Jenkinson, S; (2015) Investigation of genetic alterations in paediatric patients with T-cell lymphoblastic leukaemia. Doctoral thesis , UCL (University College London).

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Abstract

Approximately 25% of paediatric patients with T-cell acute lymphoblastic leukaemia (T-ALL) develop recurrent disease and post-relapse prognosis remains poor. Identification of molecular prognostic markers at diagnosis is needed so that earlier intervention with more intensive therapy can be targeted at those at the greatest risk of relapse, and dose reduction considered for those at a lower risk. Denaturing HPLC (dHPLC) was used to screen selected regions of the NOTCH1 and FBXW7 genes in samples from 162 paediatric T-ALL patients. Overall, 101 (62%) had NOTCH1 mutations (NOTCH MUT) and 29 (18%) were FBXW7MUT. The cohort was divided into three genotype groups for analysis: wild-type (WT) for both genes (NOTCH1WTFBXW7WT), a single NOTCH1 mutation (NOTCH1SingleFBXW7WT), and either NOTCH1DoubleFBXW7WT or NOTCH1MUTFBXW7MUT (NOTCH1±FBXW7Double). Patients with NOTCH1±FBXW7Double mutations were significantly associated with negative minimal residual disease (P=.01) and an excellent overall survival (P=.005), and should not be considered for more intensive therapy in first remission. PTEN mutation status was determined by dHPLC and the mutant level quantified by fragment analysis. Overall, 21 (13%) were PTEN MUT and median mutant level was 48% (range 10%-96%). Loss of genomic PTEN was investigated by quantification of two SNP loci in 76 informative patients and Illumina SNP array analysis in 139 patients with sufficient DNA. Of 145 patients, 15 (10%) had PTEN deletions, and combining the mutation and deletion status, 32 (22%) harboured a PTEN abnormality. PTEN genotype was not a significant prognostic indicator of response to therapy or clinical outcome; therefore it is not warranted for use in risk-adapted therapy at the present time. PTEN genotype had no impact on the favourable outcome of the patients with NOTCH1±FBXW7Double mutations; nor did it further stratify the NOTCH1SingleFBXW7WT or NOTCH1WTFBXW7WT groups. This work provides insight into the biology of NOTCH1, FBXW7 and PTEN mutations and their use as clinical markers.

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