Biomarker Commons

Promoter methylation-mediated inactivation of PCDH10 in acute lymphoblastic leukemia contributes to chemotherapy resistance.

Genes Chromosomes Cancer. 2011 Dec;50(12):1043-53

Authors: Narayan G, Freddy AJ, Xie D, Liyanage H, Clark L, Kisselev S, Un Kang J, Nandula SV, McGuinn C, Subramaniyam S, Alobeid B, Satwani P, Savage D, Bhagat G, Murty VV

Abstract
PCDH10 has been implicated as a tumor suppressor, since epigenetic alterations of this gene have been noted in multiple tumor types. However, to date, studies regarding its role in acute and chronic leukemias are lacking. Here, we have investigated the presence of promoter hypermethylation of two CpG islands of the PCDH10 gene by methylation-specific PCR in 215 cases of various subsets of myeloid- and lymphoid-lineage leukemias. We found that PCDH10 promoter hypermethylation was frequent in both B-cell (81.9%) and T-cell (80%) acute lymphoblastic leukemia (ALL), while it was present in low frequency in most subtypes of myeloid leukemias (25.9%) and rare in chronic myeloid leukemia (2.2%). PCDH10 expression was downregulated via promoter hypermethylation in primary ALL samples (N = 4) and leukemia cell lines (N = 11). The transcriptional repression caused by PCDH10 methylation could be restored by pharmacologic inhibition of DNA methyltransferases. ALL cell lines harboring methylation-mediated inactivation of PCDH10 were less sensitive to commonly used leukemia-specific drugs suggesting that PCDH10 methylation might serve as a biomarker of chemotherapy response. Our results demonstrate that PCDH10 is a target of epigenetic silencing in ALL, a phenomenon that may impact lymphoid-lineage leukemogenesis, serve as an indicator of drug resistance and may also have potential implications for targeted epigenetic therapy.

PMID: 21960365 [PubMed - indexed for MEDLINE]

Prognostic relevance of RUNX1 mutations in T-cell acute lymphoblastic leukemia.

Haematologica. 2011 Dec;96(12):1874-7

Authors: Grossmann V, Kern W, Harbich S, Alpermann T, Jeromin S, Schnittger S, Haferlach C, Haferlach T, Kohlmann A

Abstract
The runt-related transcription factor 1, RUNX1, is crucial in the development of myeloid and lymphoid cell lineages and has been reported to be mutated in myeloid malignancies in approximately 30% of cases. In this study, the mutational status of RUNX1 was investigated in 128 acute lymphoblastic leukemia patients. We detected a mutation rate of 18.3% (13 of 71) in patients with T-cell acute lymphoblastic leukemia, 3.8% (2 of 52) in patients with B-cell acute lymphoblastic leukemia and no mutation (0 of 5) in patients with natural killer cell leukemia, respectively. In T-cell acute lymphoblastic leukemia patients, RUNX1 mutations were significantly associated with higher age (P=0.017) and lower white blood cell count (P=0.038). Moreover, an inferior outcome was observed in the subgroup of early T-cell acute lymphoblastic leukemia patients carrying RUNX1 mutations for overall survival (P=0.043). In conclusion, RUNX1 mutations are an important novel biomarker for a comprehensive characterization of T-cell acute lymphoblastic leukemia with poor prognostic impact and have implications for use also in monitoring disease.

PMID: 21828118 [PubMed - indexed for MEDLINE]

A meta-analysis of MTHFR C677T and A1298C polymorphisms and risk of acute lymphoblastic leukemia in children.

