Sci Rep. 2024 Nov 12;14(1):27700. doi: 10.1038/s41598-024-79036-4.

ABSTRACT

Fluorouracil-based chemotherapy responses in colorectal cancer (CRC) patients vary widely, highlighting the role of pharmacogenomics in developing better predictive models. We analyzed 379 CRC patients receiving fluorouracil-based chemotherapy, collecting data on fluorouracil metabolism-related SNPs (TYMS, MTHFR, DPYD, RRM1), blood inflammatory markers, and clinical status. Six machine learning models-K-nearest neighbors, support vector machine, gradient boosting decision trees (GBDT), eXtreme Gradient Boosting (XGBoost), LightGBM, and random forest-were compared against multivariate logistic regression and a deep learning model (i.e., multilayer perceptron, MLP). Feature importance analysis highlighted seven predictors: histological grade, N and M staging, monocyte count, platelet-to-lymphocyte ratio, MTHFR rs1801131, and RRM1 rs11030918. In a five-fold cross-validation, XGBoost and GBDT exhibited superior performance, with Area Under Curve (AUC) of 0.88 ± 0.02. XGBoost excelled in identifying favorable prognosis (recall = 0.939). GBDT demonstrated balance in recognizing both categories, with a recall for favorable prognosis of 0.908 and a precision for unfavorable prognosis of 0.863. MLP had a similar AUC (0.87) with high precision for favorable prognosis (recall = 0.946). In external validation, XGBoost model achieved an accuracy of 0.79. An online prognostic tool based on XGBoost was developed, integrating metabolism-related SNPs and inflammatory markers, enhancing CRC treatment precision and supporting tailored chemotherapy.

PMID:39532939 | DOI:10.1038/s41598-024-79036-4

Therapie. 2024 Oct 23:S0040-5957(24)00175-6. doi: 10.1016/j.therap.2024.10.059. Online ahead of print.

ABSTRACT

INTRODUCTION: The DRAMES (décès en relation avec l'abus de médicaments et de substances) registry is a French database of drug-related deaths (medications or illicit drugs) among drug users. The DTA (décès toxiques par antalgiques) registry is a French database of analgesic-related deaths among people without a history of drug abuse. Both registries are based on the collection of data on deaths for which forensic toxicology experts have performed analyses.

MATERIAL AND METHODS: In the present study, we included drug- and analgesic-related deaths occurring from January 2013 to December 2022 in France. Subject demographic characteristics and medical history, forensic autopsy findings and toxicology reports were evaluated.

RESULTS: Among drug users (DRAMES registry), opioids used alone or in combination were the main contributor to drug-related deaths in France, as they are in most countries. However, licit methadone was the leading cause of opioid-related deaths (ahead of heroin) during the study period. The main trend was the dramatic increase in cocaine-related mortality. Among medical users of analgesics (DTA registry), tramadol was the leading cause of deaths throughout this period.

CONCLUSION: A large-scale naloxone distribution program is urgently needed in France to prevent opioid overdoses, including among licit methadone users. However, our data do not support the hypothesis of an opioid crisis in France, although close monitoring is still required, particularly for oxycodone.

PMID:39532558 | DOI:10.1016/j.therap.2024.10.059

JCO Oncol Pract. 2024 Nov;20(11):1441-1451. doi: 10.1200/OP.24.00191. Epub 2024 Nov 12.

ABSTRACT

Pharmacogenomic (PGx) testing is a growing area of personalized medicine with demonstrated clinical utility in improving patient outcomes in oncology. PGx testing of pharmacogenes affecting drug pharmacokinetics, pharmacodynamics, and response can help inform drug selection and dosing of several anticancer therapies and supportive care medications. Several PGx testing techniques exist including polymerase chain reaction (PCR), MassARRAY, microarray, and sequencing. This review article provides a clinician-friendly guide of these techniques. Understanding the advantages, limitations, ideal use, and potential clinical applications of each platform can help clinicians choose the appropriate PGx testing platform for specific use cases.

PMID:39531848 | DOI:10.1200/OP.24.00191

Genet Med. 2024 Nov 8:101323. doi: 10.1016/j.gim.2024.101323. Online ahead of print.

