Trubicka Joanna, Żemojtel Tomasz, Hecht Jochen, Falana Katarzyna, Piekutowska-Abramczuk Dorota, Płoski Rafał, Perek-Polnik Marta, Drogosiewicz Monika, Grajkowska Wiesława, Ciara Elżbieta, Moszczyńska Elżbieta, Dembowska-Bagińska Bożenna, Perek Danuta, Chrzanowska Krystyna H, Krajewska-Walasek Małgorzata, Łastowska Maria
Department of Medical Genetics, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.
Department of Pathology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.
BMC Cancer. 2017 Apr 4;17(1):239. doi: 10.1186/s12885-017-3211-y.
The defects in DNA repair genes are potentially linked to development and response to therapy in medulloblastoma. Therefore the purpose of this study was to establish the spectrum and frequency of germline variants in selected DNA repair genes and their impact on response to chemotherapy in medulloblastoma patients.
The following genes were investigated in 102 paediatric patients: MSH2 and RAD50 using targeted gene panel sequencing and NBN variants (p.I171V and p.K219fs*19) by Sanger sequencing. In three patients with presence of rare life-threatening adverse events (AE) and no detected variants in the analyzed genes, whole exome sequencing was performed. Based on combination of molecular and immunohistochemical evaluations tumors were divided into molecular subgroups. Presence of variants was tested for potential association with the occurrence of rare life-threatening AE and other clinical features.
We have identified altogether six new potentially pathogenic variants in MSH2 (p.A733T and p.V606I), RAD50 (p.R1093*), FANCM (p.L694*), ERCC2 (p.R695C) and EXO1 (p.V738L), in addition to two known NBN variants. Five out of twelve patients with defects in either of MSH2, RAD50 and NBN genes suffered from rare life-threatening AE, more frequently than in control group (p = 0.0005). When all detected variants were taken into account, the majority of patients (8 out of 15) suffered from life-threatening toxicity during chemotherapy.
Our results, based on the largest systematic study performed in a clinical setting, provide preliminary evidence for a link between defects in DNA repair genes and treatment related toxicity in children with medulloblastoma. The data suggest that patients with DNA repair gene variants could need special vigilance during and after courses of chemotherapy.
DNA修复基因缺陷可能与髓母细胞瘤的发生发展及治疗反应相关。因此，本研究旨在确定所选DNA修复基因种系变异的谱型和频率及其对髓母细胞瘤患者化疗反应的影响。
对102例儿科患者的以下基因进行研究：使用靶向基因panel测序检测MSH2和RAD50，通过桑格测序检测NBN变异（p.I171V和p.K219fs*19）。对3例出现罕见危及生命不良事件（AE）且分析基因中未检测到变异的患者进行全外显子组测序。根据分子和免疫组化评估结果，将肿瘤分为分子亚组。检测变异的存在与罕见危及生命AE及其他临床特征发生之间的潜在关联。
除两个已知的NBN变异外，我们共在MSH2（p.A733T和p.V606I）、RAD50（p.R1093*）、FANCM（p.L694*）、ERCC2（p.R695C）和EXO1（p.V738L）中鉴定出6个新的潜在致病变异。12例MSH2、RAD50和NBN基因中任一基因存在缺陷的患者中有5例发生罕见危及生命的AE，比对照组更频繁（p = 0.0005）。当考虑所有检测到的变异时，大多数患者（15例中的8例）在化疗期间发生危及生命的毒性反应。
我们基于临床环境中进行的最大规模系统研究的结果，为DNA修复基因缺陷与髓母细胞瘤患儿治疗相关毒性之间的联系提供了初步证据。数据表明，DNA修复基因变异的患者在化疗期间及化疗后可能需要特别监测。
