Clinical significance of CASP8AP2 gene methylation in childhood acute lymphoblastic leukemia.

Fei-fei Liu; China Beijing 100045; Xiao Liu; China Beijing 100045; Kai-ling Wang; China Beijing 100045; Wei-jing LI; China Beijing 100045; Guo-ren Deng; Chao Gao; China Beijing 100045; Xiao-xi Zhao; China Beijing 100045; Min-yuan WU; China Beijing 100045; Lei Cui; Zhi-gang LI

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Clinical significance of CASP8AP2 gene methylation in childhood acute lymphoblastic leukemia.

Author: Fei-Fei LIU ^{1
,

2
,

3
,

4
,

5} ; Beijing 100045, CHINA. ; Xiao LIU ¹ ; Beijing 100045, CHINA. ; Kai-Ling WANG ¹ ; Beijing 100045, CHINA. ; Wei-Jing LI ¹ ; Beijing 100045, CHINA. ; Guo-Ren DENG ⁶ ; Chao GAO ¹ ; Beijing 100045, CHINA. ; Xiao-Xi ZHAO ¹ ; Beijing 100045, CHINA. ; Min-Yuan WU ¹ ; Beijing 100045, CHINA. ; Lei CUI ¹ ; Zhi-Gang LI ¹ ;
Author Information

1. Hematologic Oncology Center, Beijing Children's Hospital, Capital Medical University
2. Key Laboratory of Major Diseases in Children, Ministry of Education
3. National Key Discipline of Pediatrics
4. Beijing Key Laboratory of Pediatric Hematology and Oncology
5. Beijing 100045, China.
6. Department of Urology, School of Medicine, University of California, San Francisco, CA 94101, USA.
Publication Type:Journal Article
MeSH: Apoptosis Regulatory Proteins; Calcium-Binding Proteins; Child; DNA Methylation; Humans; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Promoter Regions, Genetic; Recurrence; Remission Induction
From: Journal of Experimental Hematology 2015;23(1):6-11
CountryChina
Language:Chinese
Abstract:
OBJECTIVETo study the methylation level in the promoter of caspase 8 associated protein 2 (CASP8AP2) gene between samples at diagnosis and in complete remission, and to investigate its relationship with clinical features and prognosis in children with acute lymphoblastic leukemia (ALL).
METHODSDiagnostic DNA samples from 109 newly diagnosed children with ALL admitted from August 2007 to March 2010, and 94 ALL children in CR (complete remission) among them were collected. Bisulfite modification and MethyLight method established by our research team were used to determine the methylation level of the two key CpG sites (at -1189 and -1176) of the promoter of CASP8AP2 gene.
RESULTSThe average methylation level of the two CpG sites in newly diagnosted samples was higher than that in CR samples (71.1% ± 1.7% vs 64.2% ± 21.2%) (P = 0.008). Analysis with receiver operating characteristic (ROC) curve showed that the area under curve was 0.687 (P = 0.024), indicating that the methylation level of the two CpG sites was able to predict relapse efficiently to some extent, 76.9% was chosed as a cutoff value to divide the patients into high methylation group (49 patients) and low methylation group (60 patients). The incidence of relapse in high methylation group was higher than that in low methylation group (20.4% vs 6.7%) (P = 0.044), five year relapse free survival in high methylation group was also lower than that in low methylation group (Log rank, P = 0.033). Furthermore, high methylation at new diagnosis were correlated with high level of minimal residual disease (MRD) before consolidation therapy (P = 0.011). In the 34 children with MRD ≥ 10(-4) at the end of induction remission, the relapse rate of high methylation patients was significantly higher than that of low methylation patients (8/16 vs 3/18)(P = 0.038).
CONCLUSIONThe abnormal hypermethylation of the two CpG sites (at -1189 and -1176) of the promoter of the CASP8AP2 gene is possibly associated with leukemogenesis in childhood ALL. The treatment outcome is more poor in patients with hypermethylation than that in patients with low methylation. The combination of the methylation level of the two CpG sites and MRD level at the end induction remission is able to predict relapse more effectively.