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Title: Acquired abnormalities of chromosome 21 in acute lymphoblastic leukaemia
Author: Robinson, Hazel M.
ISNI:       0000 0001 3527 9820
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2008
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The intrachromosomal amplification of chromosome 21 (iAMP21) was identified as a novel and prognositically important acquired chromosomal abnormality in childhood acute lymphoblastic leukaemia (ALL). It is defined by multiple copies of the RUNX1 gene, as seen by fluorescence in situ hybridisation (FISH), localised to a single abnormal duplicated chromosome 21 [dup(21)]. The morphological form of this chromosome is highly variable between patients and currently the only reliable method of detection is FISH with probes to RUNX1. Studies of 48 iAMP21 patients using detailed FISH techniques and array-based comparative genomic hybridisation highlighted an extensive region of chromosome 21 involvement. A minimum common region of amplification, between 33.19 and 39.80Mb, including RUNX1 was identified, together with a minimum common region of deletion, between 46.54 and 46.92Mb, in 100% and 77% of patients, respectively. This study established that there were unique patterns of imbalance, with evidence of deletions, inversions and amplification, displayed on the dup(21), between individual patients. This provided evidence of an abnormality that may have arisen from a breakage-fusion-bridge mechanism, possibly initiated by loss of a telomere. Results indicated that iAMP21 represents a distinct genetic subgroup of childhood ALL and is not secondary to a cryptic abnormality of chromosome 21. Two possible variant cases were identified both involving chromosome 15. The abnormality can be distinguished from other numerical abnormalities of chromosome 21 by exploiting the unique pattern of gain, amplification and deletion seen in these patients. This allowed for the development of diagnostic tests based on copy number using either FISH or multiplex ligation dependent probe amplification (MLPA), both of which successfully identified iAMP21 patients.
Supervisor: Harrison, Christine J. ; Moorman, Anthony Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC0254 Neoplasms. Tumors. Oncology (including Cancer) ; QH426 Genetics