Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy Implicates Pharmacokinetic and Inherited Neuropathy Genes

Vincristine is an effective chemotherapeutic drug for various cancers, including acute lymphoblastic leukemia (ALL). Unfortunately, clinical utility is restricted by dose-limiting vincristine-induced peripheral neuropathies (VIPN). We sought to determine the association of VIPN with a recently identified risk variant, CEP72 rs924607, and drug absorption, distribution, metabolism, and excretion (ADME) gene variants in pediatric ALL. This was followed by a meta-analysis of pharmacogenomic data from over 500 patients. CEP72 rs924607 was significantly associated with VIPN (P = 0.02; odds ratio (OR) = 3.4). ADME analyses identified associations between VIPN and ABCC1 rs3784867 (P = 5.34 × 10 −5 ; OR = 4.9), and SLC5A7 rs1013940 (P = 9.00 × 10 −4 ; OR= 8.6); genes involved in vincristine transport and inherited neuropathies, respectively. Meta-analysis identified an association with a variant related to TTPA (rs10504361: P = 6.85 × 10 −4 ; OR = 2.0), a heritable neuropathy-related gene. This study provides essential corroboratory evidence for CEP72 rs924607 and highlights the importance of drug transporter and inherited neuropathy genes in VIPN

Clinical Practice Recommendations for the Management and Prevention of Cisplatin-Induced Hearing Loss Using Pharmacogenetic Markers

Currently no pharmacogenomics-based criteria exist to guide clinicians in identifying individuals who are at risk of hearing loss from cisplatin-based chemotherapy. This review summarizes findings from pharmacogenomic studies that report genetic polymorphisms associated with cisplatin-induced hearing loss and aims to (1) provide up-to-date information on new developments in the field, (2) provide recommendations for the use of pharmacogenetic testing in the prevention, assessment, and management of cisplatin-induced hearing loss in children and adults, and (3) identify knowledge gaps to direct and prioritize future research. These practice recommendations for pharmacogenetic testing in the context of cisplatin-induced hearing loss reflect a review and evaluation of recent literature, and are designed to assist clinicians in providing optimal clinical care for patients receiving cisplatin-based chemotherapy

Pharmacogenomic screening for anthracycline-induced cardiotoxicity in childhood cancer

10.1111/bcp.13218BRITISH JOURNAL OF CLINICAL PHARMACOLOGY8351143-114

Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy Implicates Pharmacokinetic and Inherited Neuropathy Genes.

Vincristine is an effective chemotherapeutic drug for various cancers, including acute lymphoblastic leukemia (ALL). Unfortunately, clinical utility is restricted by dose-limiting vincristine-induced peripheral neuropathies (VIPN). We sought to determine the association of VIPN with a recently identified risk variant, CEP72 rs924607, and drug absorption, distribution, metabolism, and excretion (ADME) gene variants in pediatric ALL. This was followed by a meta-analysis of pharmacogenomic data from over 500 patients. CEP72 rs924607 was significantly associated with VIPN (P = 0.02; odds ratio (OR) = 3.4). ADME analyses identified associations between VIPN and ABCC1 rs3784867 (P = 5.34 × 10 ; OR = 4.9), and SLC5A7 rs1013940 (P = 9.00 × 10 ; OR= 8.6); genes involved in vincristine transport and inherited neuropathies, respectively. Meta-analysis identified an association with a variant related to TTPA (rs10504361: P = 6.85 × 10 ; OR = 2.0), a heritable neuropathy-related gene. This study provides essential corroboratory evidence for CEP72 rs924607 and highlights the importance of drug transporter and inherited neuropathy genes in VIPN

Recommendations for genetic testing to reduce the incidence of anthracycline-induced cardiotoxicity

10.1111/bcp.13008BRITISH JOURNAL OF CLINICAL PHARMACOLOGY823683-69

Recommendations for Genetic Testing to Reduce the Incidence of Anthracycline-induced Cardiotoxicity

AIM Anthracycline-induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline-based chemotherapy. In various genetic association studies, potential genetic risk markers for ACT have been identified. Therefore, we developed evidence-based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk. METHODS We followed a standard guideline development process; including a systematic literature search, evidence synthesis and critical appraisal, and the development of clinical practice recommendations with an international expert group. RESULTS RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association with ACT. Genetic variants in ABCC1, ABCC2, ABCC5, ABCB1, ABCB4, CBR3, RAC2, NCF4, CYBA, GSTP1, CAT, SULT2B1, POR, HAS3, SLC22A7, SCL22A17, HFE and NOS3 have also been associated with ACT, but require additional validation. We recommend pharmacogenomic testing for the RARG rs2229774 (S427L), SLC28A3 rs7853758 (L461L) and UGT1A6*4 rs17863783 (V209V) variants in childhood cancer patients with an indication for doxorubicin or daunorubicin therapy (Level B - moderate). Based on an overall risk stratification, taking into account genetic and clinical risk factors, we recommend a number of management options including increased frequency of echocardiogram monitoring, follow-up, as well as therapeutic options within the current standard of clinical practice. CONCLUSIONS Existing evidence demonstrates that genetic factors have the potential to improve the discrimination between individuals at higher and lower risk of ACT. Genetic testing may therefore support both patient care decisions and evidence development for an improved prevention of ACT

Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy Implicates Pharmacokinetic and Inherited Neuropathy Genes

10.1002/cpt.1179CLINICAL PHARMACOLOGY & THERAPEUTICS1052402-41

A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer

10.1038/ng.3374NATURE GENETICS4791079-

A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer

Anthracyclines are used in over 50% of childhood cancer treatment protocols, but their clinical usefulness is limited by anthracycline-induced cardiotoxicity (ACT) manifesting as asymptomatic cardiac dysfunction and congestive heart failure in up to 57% and 16% of patients, respectively. Candidate gene studies have reported genetic associations with ACT, but these studies have in general lacked robust patient numbers, independent replication or functional validation. Thus, the individual variability in ACT susceptibility remains largely unexplained. We performed a genome-wide association study in 280 patients of European ancestry treated for childhood cancer, with independent replication in similarly treated cohorts of 96 European and 80 non-European patients. We identified a nonsynonymous variant (rs2229774, p.Ser427Leu) in RARG highly associated with ACT (P = 5.9 × 10(-8), odds ratio (95% confidence interval) = 4.7 (2.7-8.3)). This variant alters RARG function, leading to derepression of the key ACT genetic determinant Top2b, and provides new insight into the pathophysiology of this severe adverse drug reaction