Applebaum Mark A, Vaksman Zalman, Lee Sang Mee, Hungate Eric A, Henderson Tara O, London Wendy B, Pinto Navin, Volchenboum Samuel L, Park Julie R, Naranjo Arlene, Hero Barbara, Pearson Andrew D, Stranger Barbara E, Cohn Susan L, Diskin Sharon J
Department of Pediatrics, University of Chicago, Chicago, IL, USA.
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.
Eur J Cancer. 2017 Feb;72:177-185. doi: 10.1016/j.ejca.2016.11.022. Epub 2016 Dec 26.
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.
接受现代强化治疗的高危神经母细胞瘤患者在诊断后的头十年内发生第二原发性恶性肿瘤（SMN）的发生率尚不清楚。此外，这些幸存者中导致SMN的潜在种系遗传学也不明确。
分析了国际神经母细胞瘤风险组（INRG）1990年至2010年诊断的患者数据库。通过累积发病率、标准化发病率比（SIR）和绝对超额风险评估SMN风险。一项基于候选基因的关联研究评估了神经母细胞瘤幸存者对SMN的遗传易感性。
在INRG数据库中纳入临床试验且有SMN数据的5987例患者中，43例（0.72%）发生了SMN。高危患者10年SMN累积发病率为1.8%（95%置信区间[CI]1.0 - 2.6%），而低危患者为0.38%（95%CI：0.22 - 0.94%）（P = 0.01）。与年龄和性别匹配的对照组相比，高危患者的SMN发病率几乎高18倍（SIR = 17.5（95%CI：11.4 - 25.3），绝对超额风险 = 27.6）。对于接受高危和中危临床试验治疗的患者，急性髓系白血病的SIR分别为106.8（95%CI：28.7 - 273.4）和127.7（95%CI：25.7 - 373.3）。涉及DNA修复基因XRCC3（rs861539：P = 0.006；比值比：2.04，95%CI：1.19 - 3.46）和MSH2（rs17036651：P = 0.009；比值比：0.26，95%CI：0.08 - 0.81）的变异与SMN相关。
目前用于治疗高危神经母细胞瘤的强化多模式治疗策略与继发性急性髓系白血病风险显著增加相关。明确治疗暴露与促进SMN发生的遗传因素之间的相互作用对于优化生存护理至关重要。
