CLL Tables: Regions of Recurrent Copy Number Change and CN-LOH

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Table 1 - Regions of Recurrent Copy Number Change in CLL (Literature Review). The is a list of clinically significant and/or recurrent CNAs selected and evaluated based on a systematic literature search performed on 72 peer-reviewed manuscripts focusing on CNAs and CN-LOH assessment in CLL published between 2000 and 2017. Table derived from Chun et al., 2018 [PMID 30554732] with permission from Cancer Genetics.

Chromosome/

Region

Abnormality Type Prevalence (%) Relevant Genes Strength of Evidence for Gene Prognostic Significance Strength of Evidence for Prognosis (Level*) Comments References
1p Gain ?2-5 Unknown N/A Favorable Suspected (2) [1] [2] [3]
1q23.2q23.3 Loss 15 Unknown N/A Unknown N/A (3) [4] [5] [6]
2p12p25.3 Gain 5-30 ACP1, MYCN, ALK, REL, BCL11A MYCN (Established), REL, BCL11A (Candidate) Unfavorable Established (if MYCN included) (1) [1] [2] [3] [4] [5] [7] [8] [9] [10] [11] [12] [13]
3p21.31 Loss 1-5 ATRIP, CDC25A Candidate Unknown N/A (3) [4] [14] [15]
3q Gain 2-19 Unknown N/A Unfavorable Suspected (2) Appears to be particularly prevalent in Japanese [2] [16] [17]
4p15.2p16.3 Loss 14 Unknown N/A Unfavorable (occurred with del(11q) or del(17p)) Suspected (2) [18]
6p25.3 Gain 1 Unknown N/A Unknown N/A (3) [4]
6p22.1 Loss 1 Histone cluster, HFE Candidate Unknown N/A (3) [4]
6q Loss 3-6 FOXO3 Candidate Intermediate Suspected (2) [19] [20] [21] [22]
7p Gain 5-6 Unknown N/A Intermediate Suspected (2) [2]
7q Loss 1-2 Unknown N/A Unknown N/A (3) [2] [10]
8p21 Loss 2-5 TRIM35 Candidate Unfavorable Suspected (2) Associated with established unfavorable changes (11q- and 17p-). Not established as an independent prognosticator [2] [23]
8q24.1 Gain 5 MYC Candidate Unfavorable Suspected (2) Often associated with 11q and 17p deletion; may not be independent [2] [2] [4]
9q13q21.11 Loss 1 Unknown N/A Unknown N/A (3) [4]
10q24 Loss 2 Unknown N/A Unknown N/A (3) Clustered around NFKB2 gene locus [4] [9] [24]
11q22.3 Loss 10-20 ATM, BIRC3, MRE11, H2AFX ATM established, Others Candidate Unfavorable Established (1) [25]
12 Gain 10-20 Unknown N/A Intermediate Established (1) Unfavorable if NOTCH1 mutation is present [25]
13q14 Loss 50-60 DLEU2, MIR15A, MIR16-1, DLEU1 Established Favorable Established (1) Co-deletion of RB1 may negatively impact time to treatment [25] [26] [27]
14q24.1q32.3 Loss 2 Unknown N/A Unknown N/A (3) Associated with trisomy 12 [4] [28] [29]
15q15.1 Loss 4 MGA Candidate Unknown N/A (3) [4] [9]
17p13.1 Loss 5-15 TP53 Established Unfavorable Established (1) [25]
17q Gain 1 Unknown N/A Unfavorable Suspected (2) [2]
18p Loss 3 Unknown N/A Unfavorable Suspected (2) [2] [4]
18 Gain 4 Unknown N/A Unfavorable Established (1) Associated with trisomy 12 [30]
19 Gain 2-5 Unknown N/A Unfavorable Established (1) Associated with trisomy 12 [4] [9] [18] [24] [30]
Genomic complexity 3 or more CNAs 10-15 N/A Unfavorable Established (1) [9] [10] [14] [31]
Chromothripsis (>10 copy number states of 2 and 3) 5 SETD2, other markers across genome not defined Established Unfavorable Established (1) [4] [27] [32]

*Level 1: present in WHO classification or professional practice guidelines; Level 2: recurrent in well-powered studies with suspected clinical significance; Level 3: recurrent, but uncertain prognostic significance.

