Genome-wide meta-analyses identifies novel taxane-induced peripheral neuropathy-associated loci

Sucheston‐Campbell, Lara E.; Clay-Gilmour, Alyssa; Barlow, William E.; Budd, G. Thomas; Stram, Daniel O.; Haiman, Christopher A.; Sheng, Xin; Yan, Li; Zirpoli, Gary; Yao, Song; Jiang, Chen; Owzar, Kouros; Hershman, Dawn L.; Albain, Kathy S.; Hayes, Daniel F.; Moore, Halle C. F.; Hobday, Timothy J.; Stewart, James A.; Rizvi, Abbas; Isaacs, Claudine; Salim, Muhammad; Gralow, Jule R.; Hortobágyi, Gabriel N.; Livingston, Robert B.; Kroetz, Deanna L.; Ambrosone, Christine B.

doi:10.1097/fpc.0000000000000318

Cited by 30 publications

(37 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TUBB2A variants were demonstrated to increase transcription rate and protect cells from paclitaxel toxicity . Similarly, SNPs in TUBB2A were identified in subsequent studies, but not in all reports …”

Section: Introductionmentioning

confidence: 96%

“…Another study identified SNPs in CMT gene SBF2 as linked with severe TIPN in an African‐American patient cohort . Similarly, genes associated with diabetic neuropathy were found to be potentially linked to TIPN, including NXN . These results suggest common genetic pathways may contribute to taxane‐neurotoxicity.…”

Section: Introductionmentioning

confidence: 97%

“…These data suggest a multigene model, rather than a single gene‐based result, will be more appropriate to predict TIPN risk . While large‐scale GWAS studies suggested many potential genetic risk factors, there are lack of overlapping findings between studies or findings with unclear mechanistic significance …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Taxane and epothilone‐induced peripheral neurotoxicity: From pathogenesis to treatment

Tamburin

Park

Alberti

et al. 2019

J Peripheral Nervous Sys

View full text Add to dashboard Cite

Taxane-induced peripheral neurotoxicity (TIPN) is the most common nonhematological side effect of taxane-based chemotherapy, and may result in dose reductions and discontinuations, having as such a detrimental effect on patients' overall survival. Epothilones share similar mechanism of action with taxanes. The typical TIPN clinical presentation is mainly comprised of numbness and paresthesia, in a stocking-and-glove distribution and may progress more proximally over time, with paclitaxel being more neurotoxic than docetaxel. Motor and autonomic involvement is less common, whereas an acute taxane-induced acute pain syndrome is frequent. Patient reported outcomes questionnaires, clinical evaluation, and instrumental tools offer complementary information in TIPN. Its electrodiagnostic features include reduced/abolished sensory action potentials, and less prominent motor involvement, in keeping with a length-dependent, axonal dying back predominately sensory neuropathy. TIPN is dose-dependent and may be reversible within months after the end of chemotherapy. The single and cumulative delivered dose of taxanes is considered the main risk factor of TIPN development. Apart from the cumulative dose, other risk factors for TIPN include demographic, clinical, and pharmacogenetic features with several single-nucleotide polymorphisms potentially linked with increased susceptibility of TIPN. There are currently no neuroprotective strategies to reduce the risk of TIPN, and symptomatic treatments are very limited. This review critically examines the pathogenesis, incidence, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of TIPN. K E Y W O R D S assessment, chemotherapy, docetaxel, ixabepilone, neurotoxicity, paclitaxel, prevention 1 | INTRODUCTION Taxanes (paclitaxel, docetaxel, cabazitaxel) were among the most important new chemotherapy agents in the late 20th century. 1 Paclitaxel is a natural compound with potent anticancer properties, which was originally isolated from the bark of the Pacific yew tree (Taxus brevifolia) in 1967, but low natural availability and insolubility in water hindered its diffusion since the 1980s. 2 Paclitaxel and docetaxel are currently obtained through a semisynthetic process from a precursor contained in the needles of the European yew tree (Taxus baccata),which is more widely available worldwide. 2 Nanoparticle albuminbound paclitaxel (nab-paclitaxel) is a novel formulation containing human serum albumin to encapsulate hydrophobic paclitaxel molecules to increase tumor uptake and reduce hypersensitivity

show abstract

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Taxane and epothilone‐induced peripheral neurotoxicity: From pathogenesis to treatment

Tamburin

Park

Alberti

et al. 2019

J Peripheral Nervous Sys

View full text Add to dashboard Cite

show abstract

“…Previous research has attempted to discover genetic predictors of paclitaxel‐induced PN or replicate previous findings. These important discoveries need to be fully validated to establish clinical utility.…”

