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Eur J Cancer. 2017 Feb;72:177-185. doi: 10.1016/j.ejca.2016.11.022. Epub 2016 Dec 26.

Neuroblastoma survivors are at increased risk for second malignancies: A report from the International Neuroblastoma Risk Group Project.

Author information

1
Department of Pediatrics, University of Chicago, Chicago, IL, USA.
2
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.
3
Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.
4
Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
5
Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
6
Children's Oncology Group Statistics and Data Center, Department of Biostatistics, University of Florida, Gainseville, FL, USA.
7
Children's Hospital, Department of Pediatric Oncology and Hematology, University of Cologne, Cologne, Germany.
8
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.
9
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.
10
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.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

KEYWORDS:

Genetic association study; INRG; Neuroblastoma; Second malignant neoplasms

PMID:
28033528
PMCID:
PMC5258837
[Available on 2018-02-01]
DOI:
10.1016/j.ejca.2016.11.022
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