ABSTRACT

BACKGROUND: Practice is shifting toward genome-first approaches, such as opportunistic screening for secondary findings (SFs). Analysis of SFs could be extended beyond medically actionable results to include non-medically actionable monogenic disease risks, carrier status, pharmacogenomic variants, and risk variants for common complex disease. However, evidence on the clinical utility of returning these results is lacking. We assessed the outcomes of opportunistic screening for a broad spectrum of SFs by evaluating the yield, impact on clinical management, and consistency between SFs and participants' clinical features and family history.

METHODS: Adult cancer patients had GS with the option to learn multiple categories of SFs. Outcomes data were collected through chart review and participant-reported measures up to one year after return of results.

RESULTS: All participants (n=139, 85.6% female, average 54.6 years old) who elected to learn SFs had ≥1 variant reported (100% [139/139]). The yield of reportable findings was highest for pharmacogenomic variants (97.8% [135/138] of participants), followed by common disease risk variants (89.4% [118/132]), carrier status (89.3% [117/131]), and variants related to Mendelian (27.2% [34/125]), medically actionable (15.2% [21/138]), and early-onset neurodegenerative (2.6% [3/117]) disease risks. SFs from the ACMG list (v3.2, non-cancer genes) were reported in 1.4% (2/138) of participants. SFs across all categories demonstrated clinical utility by prompting management changes in 28.1% (39/139) of participants. Moreover, a considerable proportion of participants had suggestive clinical features (49.0% (24/49)]) or family history (21.8% (27/124)) potentially related to their SFs.

CONCLUSIONS: Our findings indicate there are potential benefits from opportunistic screening for a broad range of SFs.

PMID:39530317 | DOI:10.1016/j.gim.2024.101323

Nucleic Acids Res. 2024 Nov 12:gkae977. doi: 10.1093/nar/gkae977. Online ahead of print.

ABSTRACT

The Single Nucleotide Polymorphism Database (dbSNP), established in 1998 by the National Center for Biotechnology Information (NCBI), has been a critical resource in genomics for cataloging small genetic variations. Originally focused on single nucleotide polymorphisms (SNPs), dbSNP has since expanded to include a variety of genetic variants, playing a key role in genome-wide association studies (GWAS), population genetics, pharmacogenomics, and cancer research. Over 25 years, dbSNP has grown to include more than 4.4 billion submitted SNPs and 1.1 billion unique reference SNPs, providing essential data for identifying disease-related genetic variants and studying human diversity. Integrating large-scale projects like 1000 Genomes, gnomAD, TOPMed, and ALFA has expanded dbSNP's catalog of human genetic variation, increasing its usefulness for research and clinical applications. Keeping up with advancements such as next-generation sequencing and cloud-based infrastructure, dbSNP remains a cornerstone of genetic research supporting continued discoveries in precision medicine and population genomics. DATABASE URL: https://www.ncbi.nlm.nih.gov/snp.

PMID:39530225 | DOI:10.1093/nar/gkae977

J Multidiscip Healthc. 2024 Nov 7;17:5061-5062. doi: 10.2147/JMDH.S504508. eCollection 2024.

NO ABSTRACT

PMID:39529681 | PMC:PMC11552506 | DOI:10.2147/JMDH.S504508

Mol Med. 2024 Nov 11;30(1):209. doi: 10.1186/s10020-024-00934-4.

ABSTRACT

BACKGROUND: Patient-derived xenograft (PDX) is currently considered a preferred preclinical model to evaluate drug sensitivity, explore drug resistance mechanisms, and select individualized treatment regimens.

METHODS: Histopathological examination, immunohistochemistry and whole-exome sequencing confirmed similarity between our PDX tumors and primary tumors in terms of morphology and genetic characteristics. The drug reactivity of the PDX tumor was validated in vivo. The mechanisms of acquired resistance to Osimertinib PDX tumors were investigated by WES and WB.

