Graduation Date

Summer 8-14-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Bhavana J. Dave, Ph.D, FACMG

Abstract

Chronic lymphocytic leukemia (CLL) is a genetically heterogeneous disease characterized in part by a combination of conventional cytogenetic and fluorescence in situ hybridization (FISH) analyses. Previous studies have investigated the occurrence of many cytogenetic abnormalities in CLL. However, few have focused on the frequency and variation of deletions within chromosome 14 (14q32), including genes associated with the IGH gene region and the possible related prognostic implications. We performed a comprehensive analysis and examined the frequency of abnormalities, specifically, deletions of the 14q32 region, categorized the size variation of these deletions using microarray, and assessed the effect on time-to-first-treatment (TTFT) and overall survival (OS). A retrospective analysis was performed on 698 CLL cases investigated with conventional cytogenetics, FISH, or both assays in our laboratory. A 14q32 abnormality, including a deletion within this region, was detected in 35% (245/698) of cases overall, with the majority of cases containing a 5’ partial telomeric 14q32 deletion. To further define the size variation and decipher the minimum deleted region (MDR) within the 14q32 deletions, a subset of 40 available bone marrow or unstimulated peripheral blood specimens with FISH-confirmed 14q32 deletions of various types were further analyzed utilizing single nucleotide polymorphism (SNP) microarray. Deletions within 14q32 were most frequent at the 5’ telomeric end of the IGH variable region (14q32) (35/40 cases) that varied from 236 to 1401 kb and commonly involved genes FAM30A, ADAM6, LINC00226, and LINC00221. The MDR among the majority included a 213 kb region that encompassed LINC00221. We analyzed the effect of TTFT and OS among a subset of consented CLL cases with and without deletions of 14q32 that had available follow-up information. Cases with a 14q32 deletion had a median TTFT that was shorter than cases with a sole instance of a deletion or nullisomy 13q, a known good prognostic indicator, and longer than cases with a sole deletion of 11q or 17p, both of which are associated with an unfavorable prognosis. This investigation facilitates our understanding of the frequency and variability of 14q32 deletions in CLL and underscores the need for comprehensive testing, including microarray, to better comprehend clinical implications.

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