Abbreviations: CNA = copy number aberration; CLL = chronic lymphocytic leukemia; CN-LOH = copy-neutral loss-of-heterozygosity


Table 2 - Recurring regions of CN-LOH in CLL. Table derived from Chun et al., 2018 [PMID 30554732] with permission from Cancer Genetics.

CN-LOH Candidate Gene Association Strength of Evidence for Prognosis (Level*) References
13q miR15a/16-1 Biallelic deletion of 13q Established (1) [33] [34] [35] [36] [37] [38] [39] [40]
17p13 TP53 Homozygous TP53 mutations Established (1) [33] [35] [41] [38] [42]
11q13-qter Includes ATM Monoallelic ATM deletion Suspected (2) [35] [38]
20q11 Unknown None N/A (3) [41] [43]
1p36 Unknown None N/A (3) [35] [44]

*Level 1: present in WHO classification or professional practice guidelines; Level 2: recurrent in well-powered studies with suspected clinical significance; Level 3: recurrent, but uncertain prognostic significance


Table 3 - Recurrent mutated genes in CLL. Table derived from Chun et al., 2018 [PMID 30554732] with permission from Cancer Genetics.

Gene Locus Function Mutation Type Prevalence (%) Prognostic Significance Strength of Evidence (Level*) Comments References
ATM 11q22.3 DNA repair and cell-cycle control Missense, nonsense, indel 10-14 Unfavorable Established (1) Associated with unmutIGHV and 11q-; Candidate driver gene [45] [46]
BIRC3 11q22.2 Apoptosis inhibitor Frameshift, nonsense, whole gene deletion 1-10

(higher in previously treated patients)

Unfavorable Established (1) In ~25% of fludarabine-refractory CLL; Candidate driver gene [47] [48] [49] [50]
CHD2 15q26.1 Chromatin remodeler Missense, truncation 5-10 Unknown N/A (3) [47] [51]
FBXW7 4q31.3 Ubiquitin ligase subunit/targets include NOTCH1 Missense 4 Unknown N/A (3) Exclusive to NOTCH1 mutation patients; Negatively regulates NOTCH1 [52]
MYD88 3p22.2 Inflammatory pathway signal transducer Missense 2-10 Favorable/

No effect

Suspected (2) Candidate driver gene [49] [50] [53]
NOTCH1 9q34.3 Intercellular signaling Missense, nonsense, insertion, duplication, frameshift 4-10

(diagnosis)

12-30

(progression)

Unfavorable Established (1) Associated with +12; Candidate driver gene [54] [46] [50] [55] [56]
POT1 7q31.33 Telomere protector/

stabilizer; component of telomerase RNP complex

Missense, frameshift, splicing 5-10 Unfavorable Suspected (2) Associated with familial CLL [57] [58] [59]
SF3B1 2q33.1 Spliceosome component Missense 10 -18 Unfavorable Established (1) Enriched in patients with del(11q) and unmutIGHV; Candidate driver gene for disease progression [49] [50] [60] [61] [62]
TP53 17p13.1 DNA repair and cell-cycle control Missense 5-10

(higher with progressive disease)

Unfavorable Established (1) [45] [47] [63] [64] [65]
XPO1 2p15 Exports proteins/RNA fragments from nucleus into cytoplasm Missense 5-7.5 Unfavorable/

high risk of progression

Suspected (2) Associated with unmutIGHV [66] [53] [67]

*Level 1: present in WHO classification or professional practice guidelines; Level 2: recurrent in well-powered studies with suspected clinical significance; Level 3: recurrent, but uncertain prognostic significance

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