for treatment with irinotecan were pre-therapeutically genotyped for UGT1A1 ∗28 and UGT1A1 ∗93. Homozygous variant carriers (UGT1A1 poor metabolisers; PMs) received an initial 30% dose reduction. The primary endpoint was incidence of febrile neutropenia in the first two cycles of treatment. Toxicity in UGT1A1 PMs was compared to a historical cohort of UGT1A1 PMs treated with full dose therapy, and to UGT1A1 non-PMs treated with full dose therapy in the current study. Secondary endpoints were pharmacokinetics, feasibility, and costs. Of the 350 evaluable patients, 31 (8.9%) patients were UGT1A1 PM and received a median 30% dose reduction. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical UGT1A1 PMs (P = 0.04) and was comparable to the incidence in UGT1A1 non-PMs treated with full dose therapy. Systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs was still slightly higher compared to a standard-dosed irinotecan patient cohort (difference: +32%). Cost analysis showed that genotype-guided dosing was cost-saving with a cost reduction of €183 per patient. UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan, results in a therapeutically effective systemic drug exposure, and is cost-saving. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve individual patient safety. • UGT1A1 ∗28 and UGT1A1 ∗93 are associated with severe irinotecan-associated toxicity. • UGT1A1 genotype-guided dosing improves safety of irinotecan in UGT1A1 PMs. • 30% dose reduction of irinotecan in UGT1A1 PMs provided therapeutic drug exposure. • UGT1A1 genotype-guided dosing is cost saving. • UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care. [ABSTRACT FROM AUTHOR]

Extragonadal androgens play a pivotal role in prostate cancer disease progression on androgen receptor signaling inhibitors (ARSi), including abiraterone and enzalutamide. We aimed to investigate if germline variants in genes involved in extragonadal androgen synthesis contribute to resistance to ARSi and may predict clinical outcomes on ARSi. We included ARSi naive metastatic prostate cancer patients treated with abiraterone or enzalutamide and determined 18 germline variants in six genes involved in extragonadal androgen synthesis. Variants were tested in univariate and multivariable analysis for the relation with overall survival (OS) and time to progression (TTP) by Cox regression, and PSA response by logistic regression. A total of 275 patients were included. From the investigated genes CYP17A1 , HSD3B1 , CYP11B1 , AKR1C3 , SRD5A1 and SRD5A2 , only rs4736349 in CYP11B1 in homozygous form (TT), present in 54 patients (20%), was related with a significantly worse OS (HR = 1.71, 95% CI 1.09 – 2.68, p = 0.019) and TTP (HR = 1.50, 95% CI 1.08 – 2.09, p = 0.016), and was related with a significantly less frequent PSA response (OR = 0.48, 95% CI 0.24 – 0.96, p = 0.038) on abiraterone or enzalutamide in a multivariable analysis. The frequent germline variant rs4736349 in CYP11B1 is, as homozygote, an independent negative prognostic factor for treatment with abiraterone or enzalutamide in ARSi naive metastatic prostate cancer patients. Our findings warrant prospective investigation of this potentially important predictive biomarker. • A germline variant in CYP11B1 is related to response to abiraterone or enzalutamide. • In homozygous form, this germline variant is related with worse outcomes of treatment. • With a global prevalence of 20%, the homozygous variant is highly frequent. [ABSTRACT FROM AUTHOR]