Pediatr Blood Cancer. 2012 Apr;58(4):513-8

Authors: Yan J, Yin M, Dreyer ZE, Scheurer ME, Kamdar K, Wei Q, Okcu MF

Abstract
BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms have been implicated in childhood acute lymphoblastic leukemia (ALL) risk, but previously published studies were inconsistent and recent meta-analyses were not adequate.
PROCEDURES: In a meta-analysis of 21 publications with 4,706 cases and 7,414 controls, we used more stringent inclusion method and summarized data on associations between MTHFR C677T and A1298C polymorphisms and childhood ALL risk.
RESULTS: We found an overall association between 677T variant genotypes and reduced childhood ALL risk. Specifically, in the dominant genetic model, an association was found in a fixed-effect (TT + CT vs. CC: OR = 0.92; 95% CI = 0.85-0.99) but not random-effect model, whereas such an association was observed in both homozygote genetic model (TT vs. CC: OR = 0.80; 95% CI = 0.70-0.93 by fixed effects and OR = 0.78; 95% CI = 0.65-0.93 by random effects) and recessive genetic model (TT vs. CC + CT: OR = 0.83; 95% CI = 0.72-0.95 by fixed effects and OR = 0.84; 95% CI = 0.73-0.97 by random effects). These associations were also observed in subgroups by ethnicity: for Asians in all models except for the dominant genetic model by random effect and for Caucasians in all models except for the recessive genetic model. However, the A1298C polymorphism did not appear to have an effect on childhood ALL risk.
CONCLUSIONS: These results suggest that the MTHFR C677T, but not A1298C, polymorphism is a potential biomarker for childhood ALL risk.

PMID: 21495160 [PubMed - indexed for MEDLINE]

Clinical applications of epigenetic markers and epigenetic profiling in myeloid malignancies.

Semin Oncol. 2012 Feb;39(1):109-22

Authors: McDevitt MA

Abstract
Aberrant DNA methylation is frequent in the myeloid malignancies, particularly myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Promoter CpG methylation is correlated with silencing of tumor-suppressor genes (TSGs) in specific pathways that are also targets of mutation or other mechanisms of inactivation, and is thought to contribute to disease progression and poor prognosis. Epigenetic contributions to myeloid pathogenesis are more complex. Examples include TSG inactivation and oncogenic activation associated with formation of altered chromatin separate from CpG methylation. Epigenetic dysregulation occurs at multiple disease stages and at non-CpG island genomic sites, and also includes genomic hypomethylation and small RNA mechanisms of epigenetic regulation. Identification of recurrent mutations in potential epigenetic regulators, including TET2, IDH1, IDH2, DNMT3A, UTX, and ASXL1, were recently described. Accordingly, therapeutics directed towards epigenetic mechanisms including methylation inhibitors and histone deacetylase (HDAC) inhibitors have had some clinical success when applied to MDS and AML. However, identification of the underlying mechanisms associated with clinical responses and drug resistance remain enigmatic. Remarkably, in spite of significant molecular and translational progress, there are currently no epigenetic biomarkers in widespread clinical use. In this review, we explore the potential applications of epigenetic biomarker discovery, including epigenetic profiling for myeloid malignancy pathogenesis understanding, diagnostic classification, and development of effective treatment paradigms for these generally considered poor prognosis disorders.

PMID: 22289497 [PubMed - indexed for MEDLINE]

DNMT3A mutations in acute myeloid leukemia: stability during disease evolution and clinical implications.

Blood. 2012 Jan 12;119(2):559-68

Authors: Hou HA, Kuo YY, Liu CY, Chou WC, Lee MC, Chen CY, Lin LI, Tseng MH, Huang CF, Chiang YC, Lee FY, Liu MC, Liu CW, Tang JL, Yao M, Huang SY, Ko BS, Hsu SC, Wu SJ, Tsay W, Chen YC, Tien HF

Abstract
DNMT3A mutations are associated with poor prognosis in acute myeloid leukemia (AML), but the stability of this mutation during the clinical course remains unclear. In the present study of 500 patients with de novo AML, DNMT3A mutations were identified in 14% of total patients and in 22.9% of AML patients with normal karyotype. DNMT3A mutations were positively associated with older age, higher WBC and platelet counts, intermediate-risk and normal cytogenetics, FLT3 internal tandem duplication, and NPM1, PTPN11, and IDH2 mutations, but were negatively associated with CEBPA mutations. Multivariate analysis demonstrated that the DNMT3A mutation was an independent poor prognostic factor for overall survival and relapse-free survival in total patients and also in normokaryotype group. A scoring system incorporating the DNMT3A mutation and 8 other prognostic factors, including age, WBC count, cytogenetics, and gene mutations, into survival analysis was very useful in stratifying AML patients into different prognostic groups (P < .001). Sequential study of 138 patients during the clinical course showed that DNMT3A mutations were stable during AML evolution. In conclusion, DNMT3A mutations are associated with distinct clinical and biologic features and poor prognosis in de novo AML patients. Furthermore, the DNMT3A mutation may be a potential biomarker for monitoring of minimal residual disease.

