CONTEXT: Pediatric acute lymphoblastic leukemia (ALL) is the prototype for a drug-responsive malignancy. Although cure rates exceed 80%, considerable unexplained interindividual variability exists in treatment response. OBJECTIVES: To assess the contribution of inherited genetic variation to therapy response and to identify germline single-nucleotide polymorphisms (SNPs) associated with risk of minimal residual disease (MRD) after remission induction chemotherapy. DESIGN, SETTING, AND PATIENTS: Genome-wide interrogation of 476,796 germline SNPs to identify genotypes that were associated with MRD in 2 independent cohorts of children with newly diagnosed ALL: 318 patients in St Jude Total Therapy protocols XIIIB and XV and 169 patients in Children's Oncology Group trial P9906. Patients were enrolled between 1994 and 2006 and last follow-up was in 2006. MAIN OUTCOME MEASURES: Minimal residual disease at the end of induction therapy, measured by flow cytometry. RESULTS: There were 102 SNPs associated with MRD in both cohorts (median odds ratio, 2.18; P < or = .0125), including 5 SNPs in the interleukin 15 (IL15) gene. Of these 102 SNPs, 21 were also associated with hematologic relapse (P < .05). Of 102 SNPs, 21 were also associated with antileukemic drug disposition, generally linking MRD eradication with greater drug exposure. In total, 63 of 102 SNPs were associated with early response, relapse, or drug disposition. CONCLUSION: Host genetic variations are associated with treatment response for childhood ALL, with polymorphisms related to leukemia cell biology and host drug disposition associated with lower risk of residual disease.
CONTEXT: Pediatric acute lymphoblastic leukemia (ALL) is the prototype for a drug-responsive malignancy. Although cure rates exceed 80%, considerable unexplained interindividual variability exists in treatment response. OBJECTIVES: To assess the contribution of inherited genetic variation to therapy response and to identify germline single-nucleotide polymorphisms (SNPs) associated with risk of minimal residual disease (MRD) after remission induction chemotherapy. DESIGN, SETTING, AND PATIENTS: Genome-wide interrogation of 476,796 germline SNPs to identify genotypes that were associated with MRD in 2 independent cohorts of children with newly diagnosed ALL: 318 patients in St Jude Total Therapy protocols XIIIB and XV and 169 patients in Children's Oncology Group trial P9906. Patients were enrolled between 1994 and 2006 and last follow-up was in 2006. MAIN OUTCOME MEASURES: Minimal residual disease at the end of induction therapy, measured by flow cytometry. RESULTS: There were 102 SNPs associated with MRD in both cohorts (median odds ratio, 2.18; P < or = .0125), including 5 SNPs in the interleukin 15 (IL15) gene. Of these 102 SNPs, 21 were also associated with hematologic relapse (P < .05). Of 102 SNPs, 21 were also associated with antileukemic drug disposition, generally linking MRD eradication with greater drug exposure. In total, 63 of 102 SNPs were associated with early response, relapse, or drug disposition. CONCLUSION: Host genetic variations are associated with treatment response for childhood ALL, with polymorphisms related to leukemia cell biology and host drug disposition associated with lower risk of residual disease.
Authors: Alkes L Price; Nick J Patterson; Robert M Plenge; Michael E Weinblatt; Nancy A Shadick; David Reich Journal: Nat Genet Date: 2006-07-23 Impact factor: 38.330
Authors: Jianbiao Zhou; Meredith A Goldwasser; Aihong Li; Suzanne E Dahlberg; Donna Neuberg; Hongjun Wang; Virginia Dalton; Kathryn D McBride; Stephen E Sallan; Lewis B Silverman; John G Gribben Journal: Blood Date: 2007-05-07 Impact factor: 22.113
Authors: Sanne Lugthart; Meyling H Cheok; Monique L den Boer; Wenjian Yang; Amy Holleman; Cheng Cheng; Ching-Hon Pui; Mary V Relling; Gritta E Janka-Schaub; Rob Pieters; William E Evans Journal: Cancer Cell Date: 2005-04 Impact factor: 31.743
Authors: E Coustan-Smith; F G Behm; J Sanchez; J M Boyett; M L Hancock; S C Raimondi; J E Rubnitz; G K Rivera; J T Sandlund; C H Pui; D Campana Journal: Lancet Date: 1998-02-21 Impact factor: 79.321
Authors: Kirk R Schultz; D Jeanette Pullen; Harland N Sather; Jonathan J Shuster; Meenakshi Devidas; Michael J Borowitz; Andrew J Carroll; Nyla A Heerema; Jeffrey E Rubnitz; Mignon L Loh; Elizabeth A Raetz; Naomi J Winick; Stephen P Hunger; William L Carroll; Paul S Gaynon; Bruce M Camitta Journal: Blood Date: 2006-09-26 Impact factor: 22.113
Authors: M J Borowitz; D J Pullen; J J Shuster; D Viswanatha; K Montgomery; C L Willman; B Camitta Journal: Leukemia Date: 2003-08 Impact factor: 11.528
Authors: Cristen J Willer; Serena Sanna; Anne U Jackson; Angelo Scuteri; Lori L Bonnycastle; Robert Clarke; Simon C Heath; Nicholas J Timpson; Samer S Najjar; Heather M Stringham; James Strait; William L Duren; Andrea Maschio; Fabio Busonero; Antonella Mulas; Giuseppe Albai; Amy J Swift; Mario A Morken; Narisu Narisu; Derrick Bennett; Sarah Parish; Haiqing Shen; Pilar Galan; Pierre Meneton; Serge Hercberg; Diana Zelenika; Wei-Min Chen; Yun Li; Laura J Scott; Paul A Scheet; Jouko Sundvall; Richard M Watanabe; Ramaiah Nagaraja; Shah Ebrahim; Debbie A Lawlor; Yoav Ben-Shlomo; George Davey-Smith; Alan R Shuldiner; Rory Collins; Richard N Bergman; Manuela Uda; Jaakko Tuomilehto; Antonio Cao; Francis S Collins; Edward Lakatta; G Mark Lathrop; Michael Boehnke; David Schlessinger; Karen L Mohlke; Gonçalo R Abecasis Journal: Nat Genet Date: 2008-01-13 Impact factor: 38.330
Authors: Stephen P Hunger; Mignon L Loh; James A Whitlock; Naomi J Winick; William L Carroll; Meenakshi Devidas; Elizabeth A Raetz Journal: Pediatr Blood Cancer Date: 2012-12-19 Impact factor: 3.167
Authors: Eric R Gamazon; Jatinder K Lamba; Stanley Pounds; Amy L Stark; Heather E Wheeler; Xueyuan Cao; Hae K Im; Amit K Mitra; Jeffrey E Rubnitz; Raul C Ribeiro; Susana Raimondi; Dario Campana; Kristine R Crews; Shan S Wong; Marleen Welsh; Imge Hulur; Lidija Gorsic; Christine M Hartford; Wei Zhang; Nancy J Cox; M Eileen Dolan Journal: Blood Date: 2013-03-28 Impact factor: 22.113