Download The genomic landscape of chronic lymphocytic leukemia: clinical

The
genomic
landscape
of
chronic
lymphocytic
leukemia:
clinical
implications
Quesada V et al BMC Med. 2013;11:124.
The last 10-15 years has been marked by the identification of a number of
genetic biomarkers (eg IgVH mutational status and presence of genomic
mutations) which may be used to predict the clinical course of CLL. However,
although these provide insight into the biology of the disease, the genomic events
that underpin the initiation and evolution of the disease are less well understood.
This review article from the Oviedo group in Spain summarises some of the
recent
important
work
undertaken
by
the
International
Cancer
Genome
Consortium (ICGC) and the Cancer Genome Atlas (TCGA) using large scale next
generation sequencing technology has been more recently used to identify novel
genetic drivers of CLL.
Comparing the sequences of the entire genome or known coding regions (the
exome) between tumour cells and germline cells or different subsets of tumour
cells (eg mutated vs unmutated IgVH) allows identification of somatic point
mutations
which
are
known
to
be
an
important
component
of
cancer
development. The results of these studies identified a number of candidate genes
(including NOTCH1, MYD88, XPO1, KLHL6, and SF3B1) that may represent
genetic drivers to CLL. The importance of some of these genes (eg NOTCH1) in
CLL pathogenesis has previously been described although for others, this work
has identified other pathways (eg RNA splicing) that are important in CLL
development and that could be therapeutically targeted.
How best to use these data? The first drawback is that even the highest mutation
frequencies are relatively uncommon (NOTCH1 and SF3B1 are mutated in 4%
and 10% of cases of CLL respectively) with a long tail of very low frequency
events. Some of these (eg deletions of 13q14) are likely to be of limited clinical
significance; moreover many patients will not harbour any of the currently
characterised mutations. Secondly, the genetic landscape of CLL in an individual
patient is subject to variation; clonal evolution occurs in response to therapy and
as such subclones harbouring significant genetic mutations may only become
apparent over time. Thirdly, the frequency of a mutation does not correlate with
its potential significance; CLL is a heterogenous disorder and as such rare
mutations may be of significance for subsets of patients.
These data provide a tantalising insight into the biology of CLL and potential
future directions for treatment. Dysregulation of key genes acting as drivers to
CLL development appear to have a pivotal role in the pathogenesis of the disease,
and identification of these factors at an early stage may allow for more effective
targeted therapy. It is however apparent that CLL is driven by multiple
independent biological pathways and as such there is still much to be done before
this type of genomic information can be effectively utilised for personalised
treatment.
Immunogenetics shows that not all MBL are equal: the larger the clone,
the more similar to CLL
Vardi A et al Blood. 2013;121:4521.
The existence of monoclonal B cell proliferation in asymptomatic individuals
(termed monoclonal B-cell lymphocytosis – MBL) is well described although the
cut-off for diagnosis, based on level of circulating monoclonal lymphocytosis, is
uncertain. Moreover, although this has been categorised as a premalignant state
analogous to the relationship between monoclonal gammopathy of undetermined
significance (MGUS) and myeloma, the rate of progression from MBL to CLL is
variable and dependent on the level of clonal lymphocytes present in peripheral
blood. In patients with MBL >0.5x109/l (termed high count MBL – HC-MBL)
around 1-4% may be expected to progress to clinically apparent CLL requiring
treatment per year, whereas MBL <0.5x109/l (low count MBL – LC-MBL) appears
to persist over time typically without clinical progression.
The reasons for the differences in the behaviour of LC-MBL and HC-MBL are
uncertain. This study assessed IgVH repertoire and B cell receptor (BcR)
stereotypy in over 300 cases of MBL from a number of European Centres. The
results of this analysis demonstrated firstly that the frequency of unmutated IgVH
sequence (germline homology ≥98%) between LC-MBL and HC-MBL was similar
(around 25%) and less than that observed in cases of CLL (45%), although the
immunoglobulin gene repertoire employed was markedly different (eg suppressed
frequency of IGVHV1-69 and over-representation of IGVHV4-59/61 in cases of
LC-MBL). Secondly, comparison of the frequency of CLL specific BcR stereotypes
between LC-MBL and HC-MBL demonstrated a significantly greater frequency of
BcR stereotypy in HC-MCL (21.9% - similar to that in stage 0 CLL) than in LCMCL (5.5%).
The results of this study suggest for the first time that LC-MBL and HC-MBL are
biologically distinct entities and suggest that the increasing BcR stereotypy
observed in larger clones may underpin their different clinical behaviour. It would
however also be possible to contend that LC-MBL may in fact have little relation
to CLL and should be better be regarded as a physiological process related to
ageing based on the pattern of IgVH expression eg the over-representation of
IGVH4-59/61 (more common in the elderly) and lack of BcR stereotypy. Balanced
against this contention is the previously published observation that LC-MBL and
HC-MBL both harbour the same recurrent genetic mutations (deletions of 17p13,
11q23, 13q14 and trisomy 12) which are frequently observed in CLL. The authors
speculate that that the genetic mutations may be acquired early in the timeline of
MBL as a result of chronic antigenic stimulation (supported by the multiple
productive IgVH rearrangements observed in LC-MBL cases) and leading to an
aberrant phenotype, but that additional genetic cofactors are required to drive
progression to HC-MBL or CLL. This remains a hypothesis and further work would
be needed to elucidate why some LC-MBL clones are contained whilst others
transit rapidly to HC-MBL or a disease phenotype.
A diagnosis of LC-MBL can only be made using high sensitivity flow cytometry due
to the small size of the B-cell clone (typically <0.001x109/l) and taken together
with the apparent lack of progression over time, this disease classification is not
of significance for research rather than clinical practice. Nonetheless, the
observations that MBL is not a priori a pre-malignant disease provides further
insight into the ontogeny of CLL.