PMID: 22077061 [PubMed - indexed for MEDLINE]

Methylation pattern of calcitonin (CALCA) gene in pediatric acute leukemia.

J Pediatr Hematol Oncol. 2011 Oct;33(7):534-42

Authors: Ismail EA, El-Mogy MI, Mohamed DS, El-Farrash RA

Abstract
Disruption of deoxyribonucleic acid (DNA) methylation patterns has emerged as one of the possible origins of leukemogenesis. Calcitonin (CALCA) gene is a hot-spot for gene hypermethylation in acute leukemias. This study aimed to systematically analyze the methylation status of CALCA gene in pediatric acute leukemia using methylation-specific polymerase chain reaction (MSP) and assess its value as a potential prognostic biomarker. The study population consisted of 70 children divided into; 35 acute myeloblastic leukemia (AML) and 35 acute lymphoblastic leukemia (ALL) patients. CALCA gene was found to be hypermethylated in 54.3% of AML and 65.7% of ALL patients. CALCA hypermethylation was neither correlated to any of the clinicopathologic characteristics of patients, standard prognostic factors nor response to induction therapy (P>0.05). Hypermethylated AML and ALL patients displayed poorer clinical outcome when compared with hypomethylated counterparts as evidenced by high relapse and mortality rates with the occurrence of early relapse (P<0.05). The estimated overall and disease-free survival rates at 2.5-years were significantly shorter for hypermethylated patients in both groups (P<0.01). Our results suggest that CALCA gene methylation pattern is an independent prognostic factor in pediatric acute leukemia that could characterize a group of patients with enhanced risk of relapse and death.

PMID: 21423046 [PubMed - indexed for MEDLINE]

The novel member of the BCL2 gene family, BCL2L12, is substantially elevated in chronic lymphocytic leukemia patients, supporting its value as a significant biomarker.

Oncologist. 2011;16(9):1280-91

Authors: Papageorgiou SG, Kontos CK, Pappa V, Thomadaki H, Kontsioti F, Dervenoulas J, Papageorgiou E, Economopoulos T, Scorilas A

Abstract
BCL2L12 is a recently identified gene belonging to the BCL2 family, members of which are implicated in hematologic malignancies, including chronic lymphocytic leukemia (CLL). The aim of this study was to analyze the mRNA expression of the novel apoptosis-related gene BCL2L12 in patients with CLL and to examine its prognostic and predictive value and potential clinical application as a novel molecular biomarker for CLL. For this purpose, total RNA was isolated from peripheral blood of 65 CLL patients and 23 healthy donors. An ultrasensitive quantitative real-time polymerase chain reaction methodology for BCL2L12 and BCL2 mRNA quantification was developed using SYBR Green chemistry. After preparing cDNA by reverse transcription, relative quantification analysis was performed using the comparative C(T) (2(-ΔΔCT)) method. Furthermore, analysis of IGHV mutational status, CD38 expression, and detection of early apoptosis by double staining with Annexin V-FITC and propidium iodide were performed. According to our findings, BCL2L12 mRNA expression is significantly higher in CLL patients than in healthy donors. Receiver operating characteristic analysis demonstrated that BCL2L12 expression had significant discriminatory value, distinguishing very efficiently CLL patients from the non-leukemic population. Moreover, BCL2L12 expression predicts the presence of CLL, as demonstrated by both univariate and multivariate logistic regression analyses. Finally, high BCL2L12 mRNA levels are associated with advanced clinical stage and predict shorter overall survival in CLL patients.

PMID: 21737576 [PubMed - indexed for MEDLINE]