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Risk-based classification of leukemia by cytogenetic and multiplex molecular methods: results from a multicenter validation study.

ABSTRACT: Modern management of leukemia and selection of optimal treatment approaches entails the analysis of multiple recurrent cytogenetic abnormalities with independent diagnostic or prognostic value. We report the first multicenter validation of a multiplex molecular assay for 12 relevant fusion transcripts relative to cytogenetic methods. Performance was evaluated using a set of 280 adult and pediatric acute or chronic leukemias representative of the variety of presentations and pre-analytical parameters encountered in the clinical setting. The positive, negative and overall agreements were >98.5% with high concordance at each of the four sites. Positive detection of cases with low blast count or at relapse was consistent with a method sensitivity of 1%. There was 98.7% qualitative agreement with independent reference molecular tests. Apparent false negatives corresponded to rare alternative splicing isoforms not included in the panel. We further demonstrate that clinical sensitivity can be increased by adding those rare variants and other relevant transcripts or submicroscopic abnormalities. We conclude that multiplex RT-PCR followed by liquid bead array detection is a rapid and flexible method attuned to the clinical laboratory workflow, complementing standard cytogenetic methods and generating additional information valuable for the accurate diagnosis, prognosis and subsequent molecular monitoring of leukemia.

SUBMITTER: Gocke CD

PROVIDER: S-EPMC3408638 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Risk-based classification of leukemia by cytogenetic and multiplex molecular methods: results from a multicenter validation study.

Gocke C D CD Mason J J Brusca L L Laosinchai-Wolf W W Higgs C C Newell H H Masters A A Friar L L Karp J J Griffiths M M Wei Q Q Labourier E E

Blood cancer journal 20120713 7

Modern management of leukemia and selection of optimal treatment approaches entails the analysis of multiple recurrent cytogenetic abnormalities with independent diagnostic or prognostic value. We report the first multicenter validation of a multiplex molecular assay for 12 relevant fusion transcripts relative to cytogenetic methods. Performance was evaluated using a set of 280 adult and pediatric acute or chronic leukemias representative of the variety of presentations and pre-analytical parame ...[more]

PMID: 22852047

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Project description:BackgroundRAS (KRAS and NRAS) testing is required to predict anti-epidermal growth factor receptor (EGFR) treatment efficacy in metastatic colorectal cancer (CRC). Although direct sequencing (DS) with manual microdissection (MMD) is widely used, a diagnostic kit providing rapid detections of RAS mutations would be clinically beneficial. We evaluated the MEBGEN(TM) RASKET KIT (RASKET KIT), a multiplex assay using PCR-reverse sequence specific oligonucleotide and xMAP(®) technology to concurrently detect exon 2, 3, and 4 RAS mutations in a short turnaround time (4.5 h/96-specimens).MethodsFormalin-fixed paraffin-embedded (FFPE) tissues were obtained from 308 consenting patients with histologically-confirmed CRC at six hospitals in Japan. For the RASKET KIT, we used only 50-100 ng DNA from each FFPE specimen not processed by MMD. The primary endpoint was the concordance rate between RAS mutations identified with the RASKET KIT and two reference assays (DS with MMD and TheraScreen(®) K-RAS Mutation Kit). As the secondary endpoints, we evaluated the concordance rate between DS and the RASKET KIT for RAS mutations in the wild-type KRAS exon 2 population and the genotyping performance of the RASKET KIT compared with DS.FindingsAmong 307 analyzable specimens, the reference assays detected 140 (45.6%, 140/307) RAS mutations: 111 KRAS exon 2 and 29 other (minor) RAS mutations. The RASKET KIT detected 143 (46.6%, 143/307) mutations: 114 KRAS exon 2 and 29 minor RAS mutations. The between-method concordance rate was 96.7% (297/307) (95% CI: 94.1-98.4%). Minor RAS mutations were detected in 15.7% (30/191) of the wild-type KRAS exon 2 population (n = 191); the concordance rate was 98.4% (188/191) (95% CI: 95.5-99.7%). The concordance rate of RAS genotyping was 100% (139/139) (95% CI: 97-100%).InterpretationThe RASKET KIT provides rapid and precise detections of RAS mutations and consequently, quicker and more effective anti-EGFR therapy for CRC (Study ID: UMIN000011784).FundingMedical & Biological Laboratories Co., Ltd. (MBL). MBL had roles in study design, data collection, data analysis, and writing of the report for the study.

Dataset Information

Risk-based classification of leukemia by cytogenetic and multiplex molecular methods: results from a multicenter validation study.

Publications

Risk-based classification of leukemia by cytogenetic and multiplex molecular methods: results from a multicenter validation study.

Similar Datasets

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