Abstract Background Hepatic membrane transporters are involved in the transport of many endogenous and exogenous compounds, including drugs. We aimed to study the relation of age with absolute transporter protein expression in a cohort of 62 mainly fetus and newborn samples. Methods Protein expressions of BCRP, BSEP, GLUT1, MCT1, MDR1, MRP1, MRP2, MRP3, NTCP, OCT1, OATP1B1, OATP1B3, OATP2B1 and ATP1A1 were quantified with LC-MS/MS in isolated crude membrane fractions of snap-frozen post-mortem fetal and pediatric, and surgical adult liver samples. mRNA expression was quantified using RNA sequencing, and genetic variants with TaqMan assays. We explored relationships between protein expression and age (gestational age [GA], postnatal age [PNA], and postmenstrual age); between protein and mRNA expression; and between protein expression and genotype. Results We analyzed 36 fetal (median GA 23.4 weeks [range 15.3–41.3]), 12 premature newborn (GA 30.2 weeks [24.9–36.7], PNA 1.0 weeks [0.14–11.4]), 10 term newborn (GA 40.0 weeks [39.7–41.3], PNA 3.9 weeks [0.3–18.1]), 4 pediatric (PNA 4.1 years [1.1–7.4]) and 8 adult liver samples. A relationship with age was found for BCRP, BSEP, GLUT1, MDR1, MRP1, MRP2, MRP3, NTCP, OATP1B1 and OCT1, with the strongest relationship for postmenstrual age. For most transporters mRNA and protein expression were not correlated. No genotype-protein expression relationship was detected. Discussion and conclusion Various developmental patterns of protein expression of hepatic transporters emerged in fetuses and newborns up to four months of age. Postmenstrual age was the most robust factor predicting transporter expression in this cohort. Our data fill an important gap in current pediatric transporter ontogeny knowledge. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Background Multiple organizations produce guidance documents that provide opportunities to harmonize quality practices for diagnostic testing. The International Organization for Standardization ISO 15189 standard addresses requirements for quality in management and technical aspects of the clinical laboratory. One technical aspect addresses the complexities of the pre-examination phase prior to diagnostic testing. Methods The Committee for Molecular Diagnostics of the International Federation for Clinical Chemistry and Laboratory Medicine (also known as, IFCC C-MD) conducted a survey of international molecular laboratories and determined ISO 15189 to be the most referenced guidance document. In this review, the IFCC C-MD provides case-based examples illustrating the value of select pre-examination processes as these processes relate to molecular diagnostic testing. Case-based examples in infectious disease, oncology, inherited disease and pharmacogenomics address the utility of: 1) providing information to patients and users, 2) designing requisition forms, 3) obtaining informed consent and 4) maintaining sample integrity prior to testing. Conclusions The pre-examination phase requires extensive and consistent communication between the laboratory, the healthcare provider and the end user. The clinical vignettes presented in this paper illustrate the value of applying select ISO 15189 recommendations for general laboratory to the more specialized area of Molecular Diagnostics. [ABSTRACT FROM AUTHOR]

Tamoxifen is important in the adjuvant treatment of breast cancer. A plasma concentration of the active metabolite endoxifen of > 16 nM is associated with a lower risk of breast cancer-recurrence. Since inter-individual variability is high and > 20 % of patients do not reach endoxifen levels > 16 nM with the standard dose tamoxifen, therapeutic drug monitoring is advised. However, ideally, the correct tamoxifen dose should be known prior to start of therapy. Our aim is to develop a population pharmacokinetic (POP-PK) model incorporating a continuous CYP2D6 activity scale to support model informed precision dosing (MIPD) of tamoxifen to determine the optimal tamoxifen starting dose. Data from eight different clinical studies were pooled (539 patients, 3661 samples) and used to develop a POP-PK model. In this model, CYP2D6 activity per allele was estimated on a continuous scale. After inclusion of covariates, the model was subsequently validated using an independent external dataset (378 patients). Thereafter, dosing cut-off values for MIPD were determined. A joint tamoxifen/endoxifen POP-PK model was developed describing the endoxifen formation rate. Using a continuous CYP2D6 activity scale, variability in predicting endoxifen levels was decreased by 37 % compared to using standard CYP2D6 genotype predicted phenotyping. After external validation and determination of dosing cut-off points, MIPD could reduce the proportion of patients with subtherapeutic endoxifen levels at from 22.1 % toward 4.8 %. Implementing MIPD from the start of tamoxifen treatment with this POP-PK model can reduce the proportion of patients with subtherapeutic endoxifen levels at steady-state to less than 5 %. [Display omitted] • Continuous expression of CYP2D6 activity based on genotype is feasible. • A model-informed dosing strategy for tamoxifen therapy was developed. • The proportion of patients with subtherapeutic levels can be reduced from 21 % to 5 %. • This is the first clinical application for model-informed precision dosing in oncology. [ABSTRACT FROM AUTHOR]