RESULTS: We successfully established 13 NSCLC-PDXs derived from 62 patients, including eight adenocarcinomas, four squamous-cell carcinoma, and one large-cell neuroendocrine carcinoma. Histological subtype and clinical stage were significant factors affecting the successful PDXs establishment. The treatment responses to conventional chemotherapy in PDXs were entirely consistent with that of their corresponding patients. According to the genetic status of tumors, more appropriate targeted agents were selected in PDXs for their corresponding patients as alternative treatment options. In addition, a PDX model with acquired resistance to osimertinib was induced, and the overactivation of RAS mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) signaling pathway caused by the dual-specificity phosphatase 6 (DUSP6) M62I mutation was found to play a key role in the development of osimertinib resistance. Trametinib, a specific inhibitor of the MAPK-ERK pathway significantly slowed down the tumor growth in osimertinib-resistant PDX models, providing an alternative treatment in patients after osimertinib failure.

PMID:39528952 | DOI:10.1186/s10020-024-00934-4

Mol Neurobiol. 2024 Nov 11. doi: 10.1007/s12035-024-04586-7. Online ahead of print.

ABSTRACT

Prenatal excess of glucocorticoids (GCs) is considered to be one of the highly impacting factors contributing to depression development. Although GCs are crucial for normal fetal development and their administration (mainly dexamethasone, DEX) is a life-saving procedure for those at risk of preterm delivery, exposure to excess levels of GCs during pregnancy can yield detrimental consequences. Therefore, we aimed to systematically investigate the brain molecular alterations triggered by prenatal DEX administration. We used a rat model of depression based on prenatal exposure to DEX and performed integrative multi-level methylomic, transcriptomic, and proteomic analyses of adult rats' brains (i.e., frontal cortex (FCx) and hippocampus (Hp)) to identify the outcomes of DEX action. Each of the investigated levels was significantly affected by DEX in the long-term manner. Particularly, we found 200 CpG islands to be differentially methylated in the FCx and 200 in the Hp of prenatally DEX-treated rats. Global transcriptomic analysis uncovered differential expression of transcripts mostly in FCx (271) and 1 in Hp, while proteomic study identified 146 differentially expressed proteins in FCx and 123 in Hp. Among the identified enriched molecular networks, we found altered pathways involved in synaptic plasticity (i.e., cAMP, calcium, and Wnt signaling pathways or tight junctions and adhesion molecules), which may contribute to cognitive impairment, observed in DEX-treated animals. Moreover, in the FCx, DEX administration in the prenatal period downregulates the expression of ribosome protein genes associated both with large and small ribosomal subunit assembly which can lead to a global decrease in translation and protein synthesis processes and, indirectly, alterations in the neurotransmission process.

PMID:39528842 | DOI:10.1007/s12035-024-04586-7

Cell Mol Life Sci. 2024 Nov 11;81(1):450. doi: 10.1007/s00018-024-05471-1.

ABSTRACT

Phospholamban (PLN) plays a crucial role in regulating sarcoplasmic reticulum (SR) Ca2+ cycling and cardiac contractility. Mutations within the PLN gene have been detected in patients with cardiomyopathy, with the heterozygous variant c.40_42delAGA (p.R14del) of PLN being the most prevalent. Investigations into the mechanisms underlying the pathology of PLN-R14del have revealed that cardiac cells from affected patients exhibit pathological aggregates containing PLN. Herein, we performed comprehensive molecular and cellular analyses to delineate the molecular aberrations associated with the formation of these aggregates. We determined that PLN aggregates contain autophagic proteins, indicating inefficient degradation via the autophagy pathway. Our findings demonstrate that the expression of PLN-R14del results in diminished autophagic flux due to impaired fusion between autophagosomes and lysosomes. Mechanistically, this defect is linked to aberrant recruitment of key membrane fusion proteins to autophagosomes, which is mediated in part by changes in Ca2+ homeostasis. Collectively, these results highlight a novel function of PLN-R14del in regulating autophagy, that may contribute to the formation of pathogenic aggregates in patients with cardiomyopathy. Prospective strategies tailored to ameliorate impaired autophagy may hold promise against PLN-R14del disease.

PMID:39527246 | DOI:10.1007/s00018-024-05471-1

Psychiatr Genet. 2024 Dec 1;34(6):124-133. doi: 10.1097/YPG.0000000000000373. Epub 2024 Nov 6.

ABSTRACT

BACKGROUND: Previous studies have shown that genes in brain development pathways may have important roles in affecting risk of suicidal behaviors, with our previous meta-analysis supporting a role of the brain-derived neurotrophic factor (BDNF) gene. NTRK2 is a gene that encodes the neurotrophic receptor tyrosine kinase 2, which is a receptor for BDNF. In the current study, we aim to examine the potential association between NTRK2 single nucleotide polymorphism (SNPs) and suicidal ideation/behaviors.

