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Table of Contents
Year : 2022  |  Volume : 5  |  Issue : 1  |  Page : 46-51

A peek into the world of CLL genomics

1 Department of Laboratory, Transfusion and Molecular Services, New Delhi, India
2 Molecular Diagnostics, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India

Date of Submission27-May-2022
Date of Decision19-Jul-2022
Date of Acceptance26-Jul-2022
Date of Web Publication02-Sep-2022

Correspondence Address:
Dr. Himanshi Diwan
Department of Laboratory, Transfusion and Molecular Services, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jco.jco_6_22

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Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in adults in the Western Hemisphere. The divergent course of CLL has instigated a deeper look into CLL genetics. Consequently, many prognostic and predictive biomarkers have emerged. This is a brief review of the CLL genetics, including genes involved in drug resistance.

Keywords: CLL, DNA, FISH, NGS

How to cite this article:
Mehta A, Diwan H, Mattoo S. A peek into the world of CLL genomics. J Curr Oncol 2022;5:46-51

How to cite this URL:
Mehta A, Diwan H, Mattoo S. A peek into the world of CLL genomics. J Curr Oncol [serial online] 2022 [cited 2024 Feb 28];5:46-51. Available from: http://www.https://journalofcurrentoncology.org//text.asp?2022/5/1/46/355589

  Introduction Top

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world, with an annual incidence rate of 5 per lakh.[1] The incidence rate of CLL in India is reported to be 0.4 per lakh.[2] CLL is defined as the peripheral monoclonal B cell count of 5 × 109/L with a distinctive morphology and immunophenotype.[1] The peripheral monoclonal B cell count of less than 5 × 109/L without nodal or extramedullary involvement is classified as monoclonal B cell lymphocytosis, whereas the clonal B cell count of less than 5 × 109/L with organomegaly or nodal or extramedullary disease is classified as small lymphocytic lymphoma.[1] The median patient age at diagnosis is approximately 70 years.[3] The clinical heterogeneity of the disease sent the hematologists on the molecular biology trail with the aim of risk stratification and targeted therapy.

This is a concise review of the molecular pathology of CLL. Shown in [Table 1] and [Table 2], respectively, are the National Comprehensive Cancer Network (NCCN) guidelines for prognostic information and the CLL-International Prognostic Index (IPI).
Table 1: NCCN guidelines for prognostic information in CLL

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Table 2: CLL-IPI stratification system

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The genetic alterations in CLL can occur at the structural and molecular levels. The unfolding of CLL genetics began in 2000 by Döhner et al.[4] with the identification of predictive and prognostic cytogenetics alterations on fluorescence in-situ hybridization (FISH), which included deletion of the long arm of chromosome 13(13q14), 11q, 17p deletions, and trisomy 12[4] [Table 3].
Table 3: Most frequent cytogenetic aberrations in CLL

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The structural alterations are primarily in the form of deletions resulting in the loss of function of tumor suppressor genes/miRNAs. The most common structural aberration in CLL is deletion 13q14, seen in more than 50% of CLL patients.[5] The 13q14 deletion which is considered an initiating event is targeting DLEU2 and DLEU7 genes/miR-15a and miR-16-1, abolishing the inhibitory effect of the DLEU7 gene, thus constitutively activating the NF-kB pathway.[4] Contrary to this, in our experience, we have found that many cases show a subclonal population (10–15%) showing del13q14, proving that this alteration may not be the driver event always. Del13q14, when present alone, is associated with a good prognosis.[6] These patients tend to have somatic hypermutated phenotype and prolonged median overall survival (OS) rate and a progression rate of less than 1% per year.[7],[8] It can be associated with a mutation in myeloid differentiation primary response 88 (MYD88) (2–10% of cases), with L265P being the most common[9],[10],[11],[12],[13] [Figure 1].[14],[15]MYD88 associates with IL1R-associated kinase 4 (IRAK4) when stimulated by toll-like receptors or IL1R, resulting in IRAK1 phosphorylation and its degradation, activating nuclear factor (NF)-κB signaling.[10] This is frequently associated with immunoglobulin heavy variable gene (IGHV) mutated patients[9],[11] and has a good prognosis in contrast to other B cell malignancies with the same mutation.
Figure 1: Lolliplot (adopted from cbioportal.org) clearly shows the dominance of the L265P mutation in the MYD88 gene.[14],[15]

