The germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies

被引：11

作者：

Trubicka, Joanna ^{[1
,2
]}

Zemojtel, Tomasz ^{[3
,4
]}

Hecht, Jochen ^{[5
,6
]}

Falana, Katarzyna ^{[1
]}

Piekutowska-Abramczuk, Dorota ^{[1
]}

Ploski, Rafal ^{[7
]}

Perek-Polnik, Marta ^{[8
]}

Drogosiewicz, Monika ^{[8
]}

Grajkowska, Wieslawa ^{[2
,9
]}

Ciara, Elzbieta ^{[1
]}

Moszczynska, Elzbieta ^{[10
]}

Dembowska-Baginska, Bozenna ^{[8
]}

Perek, Danuta ^{[8
]}

Chrzanowska, Krystyna H. ^{[1
]}

Krajewska-Walasek, Malgorzata ^{[1
]}

Lastowska, Maria ^{[2
,9
]}

机构：

[1] Childrens Mem Hlth Inst, Dept Med Genet, Al Dzieci Polskich 20, PL-04730 Warsaw, Poland

[2] Childrens Mem Hlth Inst, Dept Pathol, Al Dzieci Polskich 20, PL-04730 Warsaw, Poland

[3] Charite, Inst Med Genet & Human Genet, Augustenburger Pl 1, D-13353 Berlin, Germany

[4] Polish Acad Sci, Inst Bioorgan Chem, PL-60569 Poznan, Poland

[5] Max Planck Inst Mol Genet, Ihnestr 63-73, D-14195 Berlin, Germany

[6] Charite, Berlin Brandenburg Ctr Regenerat Therapies, D-13353 Berlin, Germany

[7] Med Univ Warsaw, Dept Med Genet, Warsaw, Poland

[8] Childrens Mem Hlth Inst, Dept Oncol, Al Dzieci Polskich 20, PL-04730 Warsaw, Poland

[9] Polish Acad Sci, Dept Expt & Clin Pathol, Mossakowski Med Res Ctr, A Pawinskiego 5, PL-02106 Warsaw, Poland

[10] Childrens Mem Hlth Inst, Dept Endocrinol & Diabetol, Al Dzieci Polskich 20, PL-04730 Warsaw, Poland

来源：

BMC CANCER | 2017年 / 17卷

关键词：

Medulloblastoma; DNA repair genes; Toxicity; MISMATCH REPAIR; SEQUENCING DATA; CANCER SUSCEPTIBILITY; DAMAGE RESPONSE; NBS1; GENE; MUTATIONS; TEMOZOLOMIDE; MALIGNANCIES; ANNOTATION; SUBGROUPS;

D O I：

10.1186/s12885-017-3211-y

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

引用

页数：11

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