METHODS: We first conducted a literature search using keywords like 'NTRK2', 'TRKB', and 'suicid*' to identify papers on NTRK2 SNPs and suicidal ideation/behaviors. In addition, we have individual-level genotype data for all the identified SNPs in literature search. We used the R meta package to perform meta-analyses on both the genotype count and the allele count data. Moreover, we performed meta-analyses on specific haplotypes within each haplotype block.

MAIN RESULTS: Following our literature search and meta-analyses on 20 NTRK2 SNPs across up to 8467 samples, we found three SNPs, rs10868235 [N = 5,318, odds ratio (OR) = 1.34, P = 0.02], rs1867283 (N = 5,134, OR = 0.73, P = 0.04), and rs1147198 (N = 5,132, OR = 1.36, P = 0.03) to be nominally associated with suicidal attempts. Those three findings, however, did not survive multiple-testing corrections. Also, none of the haplotype blocks showed significant involvement in suicidality.

CONCLUSION: Our results suggest that the NTRK2 gene may not have a major role in suicidality. Future efforts, however, should explore gene-gene interaction and pathway analyses.

PMID:39527116 | DOI:10.1097/YPG.0000000000000373

Pediatr Pulmonol. 2024 Nov 11. doi: 10.1002/ppul.27402. Online ahead of print.

ABSTRACT

INTRODUCTION: Depression and anxiety are common in persons with cystic fibrosis (PwCF). Genetic polymorphisms in CYP2C19 and CYP2D6 are well-established predictors of selective serotonin reuptake inhibitors (SSRIs) treatment failure yet have not been studied specifically in PwCF. The purpose of this study was to determine the rate of SSRI failure in PwCF and to identify factors that predict treatment failure.

METHODS: A retrospective cohort study was conducted of PwCF prescribed an SSRI for depression or anxiety. Potential predictors of SSRI failure were compared between PwCF for SSRI treatment success and failure. When CYP2D6 and CYP2C19 pharmacogenetic (PGx) test results were available, SSRI selection was compared to appropriateness per Clinical PGx Implementation Consortium (CPIC) guideline. PGx results were not available at the time of prescribing.

RESULTS: The study included 184 PwCF and 45% experienced SSRI treatment failure. Demographics, concomitant drug-drug interactions, concomitant antidepressant medications, liver disease, and pulmonary function tests were not different between success and failure groups. Only 44 PwCF had PGx results and of these, only nine had actionable genotypes and prescribed an affected SSRI. This cohort had a failure rate of 78% (7 of 9) which was significantly higher compared to 40% (14 of 35) and 45% (83 of 184) in our PGx cohort and total cohort, respectively (p = 0.04; p = 0.04).

CONCLUSION: SSRI failure rate in PwCF is high and consistent with rates of the general population. Greater depression severity and number of SSRIs trialed were seen in the failure group. Pre-emptive PGx testing may improve SSRI success rates in PwCF.

PMID:39526586 | DOI:10.1002/ppul.27402

Clin Transl Sci. 2024 Nov;17(11):e70057. doi: 10.1111/cts.70057.

ABSTRACT

Lack of pharmacogenomics knowledge among healthcare professionals is the most significant cited barrier to implementing pharmacogenomics in clinical settings. Despite the growth in research initiatives and awareness of pharmacogenomics, healthcare professionals continue to report a lack of knowledge and confidence in practicing pharmacogenomics. This study aims to assess the current pharmacogenomics knowledge gaps and learning needs of healthcare professionals in Malaysia. A modified Delphi with a multidisciplinary expert panel was conducted, and a purposive sampling method was used with predefined selection criteria. Fourteen study sites in Malaysia were included. The cut-off value to approach consensus was predefined as a threshold of 60% or higher, and a quantitative descriptive statistical analysis was performed. The study demonstrated that all experts rated the suggested educational content components as essential/important to be included in the educational intervention. Additionally, experts highlighted the significant barriers and gaps to adopting and practicing pharmacogenomics. To conclude, this multisite Delphi study enabled the development of a tailored, effective, evidence-based, competency-based educational intervention in pharmacogenomics for healthcare professionals in Malaysia. To keep up with the rapid evolution of the pharmacogenomics field, healthcare professionals should be equipped with the necessary competencies required to practice pharmacogenomics for better health outcomes. Future research is needed to determine the feasibility of the proposed educational intervention.

