title: Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study.
abstract: BACKGROUND
  Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukaemia (ALL). Recent reports of germline ETV6 variations associated with substantial familial clustering of haematological malignancies indicated that this gene is a potentially important genetic determinant for ALL susceptibility. Our aims in this study were to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contributed to the overall risk of childhood ALL.
  
  
  METHODS
  Whole-exome sequencing of an index family with several cases of ALL was done to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was done in children from the Children's Oncology Group and St Jude Children's Research Hospital front-line ALL trials. Patients were included in this study on the basis of their enrolment in these clinical trials and the availability of germline DNA. ETV6 variant genotypes were compared with non-ALL controls to define ALL-related germline risk variants. ETV6 variant function was characterised bioinformatically and correlated with clinical and demographic features in children with ALL.
  
  
  RESULTS
  We identified a novel non-sense ETV6 variant (p.Arg359X) with a high penetrance in an index family. Subsequent targeted sequencing of ETV6 in 4405 childhood ALL cases identified 31 exonic variants (four non-sense, 21 missense, one splice site, and five frameshift variants) that were potentially related to ALL risk in 35 cases (1%). 15 (48%) of 31 ALL-related ETV6 variants clustered in the erythroblast transformation specific domain and were predicted to be highly deleterious. Children with ALL-related ETV6 variants were significantly older at leukaemia diagnosis than those without (10·2 years [IQR 5·3-13·8] vs 4·7 years [3·0-8·7]; p=0·017). The hyperdiploid leukaemia karyotype was highly over-represented in ALL cases harbouring germline ETV6 risk variants compared with the wild-type group (nine [64%] of 14 cases vs 538 [27%] of 2007 cases; p=0·0050).
  
  
  CONCLUSIONS
  Our findings indicated germline ETV6 variations as the basis of a novel genetic syndrome associated with predisposition to childhood ALL. The development of recommendations for clinical interventions and surveillance for individuals harbouring ALL-related ETV6 variants are needed.
  
  
  BACKGROUND
  US National Institutes of Health and American Lebanese Syrian Associated Charities.
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Moriyama
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Monika L
authors.initials: ML
authors.lastname: Metzger
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Rina
authors.initials: R
authors.lastname: Nishii
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Maoxiang
authors.initials: M
authors.lastname: Qian
authors.affiliation: Department of Biostatistics, College of Medicine, Public Health and Health Professions, University of Florida, Gainesville, FL, USA.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Quinn
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Susana
authors.initials: S
authors.lastname: Raimondi
authors.affiliation: Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, and Departments of Pathology and Pediatrics, Ohio State University, Columbus, OH, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Gastier-Foster
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Raetz
authors.affiliation: Maine Children's Cancer Program, Scarborough, ME, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Larsen
authors.affiliation: Department of Pediatrics, Duke University, Durham, NC, USA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Martin
authors.affiliation: Cook Children's Medical Center, Fort Worth, TX, USA.
authors.forename: W Paul
authors.initials: WP
authors.lastname: Bowman
authors.affiliation: Pediatric Hematology Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Winick
authors.affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komada
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Shuoguo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Edmonson
authors.affiliation: Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Xu
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Mardis
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Fulton
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA; Hematological Malignancies Program, Comprehensive Cancer Center, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA; Hematological Malignancies Program, Comprehensive Cancer Center, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Mullighan
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA; Hematological Malignancies Program, Comprehensive Cancer Center, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics and Center for Childhood Cancer Research, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA; Hematological Malignancies Program, Comprehensive Cancer Center, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
authors.affiliation: Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Kim E
authors.initials: KE
authors.lastname: Nichols
authors.affiliation: Department of Pediatrics, Benioff Children's Hospital and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA; Hematological Malignancies Program, Comprehensive Cancer Center, St Jude Children's Research Hospital, Memphis, TN, USA. Electronic address: jun.yang@stjude.org.
authors.forename: Jun J
authors.initials: JJ
authors.lastname: Yang
mesh_terms: D000293:Adolescent; D000367:Age Factors; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D059472:Exome; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007621:Karyotyping; D008297:Male; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D012307:Risk Factors; D016896:Treatment Outcome; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D014408:Biomarkers, Tumor; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein