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An advanced fragment analysis-based individualized subtype classification of pediatric acute lymphoblastic leukemia.

ABSTRACT: Pediatric acute lymphoblastic leukemia (ALL) is the most common neoplasm and one of the primary causes of death in children. Its treatment is highly dependent on the correct classification of subtype. Previously, we developed a microarray-based subtype classifier based on the relative expression levels of 62 marker genes, which can predict 7 different ALL subtypes with an accuracy as high as 97% in completely independent samples. Because the classifier is based on gene expression rank values rather than actual values, the classifier enables an individualized diagnosis, without the need to reference the background distribution of the marker genes in a large number of other samples, and also enables cross platform application. Here, we demonstrate that the classifier can be extended from a microarray-based technology to a multiplex qPCR-based technology using the same set of marker genes as the advanced fragment analysis (AFA). Compared to microarray assays, the new assay system makes the convenient, low cost and individualized subtype diagnosis of pediatric ALL a reality and is clinically applicable, particularly in developing countries.

SUBMITTER: Zhang H

PROVIDER: S-EPMC4508914 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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An advanced fragment analysis-based individualized subtype classification of pediatric acute lymphoblastic leukemia.

Zhang Han H Cheng Hao H Wang Qingqing Q Zeng Xianping X Chen Yanfen Y Yan Jin J Sun Yanran Y Zhao Xiaoxi X Li Weijing W Gao Chao C Gong Wenyu W Li Bei B Zhang Ruidong R Nan Li L Wu Yong Y Bao Shilai S Han Jing-Dong J JD Zheng Huyong H

Scientific reports 20150721

Pediatric acute lymphoblastic leukemia (ALL) is the most common neoplasm and one of the primary causes of death in children. Its treatment is highly dependent on the correct classification of subtype. Previously, we developed a microarray-based subtype classifier based on the relative expression levels of 62 marker genes, which can predict 7 different ALL subtypes with an accuracy as high as 97% in completely independent samples. Because the classifier is based on gene expression rank values rat ...[more]

PMID: 26196328

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Project description:We present a method that utilizes DNA methylation profiling for prediction of the cytogenetic subtypes of acute lymphoblastic leukemia (ALL) cells from pediatric ALL patients. The primary aim of our study was to improve risk stratification of ALL patients into treatment groups using DNA methylation as a complement to current diagnostic methods. A secondary aim was to gain insight into the functional role of DNA methylation in ALL.We used the methylation status of ~450,000 CpG sites in 546 well-characterized patients with T-ALL or seven recurrent B-cell precursor ALL subtypes to design and validate sensitive and accurate DNA methylation classifiers. After repeated cross-validation, a final classifier was derived that consisted of only 246 CpG sites. The mean sensitivity and specificity of the classifier across the known subtypes was 0.90 and 0.99, respectively. We then used DNA methylation classification to screen for subtype membership of 210 patients with undefined karyotype (normal or no result) or non-recurrent cytogenetic aberrations ('other' subtype). Nearly half (n?=?106) of the patients lacking cytogenetic subgrouping displayed highly similar methylation profiles as the patients in the known recurrent groups. We verified the subtype of 20% of the newly classified patients by examination of diagnostic karyotypes, array-based copy number analysis, and detection of fusion genes by quantitative polymerase chain reaction (PCR) and RNA-sequencing (RNA-seq). Using RNA-seq data from ALL patients where cytogenetic subtype and DNA methylation classification did not agree, we discovered several novel fusion genes involving ETV6, RUNX1, and PAX5.Our findings indicate that DNA methylation profiling contributes to the clarification of the heterogeneity in cytogenetically undefined ALL patient groups and could be implemented as a complementary method for diagnosis of ALL. The results of our study provide clues to the origin and development of leukemic transformation. The methylation status of the CpG sites constituting the classifiers also highlight relevant biological characteristics in otherwise unclassified ALL patients.

Project description:BackgroundOne of the most important application spectrums of transcriptomic data is cancer phenotype classification. Many characteristics of transcriptomic data, such as redundant features and technical artifacts, make over-fitting commonplace. Promising classification results often fail to generalize across datasets with different sources, platforms, or preprocessing. Recently a novel differential network rank conservation (DIRAC) algorithm to characterize cancer phenotypes using transcriptomic data. DIRAC is a member of a family of algorithms that have shown useful for disease classification based on the relative expression of genes. Combining the robustness of this family's simple decision rules with known biological relationships, this systems approach identifies interpretable, yet highly discriminate networks. While DIRAC has been briefly employed for several classification problems in the original paper, the potentials of DIRAC in cancer phenotype classification, and especially robustness against artifacts in transcriptomic data have not been fully characterized yet.ResultsIn this study we thoroughly investigate the potentials of DIRAC by applying it to multiple datasets, and examine the variations in classification performances when datasets are (i) treated and untreated for batch effect; (ii) preprocessed with different techniques. We also propose the first DIRAC-based classifier to integrate multiple networks. We show that the DIRAC-based classifier is very robust in the examined scenarios. To our surprise, the trained DIRAC-based classifier even translated well to a dataset with different biological characteristics in the presence of substantial batch effects that, as shown here, plagued the standard expression value based classifier. In addition, the DIRAC-based classifier, because of the integrated biological information, also suggests pathways to target in specific subtypes, which may enhance the establishment of personalized therapy in diseases such as pediatric AML. In order to better comprehend the prediction power of the DIRAC-based classifier in general, we also performed classifications using publicly available datasets from breast and lung cancer. Furthermore, multiple well-known classification algorithms were utilized to create an ideal test bed for comparing the DIRAC-based classifier with the standard gene expression value based classifier. We observed that the DIRAC-based classifier greatly outperforms its rival.ConclusionsBased on our experiments with multiple datasets, we propose that DIRAC is a promising solution to the lack of generalizability in classification efforts that uses transcriptomic data. We believe that superior performances presented in this study may motivate other to initiate a new aline of research to explore the untapped power of DIRAC in a broad range of cancer types.

Dataset Information

An advanced fragment analysis-based individualized subtype classification of pediatric acute lymphoblastic leukemia.

Publications

An advanced fragment analysis-based individualized subtype classification of pediatric acute lymphoblastic leukemia.

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