PMID:39523855 | DOI:10.1111/cts.70057

J Egypt Natl Canc Inst. 2024 Nov 11;36(1):35. doi: 10.1186/s43046-024-00245-z.

ABSTRACT

Functional genomics, a multidisciplinary subject, investigates the functions of genes and their products in biological systems to better understand diseases and find new drugs. Drug repurposing is an economically efficient approach that entails discovering novel therapeutic applications for already-available medications. Genomics enables the identification of illness and therapeutic molecular characteristics and interactions, which in turn facilitates the process of drug repurposing. Techniques like gene expression profiling and Mendelian randomization are helpful in identifying possible medication candidates. Progress in computer science allows for the investigation and modeling of gene expression networks that involve large amounts of data. The amalgamation of data concerning DNA, RNA, and protein functions bears similarity to pharmacogenomics, a crucial aspect in crafting cancer therapeutics. Functional genomics in drug discovery, particularly for cancer, is still not thoroughly investigated, despite the existence of a significant amount of literature on the subject. Next-generation sequencing and proteomics present highly intriguing opportunities. Publicly available databases and mining techniques facilitate the development of cancer treatments based on functional genomics. Broadening the exploration and utilization of functional genomics holds significant potential for advancing drug discovery and repurposing, particularly within the realm of oncology.

PMID:39523244 | DOI:10.1186/s43046-024-00245-z

Drug Metab Pers Ther. 2024 Nov 11. doi: 10.1515/dmpt-2024-0042. Online ahead of print.

ABSTRACT

INTRODUCTION: Pharmacogenetics (PGx) has the potential to improve patient care, allowing to transform medical interventions by providing personalized therapeutic strategies. Scientific evidence supports the use of PGx in clinical practice and international organizations are developing clinical guidelines to facilitate the utilization of PGx testing. However, clinical implementation of PGx is limited and unequal worldwide.

CONTENT: This review summarizes regional and national Spanish initiatives to implement PGx in the clinical practice.

SUMMARY AND OUTLOOK: Diverse strategies to implement PGx in healthcare are applied across countries or even in the different regions of a specific country. Such was the case of Spain, a European country with 17 Autonomous Regions and two Autonomous Cities, each one with capacity to manage their own healthcare systems. Nevertheless, during the past years, many initiatives and strategies have been launched in Spain to develop different aspects of PGx. Importantly, the National Healthcare System has approved a PGx testing catalogue. This review highlights the crucial work and efforts of scientific societies (like the Spanish Society of Pharmacogenetics and Pharmacogenomics), of experts in PGx, of healthcare providers and of governmental parties in the implementation of PGx to personalize patient therapy, focused in Spain.

PMID:39523122 | DOI:10.1515/dmpt-2024-0042

Arch Immunol Ther Exp (Warsz). 2024 Nov 10;72(1). doi: 10.2478/aite-2024-0023. eCollection 2024 Jan 1.

ABSTRACT

Vitamin D levels have been related to the severity and progression of various autoimmune disorders. In this study, we aimed to investigate the impact of genetic variability in the vitamin D receptor (VDR) gene on disease susceptibility and progression in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor (TNF) inhibitors. The study comprises 121 RA patients subjected to anti-TNF therapy genotyped for four VDR polymorphic variants: rs1544410 (BsmI), rs2228570 (FokI), rs731236 (TaqI), and rs7975232 (ApaI). There was no significant association between RA susceptibility and VDR genetic variants. The study results revealed that patients with the rs2228570 CC genotype were characterized by lower vitamin D3 levels (p = 0.028) than those with the T allele. Also, the vitamin D3 levels (p = 0.029) and age at diagnosis (p = 0.017) were significantly lower in rs7975232 A allele carriers compared to CC homozygotes. However, after 6 months of therapy, the A allele seemed to be related to lower disease activity score 28 (DAS28) values (p = 0.030) and more common in patients who achieved remission (p = 0.004) compared to the CC genotype. Concerning other investigated polymorphisms, patients carrying rs1544410 AA and rs731236 CC homozygosity had lower C-reactive protein (CRP) levels before therapy (p = 0.009). In conclusion, VDR rs2228570 and rs7975232 polymorphic variants were found to be related to vitamin D3 levels. Moreover, the genotyping of rs7975232 was also useful in evaluating disease onset and disease activity after 6 months of therapy with TNF inhibitors in RA patients.