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The next frequent structural abnormality in CLL is trisomy 12, encountered in approximately 16% of the diagnosed patients.[16]The mouse double minute 2 homolog (MDM2) gene located on chromosome 12 is presumed to be instrumental owing to its role in the suppression of TP53; however, contrary view exists.[9],[17] It confers an intermediate prognostic risk and is frequently associated with NOTCH1 mutation. The most frequently encountered NOTCH1 mutation is a 2-bp frameshift deletion (c.7541_7542delCT) in exon 34 in CLL, resulting in a premature stop codon and hence deletion of the PEST domain (P2514fs*4), increasing the half-life of intracellular domain of NOTCH1 (ICN1) protein. Other mutations in NOTCH1 are summarized in [Table 4]. This corresponds to a progressive clinical course and Richter transformation.[3],[6],[18]
Table 4: Most frequent mutations in NOTCH1

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Deletion of the long arm of chromosome 11 (11q22–23) and the short arm of chromosome 17 (17p13) confers an unfavorable outcome in CLL patients. Deletion of 11q22–23 is observed in less than 10% of CLL at the time of diagnosis, whereas the prevalence increases to approximately 20% at the time of treatment and 30% at relapse.[5] The deleted 11q23 region harbors the Ataxia Telangiectasia Mutated (ATM) gene, involved in the deoxyribonucleic acid (DNA) damage repair pathway. About 30% of these 11q-deleted CLL patients encompassed ATM mutations in the remaining allele.[19],[20],[21] These patients exhibit unmutated somatic IGHV phenotype, a rapidly progressive disease course with bulky lymphadenopathy, and a poor prognosis.[5] The most frequent clinically significant ATM variants affect the PI-3-K domain of ATM.[22] Most of the mutations are truncating, followed by missense mutations [Figure 2].[14],[15]
Figure 2: Lolliplot showing hotspot regions of ATM mutations[14],[15]

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The germline mutation of the ATM gene can be rarely seen in CLL. The germline heterozygosity of ATM, however, predisposes to rapid progression of the disease through successive del11q34, resulting in functional loss of ATM function. ATM mutations are also encountered in CLL without evidence of chromosomal 11q deletion, indicating that ATM can be disrupted by mutation, deletion, or both. ATM mutation co-occurs with SF3B1 mutation and is mutually exclusive with TP53 mutation. Several studies have suggested the role of poly(ADP-ribose) polymerase inhibitors in treatment-refractory ATL mutant CLL.[23]

Loss of function in the TP53 gene is observed in 4–8% of CLL by deletions, mutations, or both at the time of diagnosis, and the incidence increases with the temporal evolution of the disease. TP53 aberration is estimated to be around 10% at the time of first-line treatment. About 30–40% of refractory/relapsed CLL harbors TP53 loss of function with an incidence of 50–60% in the case of Richter transformation,[5] illustrating the clonal evolution of TP53 in the disease. CLL with del17p13 has a dismal prognosis with an estimated median OS of 3–5 years.[8] As the deletion is monoallelic, biallelic inactivation of TP53 can be explained by the associated mutation in one allele and deletion in another in more than 80% of the CLL cases with del 17p13. TP53 mutations include missense or nonsense mutations, indels, or splice-site mutations. The modifications are often observed in the DNA binding domain encoded by exons 4–8, followed by the oligomerization or C-terminal domain of the TP53 gene.[24] The prime hotspot regions described in the literature are codons 175, 245, 248, 249, 273, and 282.[24],[25] The mutated p53 protein exerts a dominant-negative effect. It hampers the tumor suppressive role of the wild-type allele, thus explaining the putative pathogenic effect even in the case of monoallelic TP53inactivation.[26] At least exons 4–10 should be sequenced; however, the sequencing of exons 2–11 is highly recommended.[24] The TP53 Network of European Research Initiative on Chronic Lymphocytic Leukemia (ERIC)[24] recommends reporting TP53 mutations with a variant allele frequency (VAF) of more than 10%, given the lack of evidence of any therapeutic benefit in patients with low VAF. Thus, a note should always be stated while reporting variants at a VAF less than 10%.

