Frequency, variations, and prognostic implications of chromosome 14q32 deletions in chronic lymphocytic leukemia

Highlights

• Abnormalities of 14q32 occur in a high frequency of cases with CLL.

• Deletions within the IGH variable region range in size in cases with CLL.

• Minimum deleted region of 14q32 encompassed LINC00221.

• Cases with sole 14q32 deletions had a shorter median TTFT than cases with sole 13q abnormalities.

Abstract

The clinical implications of deletions within chromosome 14q32 in CLL pathogenesis remain unclear. We examined the frequency of 14q32 deletions among CLL cases by karyotype and FISH, categorized the variation using genomic microarray, and assessed the prognostic impact by time-to-first-treatment (TTFT) analysis. A 14q32 abnormality was detected in 35 % (245/698) of cases, with the majority containing a 5′ partial telomeric 14q32 deletion. These deletions within the IGH variable region (35/40) ranged from 236 kb to 1.4 Mb involving FAM30A, ADAM6, LINC00226, and LINC00221. The 214 kb minimum deleted region implicated in CLL pathogenesis encompassed LINC00221. Cases with a 14q32 deletion had a shorter median TTFT compared to cases with a sole deletion/nullisomy 13q, a good prognostic indicator, and longer than cases with a sole deletion of 11q or 17p, conferring an unfavorable prognosis. This investigation underscores the importance of comprehensive testing to apprehend the implications of 14q32 deletions in CLL.

Introduction

Chronic lymphocytic leukemia (CLL) is the most predominant leukemia in the Western world, with nearly 21,040 newly diagnosed cases in the United States in 2020 [1]. CLL is now known to be heterogeneous with differences in cytogenetic abnormalities, gene mutations, and proliferation [2,3]. Heterogeneity in CLL ultimately has an impact on treatment strategies and survival outcomes. The current gold standard for genetic testing in cases with CLL includes conventional cytogenetics and fluorescence in situ hybridization (FISH) [[4], [5], [6], [7], [8]]. Historically, cytogenetics has provided prognostic insight by describing genetic abnormalities, including balanced translocations, and defined disease progression [9]. Numerical chromosome abnormalities and submicroscopic deletions are characteristic of CLL. Recurrent cytogenetic aberrations in CLL include deletions of 6q, 11q, 13q, and 17p and gain of chromosome 12 [4,7,8].

The immunoglobulin heavy chain locus (IGH) located on chromosome 14 at band q32 is genetically involved in many leukemias and lymphomas. Abnormalities of 14q32, specifically deletions within the region, can occur in CLL and are not readily visualized by karyotypic analysis. Early studies that utilized FISH testing to determine the frequency of chromosomal abnormalities associated with prognostic significance in CLL did not study the IGH gene region, and other studies targeted the region with a less informative FISH probe that was unable to detect smaller deletions in this region. Consequently, the reported frequency of deletions of 14q32 varies greatly in the literature, with an incidence range of 2–24 %; however, not all studies separated the differences between unique probe signal patterns observed with a dual-color break-apart probe to characterize these deletions, and hence the information regarding the types of 14q32 deletions in CLL may be skewed [5,[10], [11], [12]]. The dual-color break-apart FISH probe (Abbott Molecular) can distinguish between 5′ partial and complete telomeric deletions as well as 3′ centromeric deletions of 14q32.

More recently, microarray has been used to determine the genomic variation in CLL [7,9,[13], [14], [15]]. Microarray can help delineate a complex karyotype and increase the detection of sub-microscopic deletions/duplications that would otherwise go unnoticed by traditional cytogenetics and predefined FISH panels [2,7,16,17]. CLL is primarily characterized by chromosomal gains and losses, which are easily detected by microarray [18]. Additionally, the SNP microarray can also detect copy-neutral loss-of-heterozygosity (CN-LOH) and genome-wide genomic instability that would be missed by karyotyping and FISH [19,20].

Karyotypic analysis and FISH combined with genomic microarray might produce a more comprehensive profile [7]. Previous studies have shown that IGH deletions are recurrent in CLL but occur at a lower frequency than other common abnormalities of CLL [5,[10], [11], [12]]. However, to the best of our knowledge, no studies have focused on the possible variation in the size of 5′ telomeric deletions and the genes involved. In this single-institution study, we have performed a comprehensive analysis utilizing karyotypes, FISH, and microarray to better define the frequency and size variations in deletions of 14q32 and have investigated the prognostic implications of 14q32 deletions in CLL by assessing the time-to-first-treatment (TTFT) among cases with and without 14q32 deletions.