PMID:39522115 | DOI:10.2478/aite-2024-0023

Molecules. 2024 Nov 2;29(21):5186. doi: 10.3390/molecules29215186.

ABSTRACT

The bioactive flavonoids pinostrobin (PN) and panduratin A (PA) from Boesenbergia rotunda are essential for research and therapeutic applications. This study introduces an innovative method utilizing ultrasound-assisted extraction with n-hexane pre-treatment, followed by one-step centrifugal partition chromatography (CPC) purification. Extraction efficiency was evaluated using ultra high-performance liquid chromatography (UHPLC), and the isolated compounds were characterized through 1H-NMR and liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS), adhering to AOAC validation guidelines. Optimal extraction conditions comprised a particle size of 125 μm, a solid-to-liquid ratio of 1:30 g/mL, and a 10 min extraction time, yielding a crude extract of 6.96 ± 0.07%. Using an n-hexane/MeOH/water (5/3.4/1.6, v/v) solvent system in ascending mode, PN (2.16 mg, 98.78% purity) and PA (0.4 mg, 99.69% purity) were isolated from 67 mg of crude extract within 30 min. This streamlined approach enhances purification efficiency, allowing for faster extraction and higher purity, making it a suitable method for commercial applications.

PMID:39519827 | DOI:10.3390/molecules29215186

Int J Mol Sci. 2024 Oct 26;25(21):11505. doi: 10.3390/ijms252111505.

ABSTRACT

One of the most critical goals in healthcare is safe and effective drug therapy, which is directly related to an individual's response to treatment. Precision medicine can improve drug safety in many scenarios, including polypharmacy, and it requires the development of new genetic characterization methods. In this report, we use real-time PCR, microarray techniques, and mass spectrometry (MALDI-TOF), which allows us to compare them and identify the potential benefits of technological improvements, leading to better quality medical care. These comparative studies, as part of our pharmacogenetic Five-Step Precision Medicine (5SPM) approach, reveal the superiority of mass spectrometry over the other methods analyzed and highlight the importance of updating the laboratory's pharmacogenetic methodology to identify new variants with clinical impact.

PMID:39519058 | DOI:10.3390/ijms252111505

Int J Mol Sci. 2024 Oct 25;25(21):11460. doi: 10.3390/ijms252111460.

ABSTRACT

Dilated cardiomyopathy (DCM) is characterized by reduced systolic function and cardiac dilation. Cases without an identified secondary cause are classified as idiopathic dilated cardiomyopathy (IDC). Over the last 35 years, many cases of IDC have increasingly been recognized to be genetic in etiology with a core set of definitively causal genes in up to 40% of cases. While over 200 genes have been associated with DCM, the evidence supporting pathogenicity for most remains limited. Further, rapid advances in sequencing and bioinformatics have recently revealed a complex genetic spectrum ranging from monogenic to polygenic in DCM. These advances have also led to the discovery of causal and modifier genetic variants in secondary forms of DCM (e.g., alcohol-induced cardiomyopathy). Current guidelines recommend genetic counseling and screening, as well as endorsing a handful of genotype-specific therapies (e.g., device placement in LMNA cardiomyopathy). The future of genetics in DCM will likely involve polygenic risk scores, direct-to-consumer testing, and pharmacogenetics, requiring providers to have a thorough understanding of this rapidly developing field. Herein we outline three decades of genetics in DCM, summarize recent advances, and project possible future avenues for the field.

PMID:39519012 | DOI:10.3390/ijms252111460

BMC Cancer. 2024 Nov 8;24(1):1369. doi: 10.1186/s12885-024-13122-8.