Occurrence of hand-foot syndrome (HFS) during capecitabine treatment often results in treatment interruptions (26 %) or treatment discontinuation (17 %), and can severely decrease quality of life. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in genes involved in capecitabine metabolism – other than DPYD – are associated with an increased risk for capecitabine-induced HFS. Patients treated with capecitabine according to standard of care were enrolled after providing written informed consent for genotyping purposes. Prospectively collected blood samples were used to extract genomic DNA, which was subsequently genotyped for SNPs in CES1 , CES2 and CDA. SNPs and clinical baseline factors that were univariably associated with HFS with P ≤ 0.10, were tested in a multivariable model using logistic regression. Of the 446 patients eligible for analysis, 146 (32.7 %) developed HFS, of whom 77 patients (17.3 %) experienced HFS ≥ grade 2. In the multivariable model, CES1 1165–33 C>A (rs2244613, minor allele frequency 19 %) and CDA 266 + 242 A>G (rs10916825, minor allele frequency 35 %) variant allele carriers were at higher risk of HFS ≥ grade 2 (OR 1.888; 95 %CI 1.075–3.315; P = 0.027 and OR 1.865; 95 %CI 1.087–3.200; P = 0.024, respectively). We showed that CES1 1165–33 C>A and CDA 266 + 242 A>G are significantly associated with HFS grade 2 and grade 3 in patients treated with capecitabine. Prospective studies should assess whether this increased risk can be mitigated in carriers of these SNPs, when pre-emptive genotyping is being followed by dose adjustment or by alternative treatment by a fluoropyrimidine that is not substrate to CES1, such as S1. • Over half of patients treated with capecitabine develop hand-foot syndrome. • Hand-foot syndrome often results in treatment interruption or discontinuation. • CES1 1165–33 A and CDA 266 + 242 G carriers are at increased risk of hand-foot syndrome. [ABSTRACT FROM AUTHOR]

Background and aims To assess the relationship between the extent and phenotype of coronary atherosclerosis, as assessed by in-vivo grayscale and radiofrequency intravascular ultrasound (IVUS), and circulating Troponin levels in patients with established stable coronary artery disease (CAD). Methods In this single-center, cross-sectional analysis, high-sensitivity Troponin T (hsTnT) was measured and IVUS was performed in a predefined non-stenotic segment of a non-culprit coronary artery in 231 patients with stable CAD undergoing elective angiography. Results HsTnT was detectable (>3 pg/mL) in 212 patients (92%) and a concentration above 14 pg/mL was observed in 19.5%. Normalised segmental plaque volumes were positively associated with hsTnT levels (25.0 mm 3 increase in segmental plaque volume per SD increase in ln-transformed hsTnT, 95% CI: 6.0–44.0, p = 0.010). Higher hsTnT levels were measured in patients with a virtual histology derived thin-cap fibroatheroma (VH-TCFA, adj. odds ratio for presence of VH-TCFA = 1.52 per SD increase in ln-transformed hsTnT, 95% CI: 1.10–2.11, p = 0.011). Patients with a VH-TCFA had a 2-fold increased prevalence of hsTnT concentration ≥14 pg/mL (adj. OR 2.35, 95% CI: 1.12–4.91, p = 0.024). In addition, a 3-fold increased prevalence of hsTnT concentration ≥14 pg/mL was observed in patients with a VH-TCFA with a lesional plaque volume higher than the median (adj. OR 3.36, 95% CI: 1.44–7.84, p = 0.005). Conclusions Segmental plaque volume and presence of VH-TCFA lesions are associated with higher circulating hsTnT concentrations in stable CAD patients. Subclinical plaque rupture or erosion and distal embolisation may be hypothesized as a potential pathophysiological mechanism with respect to Troponin elevation and its relation with adverse outcome in this patient population. [ABSTRACT FROM AUTHOR]

Developments in '-omics' are creating a paradigm shift in laboratory medicine leading to personalized medicine. This allows the increase in diagnostics and therapeutics focused on individuals rather than populations. In order to investigate whether laboratory medicine is ready to play a key role in the integration of personalized medicine in routine health care and set the state-of-the-art knowledge about personalized medicine and laboratory medicine in Europe, a questionnaire was constructed under the auspices of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) and the European Society of Pharmacogenomics and Personalised Therapy (ESPT). The answers of the participating laboratory medicine professionals indicate that they are aware that personalized medicine can represent a new and promising health model, and that laboratory medicine should play a key role in supporting the implementation of personalized medicine in the clinical setting. Participants think that the current organization of laboratory medicine needs additional/relevant implementations such as (i) new technological facilities in -omics; (ii) additional training for the current personnel focused on the new methodologies; (iii) incorporation in the laboratory of new competencies in data interpretation and counseling; and (iv) cooperation and collaboration among professionals of different disciplines to integrate information according to a personalized medicine approach. [ABSTRACT FROM AUTHOR]

