title: Neuroblastoma survivors are at increased risk for second malignancies: A report from the International Neuroblastoma Risk Group Project.
abstract: The incidence of second malignant neoplasm (SMN) within the first ten years of diagnosis in high-risk neuroblastoma patients treated with modern, intensive therapy is unknown. Further, the underlying germline genetics that contribute to SMN in these survivors are not known.
  
  
  
  The International Neuroblastoma Risk Group (INRG) database of patients diagnosed from 1990 to 2010 was analysed. SMN risk was accessed by cumulative incidence, standardised incidence ratios (SIRs) and absolute excess risk. A candidate gene-based association study evaluated genetic susceptibility to SMN in neuroblastoma survivors.
  
  
  
  Of the 5987 patients in the INRG database with SMN data enrolled in a clinical trial, 43 (0.72%) developed a SMN. The 10-year cumulative incidence of SMN for high-risk patients was 1.8% (95% confidence interval [CI] 1.0-2.6%) compared with 0.38% (95% CI: 0.22-0.94%) for low-risk patients (P = 0.01). High-risk patients had an almost 18-fold higher incidence of SMN compared to age- and sex-matched controls (SIR = 17.5 (95% CI: 11.4-25.3), absolute excess risk = 27.6). For patients treated on high- and intermediate-risk clinical trials, the SIR of acute myelogenous leukaemia was 106.8 (95% CI: 28.7-273.4) and 127.7 (95%CI: 25.7-373.3), respectively. Variants implicating DNA repair genes XRCC3 (rs861539: P = 0.006; odds ratio: 2.04, 95%CI: 1.19-3.46) and MSH2 (rs17036651: P = 0.009; odds ratio: 0.26, 95% CI: 0.08-0.81) were associated with SMN.
  
  
  
  The intensive multi-modality treatment strategy currently used to treat high-risk neuroblastoma is associated with a significantly increased risk of secondary acute myelogenous leukaemia. Defining the interactions of treatment exposures and genetic factors that promote the development of SMN is critical for optimising survivorship care.
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Applebaum
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Zalman
authors.initials: Z
authors.lastname: Vaksman
authors.affiliation: Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.
authors.forename: Sang Mee
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hungate
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors.forename: Tara O
authors.initials: TO
authors.lastname: Henderson
authors.affiliation: Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Wendy B
authors.initials: WB
authors.lastname: London
authors.affiliation: Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
authors.forename: Navin
authors.initials: N
authors.lastname: Pinto
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Volchenboum
authors.affiliation: Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Park
authors.affiliation: Children's Oncology Group Statistics and Data Center, Department of Biostatistics, University of Florida, Gainseville, FL, USA.
authors.forename: Arlene
authors.initials: A
authors.lastname: Naranjo
authors.affiliation: Children's Hospital, Department of Pediatric Oncology and Hematology, University of Cologne, Cologne, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hero
authors.affiliation: Divisions of Cancer Therapeutics and Clinical Studies, Institute of Cancer Research and Children and Young People's Unit, The Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK - Retired.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Pearson
authors.affiliation: Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA; Institute for Genomics and Systems Biology, Center for Data Intensive Science, University of Chicago, Chicago, IL, USA.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Stranger
authors.affiliation: Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Cohn
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, Philadelphia, PA, USA. Electronic address: diskin@email.chop.edu.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Diskin
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy / Q000009:adverse effects; D004260:DNA Repair / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000453:epidemiology*; D008297:Male; D016609:Neoplasms, Second Primary / Q000453:epidemiology*; D009447:Neuroblastoma / Q000628:therapy*; D018570:Risk Assessment; D012307:Risk Factors; D017741:Survivors; D055815:Young Adult
keywords: Genetic association study; INRG; Neuroblastoma; Second malignant neoplasms