ABSTRACT

BACKGROUND: Fluoropyrimidine (FP) chemotherapies are commonly prescribed for upper and lower gastrointestinal, breast and head and neck malignancies. Over 16,000 people with cancer require FP chemotherapies per annum in Australia. Between 10 and 40% patients experience grade 3-4 (≥ G3) toxicities that require hospital-based management ± intensive care admission. Approximately 1% of patients die secondary to FP toxicities. Prospective screening for DPYD gene variants (encoding the key enzyme for FP catabolism) can identify patients at risk of ≥ G3 toxicity and allow for dose adjustment prior to first FP exposure. Evidence supports this as a cost-effective method of improving patient safety and reducing healthcare burden internationally; however, no Australian data confirms its feasibility on a large scale.

METHOD: This investigator-led, single-arm study will determine large scale feasibility of prospective DPYD genotyping, confirming patient safety and cost-effectiveness within the Australian health care system. 5000 patients aged 18 years and older with solid organ cancers requiring FP chemotherapy will be consented and genotyped prior to commencing treatment, and early toxicity (within 60 days) post-FP exposure will be determined. Toxicity data for DPYD variant carriers who have dose adjustments will be compared to the wild-type cohort and historical cohorts of carriers who did not undergo genotyping prior to FP exposure, and prospective variant carriers who do not undergo dose-adjustment. Prevalence of the four standard DPYD gene variants will be confirmed in an Australian population. Additionally, health economic analysis, implementation research via semi-structured interviews of patients and clinicians, and feasibility of UGT1A1 genotyping will be conducted.

DISCUSSION: This study will determine the prevalence of DPYD gene variant status in Australia and its impact on FP-induced toxicity among Australians with cancer. Feasibility and cost-effectiveness for Australian health care system will be estimated to support national roll-out of prospective DPYD genotyping prior to FP administration. Additionally, feasibility will be confirmed with the intention of including UGT1A1 in future pharmacogenomic panels to aid chemotherapy prescribing.

TRIAL REGISTRATION: This trial was registered with the Australian and New Zealand Cancer Trials Registry on 13th Dec 2023, ACTRN12623001301651.

PMID:39516829 | DOI:10.1186/s12885-024-13122-8

Vet Anaesth Analg. 2024 Oct 16:S1467-2987(24)00305-2. doi: 10.1016/j.vaa.2024.10.131. Online ahead of print.

ABSTRACT

OBJECTIVE: Evaluate a precision medicine approach to confirm a tentative diagnosis of fatal malignant hyperthermia (MH) in isoflurane-anesthetized pet dogs by identifying novel risk variants in known MH susceptibility genes.

STUDY DESIGN: Retrospective case series.

ANIMALS: A male Pit Bull mix aged 7 years (case #1), a male Golden Retriever aged 12 months (case #2) and the dam and sire of case #2.

METHODS: Available case histories and medical records were reviewed. Missense variants in MH susceptibility genes RYR-1, CACNA1S and STAC3 (case #2 only) were identified by next-generation sequencing of DNA from each case and the parents of case #2 with confirmation by Sanger sequencing. The pathogenicity of variants was evaluated by multiple in silico approaches.

RESULTS: Both cases demonstrated clinical signs during isoflurane anesthesia consistent with volatile anesthetic-induced MH, including tachypnea, tachycardia, severe hyperthermia and muscle rigidity. Despite whole body cooling and other treatments, both dogs died after cardiac arrest within 15 minutes of detecting hyperthermia. Gene sequencing identified novel missense RYR-1 variants in case #1 (p.Gly2375Arg) and case #2 (p.Pro152Leu). Both variants were likely pathogenic based on multiple criteria, including gene location, amino acid alteration and population allele frequency. The case #1 variant was identical to a known human diagnostic MH variant (p.Gly2375Arg). Neither parent of case #2 had the case #2 variant, indicating this variant was not inherited, but arose de novo in a germ cell of either parent or early in embryogenesis. Whole genome sequence analysis confirmed parentage. Two missense variants were identified in CACNA1S. Both variants were considered nonpathogenic. No variants were identified in STAC3.

CONCLUSIONS AND CLINICAL RELEVANCE: Like humans, MH susceptibility in dogs is associated with different rare variants located in pathogenic hotspots in the RYR-1 gene. Next-generation sequencing is a useful tool to assist in the definitive diagnosis of MH in dogs.

PMID:39516111 | DOI:10.1016/j.vaa.2024.10.131