Bacterial Artificial Chromosome (BAC) Array CGH Study of B-CLL Patients with 17p13 Deletion.
Authors: Brito-Babapulle Vasantha , Rudenko Hannah , Dearden Claire , Fenwick Kerry , Mckay Alan , Ashworth Alan , Matutes Estella , Catovsky Daniel , Morgan Gareth 
Published: October 2019

Abstract
B-cell chronic lymphocytic leukaemia is characterised by a highly variable clinical course. Clone specific chromosomal imbalances have a significant prognostic ability with deletion of 17p13 being associated with advanced disease and resistance to therapy, deletion of 11q with progressive disease and extensive lymphadenopathy, deletion of 13q14 on its own with good prognosis and trisomy 12 with atypical morphology and an intermediate prognosis. In the MRC CLL 4 trial, a randomised study of conventional therapy with chlorambucil vs fludarabine either on its own or in combination with cyclophosphamide, 7% (40/580) of patients had deletions at 17p13. In this study 17p13 deletion was associated with the worst clinical outcome. However, considerable heterogeneity in clinical behaviour was observed with 60% dying within 1 year and 18 % alive at 3 years. This raises the question of whether other genetic variants co-segregating with 17p- modulate clinical behaviour. In order to investigate these possibilities we have identified seven patients with 17p13.1 deletion and screened them for p53 mutation. Using FISH they were screened for deletions of 11q22, 13q14 and trisomy12. One had an associated deletion at 11q22 and four at 13q14. Trisomy 12 was not detected in this group. Subsequently a global genome analyses using a 5.8K BAC array CGH platforms was carried out looking for regions of amplifications and deletions. Using this system to characterise the 17p deletion region further we were able to show that deletions were present at 17 p11.2, 17 p12–13.1 and 17p13.2–3. with variation in site and extent of deletion. These findings suggest that although the p53 gene on 17p13.1 is considered the target gene in this deletion, more than 1 gene in the region could be involved in contributing to poor prognosis. We are investigating whether this may contribute to the differential outcome in this group. Considering changes at other sites in the genome we have shown amplifications at 2p14–p25(1/7), 5q23(1/7), 6q14(1/7), 7q21(1/7), 8q24(1/7), 11p15(1/7), 11q13(1/7), 12p13(1/7), 16p12 –13(2/7), 17q21.2–q21.31(2/7) and deletions at 3p12.3–p26(1/7), 6q14–q22(2/7), 6q16–25(1/7), 9p21–p22.3(1/7), 9q31–q33(1/7), 11q13–22/23.1(1/7), 11q25(1/7), 12q13(1/7), 13q14.3–q21.1(4/7) 13q13.1–q13.3(1/7), 18p11.2–13.3(2/7) and 20p11.21–13 (1/7). Chromosomal sites recurrently involved in the 7 patients or known to be involved in CLL are in bold. Multiple cases with either amplification at 17q or deletion of 13q and 18p suggest that oncogene and tumour suppressor genes may be located at these regions. The zygosity states of these regions and the genes contained within them will be examined further and presented. The presence of multiple changes in the genome of CLL with 17p deletion is suggestive of genomic instability in this disease subgroup. We will compare these findings with changes in CLLs lacking such deletions. In addition we will analyse more cases to define recurrent genetic events contributing to this poor risk group of CLL and the deletion pattern on 17p together with p53 inactivation by mutation.