A study of the INK4A/ARF and INK4B loci in childhood acute lymphoblastic leukaemia using quantitative real time polymerase chain reaction

[Truncated abstract] Childhood acute lymphoblastic leukaemia (ALL) accounts for the largest number of cases of childhood cancer (25-35%) and is the primary cause of cancer related morbidity. Today more than 76% of children with ALL are alive and disease free at 5 years. Approximately one in 900 individuals between the ages of 16 and 44 years is a survivor of childhood cancer. In contrast, those patients who relapse with childhood ALL currently have a 6-year event free survival of 20-30%. The short arm of chromosome 9p is mutated or deleted in many cancers including leukaemia. Aberrations of the INK4A/ARF and INK4B loci at the 9p21 band are linked to the development and progression of cancer. In murine cancer models there is evidence to suggest that mutations of Ink4a/Arf and p53 gene loci promote resistance to chemotherapeutic drugs known to trigger apoptosis. The initial aim of this project was to develop an accurate, reproducible method to detect deletions at the INK4A/ARF locus in patient bone marrow specimens. This technique was then applied to detect the incidence of deletions of this locus in childhood ALL specimens. The hypothesis developed was that deletion at the INK4A/ARF locus at diagnosis in childhood ALL is an independent prognostic marker and is involved in disease progression. A secondary aim of this study was to determine which deletions at the INK4A/ARF and INK4B loci are the most relevant in leukaemogenesis in childhood ALL. ... This study has shown that deletion of the INK4A/ARF locus is an independent prognostic indicator in childhood ALL. In addition, the frequency of deletion at the INK4A/ARF and INK4B loci is increased at relapse compared to diagnosis in childhood ALL. In the relapse study group, deletion of the p16INK4A gene at diagnosis was associated with a decreased median time to relapse compared to other genes analysed. Murine studies suggest that such deletions may result in an increased resistance to chemotherapy. If the findings from this study are confirmed in a larger cohort, it is expected that therapeutic interventions based on assessment of the p16INK4A gene in diagnostic childhood ALL specimens will be implemented to prevent relapse in standard risk patients and help to improve the outcome in high risk patients.