Abstract: Background: Total PSA assays measure both complexed and non-complexed forms of PSA while free PSA assays only measure non-complexed forms. Free PSA is a mixture of isoforms including immature PSA (proPSA) with retained portions of the leader sequence (e.g. [−7], [−4], and [−2]proPSA) and nicked forms (BPSA). ProPSA isoforms in male sera have been associated with prostate cancer. This study characterized the analytical performance of a chemiluminescent immunoassay for [−2]proPSA. Methods: The Access Hybritech p2PSA assay is a sandwich immunoassay using an anti-[−2]proPSA monoclonal antibody attached to paramagnetic beads and an anti-PSA monoclonal antibody conjugated to alkaline phosphatase calibrated with recombinant [−2]proPSA. Analytical studies including sensitivity (CLSI EP17-A) and imprecision (CLSI EP5-A2) were performed. Results: The Access Hybritech p2PSA assay for [−2]proPSA had a dynamic range of 0.5 to 5000pg/ml. The total CV of the assay was <7% for [−2]proPSA concentrations between 20 and 1000pg/ml. The LOB was 0.50pg/ml, LOD 0.69pg/ml, and LOQ 3.23pg/ml (20% CV). There was no hook effect up to 15,000pg/ml. There was a <5% difference between calibrator and reagent lots and no interference from normal serum constituents. Conclusions: The Access Hybritech p2PSA assay is a robust immunoassay for the measurement of serum [−2]proPSA. [Copyright &y& Elsevier]

Abstract: Purpose: To study if polymorphisms in genes encoding for CYP3A enzymes, that play a role in steroid hormone metabolism, affect steroid hormone serum levels and prostate cancer incidence or mortality. Methods: 3048 male participants of The Rotterdam Study were included. Prostate cancer cases and non-cases were studied for differences in baseline hormone levels with Student''s t-test. General linear models were performed on different random subsets of hormone levels to study associations with genotype. Cox’ proportional hazard models were used to study prostate cancer incidence and mortality among genotypes. Results: Both DHEAS sulphate as free-testosterone were significantly increased at baseline in males who developed a prostate cancer within the study period. CYP3A4 G-allele carriage was associated with lower levels of estrone sulphate (p =0.005) and higher levels of estradiol (p =0.04) compared to non-carriers. CYP3A5 A-allele carriage was associated with increased levels of estrone sulphate (p =0.02). CYP3A7 G-allele carriage was associated with the highest number of significant differences in steroid hormone levels. Carriers of the allele resulting in continued enzyme expression during adulthood had decreased levels of dehydroepiandrosterone (DHEA) sulphate (p =0.05), androstenedione (p =0.006), estrone (p =0.0001) and estrone sulphate (p =0.003) compared to mean levels of these hormones in homozygous wild type carriers. CYP3A43 genotype was not associated with any of the studied hormone levels. However, carriers of the CYP3A43 G-allele showed a significant 5-fold increase in mortality among early onset diagnosed prostate cancers. Conclusion: Increased levels of free testosterone and DHEA sulphate were associated with prostate cancer incidence along the study period. Primarily the amount of CYP3A7 expression seemed to affect steroid hormone levels. Nevertheless, testosterone, a precursor of the prostate growth and differentiation stimulating dehydrotestosterone, was not influenced by CYP3A genotype. In line with this, no significant associations were observed for CYP3A genotypes and prostate cancer incidence. [Copyright &y& Elsevier]

Abstract: Objectives: CA 15-3 is a widely used tumor marker for breast cancer. We have investigated whether the MUC1 568 A/G polymorphism can influence CA 15-3 levels in healthy women and patients with breast tumors. Design and methods: CA 15-3 was measured in 208 healthy women, in 67 with benign disease, and in 162 women with breast cancer. All subjects were genotyped for the MUC1 568 A/G polymorphism. Results: Significant differences were observed between mean CA 15-3 levels of control subjects grouped according to the MUC1 568 genotype (mean±SD): AA (10.3±3.8), AG (15.9±5.0) and GG (19.0±5.6) U/mL, p <0.0001. Similar (median) results were observed in women with benign breast disease: AA (10.2), AG (14.2) and GG (16.6) U/mL, p <0.0001, and those with breast cancer: AA (10.4), AG (17.1) and GG (23.9) U/mL, p <0.0001. Conclusions: The MUC1 568 A/G polymorphism strongly influences CA 15-3 levels in healthy women and women with either benign or malignant breast tumors. [Copyright &y& Elsevier]