Patients having TP53 abnormalities do not respond to the conventional chemotherapy regime as the TP53 inactivation prohibits apoptosis of leukemic cells with chemotherapy-induced DNA damage. Ibrutinib, acalabrutinib, idelalisib, and venetoclax are effective given their antileukemic effect through other mechanisms.[27],[28],[29],[30],[31] Acalabrutinib has also been studied to be effective in relapsed/refractory cases.

Other frequent mutations in CLL are found in SF3B1 and BIRC3. Both are associated with IGHV-unmutated phenotype and an unfavorable outcome. SF3B1, located on chromosome 2q33, is one of CLL’s most identified somatic mutations (14.3%), among other reported CLL-associated driver mutations. It has a lower incidence in the early stages of CLL and occurs more commonly in advanced diseases. These patients have short survival and rapid disease progression. Eventually, this can be used as a prognostic marker to improve the prediction of disease progression.[32],[33] Most mutations in SF3B1 are present in its C-terminal domain, which comprises 22 Huntington Elongation Factor 3 PR65/A TOR (HEAT) repeats. Most mutations have been detected between the fifth and eighth HEAT repeats (encoded by exons 14–16), with K700E as the most frequently mutated site. Additionally, G742, K666, and H662 are other hotspots for mutation.[32]

Baculoviral IAP repeat containing 3 (BIRC3) is located on chromosome 11q22.2 in propinquity to the ATM gene, 6 Mb centromeric to the latter, and is found in 3–5% of treatment-naive CLL cases.[34],[35]BIRC3 mutations are mostly truncating [Figure 3][14],[15] and cause constitutive activation of the non-canonical NF-κB pathway. BIRC3 is responsible for proteasomal degradation of MAP3K14 and acts as a checkpoint to avoid constant activation of NF-κB. Deleting 11q22-23 or non-sense or frameshift termination mutation in BIRC3 removes the C-terminal RING domain responsible for ubiquitination and thus proteasomal degradation of MAP3K14. Due to the rarity of this mutation, only limited data are available about the prognostic role of BIRC3. However, the mutation has not been observed to impact a poor prognosis compared with del17p/TP53-mutated cases.[34],[35],[36] Few studies postulate that BIRC3 mutation may cause refractoriness to chemotherapy as in TP53.[37] The BIRC3 mutation can also co-occur with NOTCH1 mutations.
Figure 3: Lolliplot showing frequent BIRC3 mutations[14],[15]

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Despite the availability of targeted drugs against CLL, many patients fail to respond to therapy. Acquired mutation in the Bruton tyrosine kinase (BTK) gene has been described in CLL patients relapsing on ibrutinib,[38] with C481S being the most common mutation disrupting the binding site of the drug.[38] Ibrutinib irreversibly binds to BTK and hinders the downstream signaling activated by the NF-κB pathway. Phospholipase C gamma 2 (PLCG2) mutations are the second most common mutation after BTK in CLL patients with ibrutinib failure.[39] The PLCG2 gene encodes Cγ2, the protein involved in the BTK driven pathway resulting in constitutive BCR signaling.[39],[40] These mutations are described in 80% of the ibrutinib-resistant CLL patients. Del8p, del18p, del17p, the mutation in SF3B1, BIRC3, EIF2A, and MYC amplification are other changes described in treatment-resistant CLL cases.

The summary of CLL genomics is elucidated in [Figure 4], and a detailed overview of detection methods for genomic alterations in CLL is described in [Table 5].
Figure 4: Summary of CLL genomics

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Table 5: Detailed overview of detection methods of various genomic aberrations in CLL

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  Conclusion Top

Genomic approaches have provided a detailed and comprehensible picture of somatic alterations in CLL and the association of the mutational profile of CLL with the prognosis. This is a concise review of structural and genomic alterations in CLL with relevance to the clinical and prognostic profile. TP53 aberrations (structural as well as molecular), del11q, complex karyotype, and mutations in ATM, SF3B1 and BIRC3 are associated with a grim prognosis. In contrast, trisomy 12 and NOTCH1 mutations are associated with intermediate prognosis, and CLL patients with isolated del13q14 and MYD88 mutations have favorable outcomes. Somatic hypermutation of IGHV portends a better prognosis.


All the lolliplots have been adopted from cbioportal.org.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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