The clinical utility of (epi)genomic biomarkers in chronic lymphocytic leukaemia

Abstract

Chronic lymphocytic leukaemia (CLL) presents as a biological and clinically heterogenous disease, with some patients requiring immediate intervention whilst other have a more benign disease. In this thesis, a large cohort of patients enrolled in chemo(immuno-) therapy clinical trials, CLL4, ARCTIC or ADMIRE, with extensive molecular characterisation is used to examine the clinical power of three novel CLL biomarkers, methylation based epitype, telomere length (TL) and genomic complexity (GC). Published work have reported that these biomarkers are clinically relevant. However, they have not been analysed together within a single clinical trial cohort. Also, a description of the biological context of these biomarkers is an additional aim. A systematic review with narrative synthesis was completed. Various experimental work and bioinformatic analysis, undertaken by myself, generated new copy number aberration (CNA) (n=153), TL (n=83) and variant (n=42) data using shallow whole genome sequencing, monochrome multiplex QPCR and HS2 target enrichment techniques, respectively. Extensive statistical and survival analysis was completed. Data classifying CLL patients into three epitype subgroups: naïvelike (n-CLL), intermediate (i-CLL), and memory-like CLL (m-CLL) was utilised. GC was defined as low (0-2 CNAs), intermediate (3-4 CNAs) and high (≥5 CNAs) GC. Published TL cut-offs (TL-Short <2.92kb, TL-Intermediate 2.92–3.57kb, TL-Long >3.57kb) was also used. Results found the n-CLL epitype, TL-S and high GC variables were associated with many other poor risk features and were predictive of a poor survival. A strong relationship between TL and epitype was also found. As well as confirming previously reported results, the key results of this project include: 1) a significant enrichment of i-CLL epitype in intermediate GC patients was found; 2) greater GC was correlated with shortening TL (TL-S) and an increased prevalence of the n-CLL epitype; 3) survival analysis showed that the i-CLL subgroup can be further stratified by TL, with TL-L predicting a prolonged survival; 4) Both TL and epitype have prognostic utility in identifying patients destined to have poor survival; 5) high GC, but not intermediate GC, was an predictor of a dismal overall survival independently of TP53 aberration or unmutated IGHV status. In conclusion, for the first time the clinical significance of TL, epitype and GC was examined together within a clinical trial cohort. Results suggest that the combination of TL and epitype can further stratify the mutated IGHV group. Additionally, the biological composition and clinical significance of three GC subgroups was described. This work supports the use of GC as a prognostic biomarker in the clinical setting. However, as reported in the systematic review, a consensus within the CLL community about the metric used to define GC and what technology should be used to detect GC needs to be reached before this biomarker can be fully validated.

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Identifiers

ORCID for Helen Parker: orcid.org/0000-0001-8308-9781

ORCID for Jon Strefford: orcid.org/0000-0002-0972-2881

ORCID for Jane Gibson: orcid.org/0000-0002-0973-8285

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