title: Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia.
abstract: OBJECTIVE
  With cure rates of childhood acute lymphoblastic leukemia (ALL) exceeding 85%, there is a need to mitigate treatment toxicities that can compromise quality of life, including peripheral neuropathy from vincristine treatment.
  
  
  OBJECTIVE
  To identify genetic germline variants associated with the occurrence or severity of vincristine-induced peripheral neuropathy in children with ALL.
  
  
  METHODS
  Genome-wide association study of patients in 1 of 2 prospective clinical trials for childhood ALL that included treatment with 36 to 39 doses of vincristine. Genome-wide single-nucleotide polymorphism (SNP) analysis and vincristine-induced peripheral neuropathy were assessed in 321 patients from whom DNA was available: 222 patients (median age, 6.0 years; range, 0.1-18.8 years) enrolled in 1994-1998 in the St Jude Children's Research Hospital protocol Total XIIIB with toxic effects follow-up through January 2001, and 99 patients (median age, 11.4 years; range, 3.0-23.8 years) enrolled in 2007-2010 in the Children's Oncology Group (COG) protocol AALL0433 with toxic effects follow-up through May 2011. Human leukemia cells and induced pluripotent stem cell neurons were used to assess the effects of lower CEP72 expression on vincristine sensitivity.
  
  
  METHODS
  Treatment with vincristine at a dose of 1.5 or 2.0 mg/m2.
  
  
  METHODS
  Vincristine-induced peripheral neuropathy was assessed at clinic visits using National Cancer Institute criteria and prospectively graded as mild (grade 1), moderate (grade 2), serious/disabling (grade 3), or life threatening (grade 4).
  
  
  RESULTS
  Grade 2 to 4 vincristine-induced neuropathy during continuation therapy occurred in 28.8% of patients (64/222) in the St Jude cohort and in 22.2% (22/99) in the COG cohort. A SNP in the promoter region of the CEP72 gene, which encodes a centrosomal protein involved in microtubule formation, had a significant association with vincristine neuropathy (meta-analysis P = 6.3×10(-9)). This SNP had a minor allele frequency of 37% (235/642), with 50 of 321 patients (16%; 95% CI, 11.6%-19.5%) homozygous for the risk allele (TT at rs924607). Among patients with the high-risk CEP72 genotype (TT at rs924607), 28 of 50 (56%; 95% CI, 41.2%-70.0%) developed at least 1 episode of grade 2 to 4 neuropathy, a higher rate than in patients with the CEP72 CC or CT genotypes (58/271 patients [21.4%; 95% CI, 16.9%-26.7%]; P = 2.4×10(-6)). The severity of neuropathy was greater in patients homozygous for the TT genotype compared with patients with the CC or CT genotype (2.4-fold by Poisson regression [P<.0001] and 2.7-fold based on mean grade of neuropathy: 1.23 [95% CI, 0.74-1.72] vs 0.45 [95% CI, 0.3-0.6]; P = .004 by t test). Reducing CEP72 expression in human neurons and leukemia cells increased their sensitivity to vincristine.
  
  
  CONCLUSIONS
  In this preliminary study of children with ALL, an inherited polymorphism in the promoter region of CEP72 was associated with increased risk and severity of vincristine-related peripheral neuropathy. If replicated in additional populations, this finding may provide a basis for safer dosing of this widely prescribed anticancer agent.
authors.affiliation: Hematological Malignancies Program, Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Barthelemy
authors.initials: B
authors.lastname: Diouf
authors.affiliation: Hematological Malignancies Program, Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Kristine R
authors.initials: KR
authors.lastname: Crews
authors.affiliation: Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta/Emory University, Atlanta, Georgia.
authors.forename: Glen
authors.initials: G
authors.lastname: Lew
authors.affiliation: Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Deqing
authors.initials: D
authors.lastname: Pei
authors.affiliation: Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Ju
authors.initials: J
authors.lastname: Bao
authors.affiliation: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Jie J
authors.initials: JJ
authors.lastname: Zheng
authors.affiliation: Hematological Malignancies Program, Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Wheeler
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wing
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Delaney
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Hematological Malignancies Program, Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Paugh
authors.affiliation: Hematological Malignancies Program, Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Joseph Robert
authors.initials: JR
authors.lastname: McCorkle
authors.affiliation: Department of Biostatistics, Colleges of Medicine, Public Health and Health Professions, University of Florida, Gainesville.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Lu
authors.affiliation: Division of Pediatric Hematology/Oncology, University of Texas Southwestern School of Medicine, Dallas.
authors.forename: Naomi J
authors.initials: NJ
authors.lastname: Winick
authors.affiliation: New York University Cancer Institute, New York, New York.
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.affiliation: Department of Pediatrics, University of California, San Francisco, School of Medicine, San Francisco.
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.affiliation: Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, Center for Cancer and Blood Disorders, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.affiliation: Department of Biostatistics, Colleges of Medicine, Public Health and Health Professions, University of Florida, Gainesville.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
authors.affiliation: Hematological Malignancies Program, Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
authors.affiliation: Hematological Malignancies Program, Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
mesh_terms: D000293:Adolescent; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000188:drug therapy*; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C542475:CEP72 protein, human; D008869:Microtubule-Associated Proteins; D014750:Vincristine