Section: Introductionmentioning

confidence: 99%

“…Pioneering studies exploring these associations mostly utilized a case–control approach with the endpoint of occurrence of PN. More recent studies have explored PN susceptibility by accounting for the cumulative dose at PN occurrence. Within these studies, variants in genes encoding ephrin ( EPHA) receptors from the receptor tyrosine kinase family, which have a role in neuronal development, have been observed to increase risk of paclitaxel‐induced PN (i.e.…”

Section: Introductionmentioning

confidence: 99%

Genetic variation in EPHA contributes to sensitivity to paclitaxel‐induced peripheral neuropathy

Marcath

Kidwell

Vangipuram

et al. 2020

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

Aims: Chemotherapy-induced peripheral neuropathy (PN) is a treatment limiting toxicity of paclitaxel. We evaluated if EPHA genetic variation (EPHA4, EPHA5, EPHA6, and EPHA8) is associated with PN sensitivity by accounting for variability in systemic paclitaxel exposure (time above threshold). Methods:Germline DNA from 60 patients with breast cancer was sequenced. PN was measured using the 8-item sensory subscale (CIPN8) of the patient-reported CIPN20. Associations for 3 genetic models were tested by incorporating genetics into previously published PN prediction models integrating measured paclitaxel exposure and cumulative treatment. Significant associations were then tested for association with PN-related treatment disruption.Results: EPHA5 rs7349683 (minor allele frequency = 0.32) was associated with increased PN sensitivity (β-coefficient = 0.39, 95% confidence interval 0.11-0.67, p = 0.007). Setting a maximum tolerable threshold of CIPN8 = 30, optimal paclitaxel exposure target is shorter for rs7349683 homozygous (11.6 h) than heterozygous (12.6 h) or wild-type (13.6 h) patients. Total number of missense variants (median = 0, range 0-2) was associated with decreased PN sensitivity (β-coefficient: −0.42, 95% confidence interval −0.72 to −0.12, P = .006). No association with treatment disruption was detected for the total number of missense variants or rs7349683. Conclusion:Isolating toxicity sensitivity by accounting for exposure is a novel approach, and rs7349683 represents a promising marker for PN sensitivity that may be used to individualize paclitaxel treatment. K E Y W O R D Sbreast cancer, genetic polymorphism, pharmacodynamics, pharmacogenomics, pharmacokinetics Principal statement: The authors confirm that the PI for this paper is D.L. Hertz and that the coinvestigator N. Lynn Henry had direct clinical responsibility for patients.

show abstract

Role of hemoglobin alpha and hemoglobin beta in non‐small‐cell lung cancer based on bioinformatics analysis

Kang

Qiu

Wang

et al. 2022

Molecular Carcinogenesis

View full text Add to dashboard Cite

The differentially expressed genes (DEGs) were identified and screened differentially in non‐small‐cell lung cancer (NSCLC) using information from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases, and the correlation of DEGs in protein interaction, function, and pathway enrichment were analyzed to search for new biomarkers and potential therapeutic targets for NSCLC. Protein–protein interaction network (PPI) analysis showed that CDK1 and GNGT1 were the most significantly upregulated hub nodes, while FPR2 was the most significantly downregulated. Gene Ontology enrichment analysis showed that upregulated DEGs were significantly enriched in protein heterodimerization activity and other functions, while downregulated DEGs were enriched in functions such as heparin‐binding. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that upregulation of DEGs were significantly associated with neuroactive ligand‐receptor interaction pathways, while downregulation of DEGs were significantly associated with malaria pathways. According to the analysis results, we identified hemoglobin alpha (HBA) and hemoglobin beta (HBB) as the genes of interest for further study. Through tissue level and cell level experiments, we found that the expressions of HBA and HBB in NSCLC tissues were significantly lower than those in paracancerous tissues, and downregulation of HBA and HBB could significantly affect the proliferation ability of NSCLC cells. In addition, we also found that changes in HBA and HBB may affect NSCLC cells through the p38/MAPK pathway and JNK pathway, and ultimately affect the occurrence and development of NSCLC.

show abstract

Genome-wide meta-analyses identifies novel taxane-induced peripheral neuropathy-associated loci

Cited by 30 publications

References 44 publications

Taxane and epothilone‐induced peripheral neurotoxicity: From pathogenesis to treatment

Taxane and epothilone‐induced peripheral neurotoxicity: From pathogenesis to treatment

Genetic variation in EPHA contributes to sensitivity to paclitaxel‐induced peripheral neuropathy

Role of hemoglobin alpha and hemoglobin beta in non‐small‐cell lung cancer based on bioinformatics analysis

Contact Info

Product

Resources

About