| Summary: | 博士 === 國立臺灣大學 === 臨床醫學研究所 === 100 === Background: Acute lymphoblastic leukemia (ALL) is the most common pediatricmalignancy and accounts for 25% of childhood cancers. ALL is thought to originatefrom various important genetic lesions in blood-progenitor cells that are committed todifferentiate in the T-cell or B-cell pathway, including mutations that impart thecapacity for unlimited self-renewal and those that lead to stage-specific developmentalarrest. Cure rates have improved dramatically over the past 40 years, with 5-year overall survival rates increasing from <10% in the late 1960s to nearly 90% in 2000-2004 inadvanced countries. The success of treatment of childhood ALL depends upon theidentifications of risk factors. The advent of high-resolution genome-wide analyses ofgene expression, DNA copy number alterations and loss of heterozygosity, andwhole-gemone sequencing have led to the detection of many novel geneticabnormalities. These studies also provide new insights into the complex interactions ofmultiple genetic alterations in leukemogenesis and response to chemotherapy. Some ofthem also had strong prognostic implications.
In 1988, the Taiwan Pediatric Oncology Group (TPOG) was formed with thecooperation of all leukemia treatment centers and has since initiated nationalcooperative group studies. The treatment results were published recently. Most of theadvance of treatment rely on the intensification of chemotherapy, not the improvementof identification of risk factors. For the purpose to improve the clinical outcomes by theidentifications of prognostic factors, this thesis focused upon the studies of geneticbackgrounds of the leukemic cells and the host.
Thesis: The purpose of this thesis is to investigate the prognostic factors in childhoodALL in Taiwan. (1) Four common chromosomal translocations screening includingt(12;21), t(1;19), t(4,11) and t(9;22). (2) The prognostic value of three apoptoticBCL2L13, CASP8AP2, and Livin gene expression in the childhood ALL (3) seventeenpharmacogenetic polymorphisms for outcomes (4) the prognostic value of IKZF1deletions for B-lineage ALL (5) the prognostic impact of absence of biallelic TCRγdeletions (ABD) for patients with T-cell ALL.
Methods and Results: Diagnostic bone marrow or peripheral blood and remissionsamples were obtained from 369 children diagnosed with ALL between July 1996 andJune 2010 at the National Taiwan University Hospital, National Cheng Kung UniversityHospital, Chang Gung Memorial Hospital-Kaohsiung Medical Center, China MedicalUniversity Hospital, Changhua Christian Hospital, and Veterans General Hospital-Taichung. Among them, 307 were newly diagnosed B-precursor ALL and 62 wereT-cell ALL.
The hallmark of childhood ALL is chromosomal alterations. Multiplex RT-PCR and nested-PCR assays were used to detect the four common chromosomal translocations,including t(9;22), t(1;19), t(4;11), and 2 variants of t(12;21) in 148 leukemic samplesupon diagnosis. Patients with ETV6-RUNX1 fusion, hyper-diploidy, and t(1;19)/TCF-PBX1fusion had the most favorable outcomes whereas those with the t(9;22)/BCR-ABL1fusion or t(4;11) and other MLL gene re-arrangement had poor prognosis (p<0.001 forevent-free survival and overall survival). We investigated the expression of threeapoptosis related genes, BCL2L13, CASP8AP2, and Livin by the method of Q-RT-PCR, as well as their prognostic significance, in a retrospective study of 90 pediatric ALLpatients diagnosed between 1996 and 2007 in Taiwan. Multivariate analysis for EFSand OS demonstrated that high expression of BCL2L13 was an independent prognostic factor for childhood ALL in this ethnic group. Seventeen genetic polymorphisms in 13pharmacogenomic targets were analyzed by PCR-based RFLP and sequence-specificoligonucleotide (SSO) probe hybridization .The pharmacogenetic polymorphisms of the host were also evaluated. Three polymorphic alleles in the multi-drug resistant 1(MDR1) gene and homozygotic MDR1 2677GG, 3435CC, and 2677G-3435Cgenotypes were also highly associated with significant reduction in event-free survival(EFS) and overall survival (OS)in patients treated by the standard risk protocol(TPOG-ALL-93 SR).
Recent genome-wide analyses have identified that an alteration of IKZF1 isassociated with very poor outcomes in B-cell progenitor ALL and the absence ofbi-allelic TCRγ deletions (ABD) reportedly predicts early treatment failure in childhoodT-cell ALL. In this cohort, patients with IKZF1 deletions had inferior event-freesurvival (p<0.001) and overall survival (p=0.0016). In T-cell ALL, patients with ABDhad higher incidences of induction failure and inferior OS than those without ABD(p=0.03 and 0.0196, respectively) after multivariate regression analysis.
Conclusions: The multiplex RT-PCR can complement the cytogenetic study.Chromosomal alterations had prognostic implications in childhood ALL. Theexpression of BCL2L13 was an independent prognostic factor for childhood ALL in this ethnic group. Pharmacogenetic variations had some prognostic impacts in some subsets of patients with childhood ALL. IKZF1 deletions predict poor clinical outcomes forpatient with B-cell precursor ALL. ABD also predict induction failure in T-cell ALL.These prognostic genetic alterations may be included in risk-directed therapy in thefuture. Patients with poor outcomes (such as patients with IKZF1 deletions or T-cellALL with ABD) may benefit from alternative treatment regimes.
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