CLL Tables: Regions of Recurrent Copy Number Change and CN-LOH
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
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
Reference
- ↑ 1.0 1.1 D, Pfeifer; et al. (2007). "Genome-wide analysis of DNA copy number changes and LOH in CLL using high-density SNP arrays". PMID 17053054.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 J, Houldsworth; et al. (2014). "Genomic imbalance defines three prognostic groups for risk stratification of patients with chronic lymphocytic leukemia". doi:10.3109/10428194.2013.845882. PMC 6905429. PMID 24047479.CS1 maint: PMC format (link)
- ↑ 3.0 3.1 E, Chapiro; et al. (2010). "Gain of the short arm of chromosome 2 (2p) is a frequent recurring chromosome aberration in untreated chronic lymphocytic leukemia (CLL) at advanced stages". PMID 19406473.
- ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 J, Edelmann; et al. (2012). "High-resolution genomic profiling of chronic lymphocytic leukemia reveals new recurrent genomic alterations". PMID 23047824.
- ↑ 5.0 5.1 D, Ma; et al. (2011). "Array comparative genomic hybridization analysis identifies recurrent gain of chromosome 2p25.3 involving the ACP1 and MYCN genes in chronic lymphocytic leukemia". doi:10.1016/j.clml.2011.03.031. PMC 4845643. PMID 22035742.CS1 maint: PMC format (link)
- ↑ A, Tyybakinoja; et al. (2007). "High-resolution oligonucleotide array-CGH pinpoints genes involved in cryptic losses in chronic lymphocytic leukemia". PMID 17901694.
- ↑ L, Shao; et al. (2010). "Array comparative genomic hybridization detects chromosomal abnormalities in hematological cancers that are not detected by conventional cytogenetics". doi:10.2353/jmoldx.2010.090192. PMC 2928432. PMID 20724749.CS1 maint: PMC format (link)
- ↑ A, Patel; et al. (2008). "Validation of a targeted DNA microarray for the clinical evaluation of recurrent abnormalities in chronic lymphocytic leukemia". PMID 18161787.
- ↑ 9.0 9.1 9.2 9.3 9.4 Mj, Stevens-Kroef; et al. (2014). "Identification of prognostic relevant chromosomal abnormalities in chronic lymphocytic leukemia using microarray-based genomic profiling". doi:10.1186/1755-8166-7-3. PMC 3905918. PMID 24401281.CS1 maint: PMC format (link)
- ↑ 10.0 10.1 10.2 Cd, Schweighofer; et al. (2013). "Genomic variation by whole-genome SNP mapping arrays predicts time-to-event outcome in patients with chronic lymphocytic leukemia: a comparison of CLL and HapMap genotypes". doi:10.1016/j.jmoldx.2012.09.006. PMC 3586684. PMID 23273604.CS1 maint: PMC format (link)
- ↑ S, Fabris; et al. (2013). "Chromosome 2p gain in monoclonal B-cell lymphocytosis and in early stage chronic lymphocytic leukemia". PMID 23044996.
- ↑ F, Forconi; et al. (2008). "Genome-wide DNA analysis identifies recurrent imbalances predicting outcome in chronic lymphocytic leukaemia with 17p deletion". PMID 18752589.
- ↑ M, Jarosova; et al. (2010). "Gain of chromosome 2p in chronic lymphocytic leukemia: significant heterogeneity and a new recurrent dicentric rearrangement". PMID 20078324.
- ↑ 14.0 14.1 Ka, Kolquist; et al. (2011). "Evaluation of chronic lymphocytic leukemia by oligonucleotide-based microarray analysis uncovers novel aberrations not detected by FISH or cytogenetic analysis". doi:10.1186/1755-8166-4-25. PMC 3253687. PMID 22087757.CS1 maint: PMC format (link)
- ↑ I, Salaverria; et al. (2015). "Detection of chromothripsis-like patterns with a custom array platform for chronic lymphocytic leukemia". doi:10.1002/gcc.22277. PMC 4832286. PMID 26305789.CS1 maint: PMC format (link)
- ↑ N, Kawamata; et al. (2013). "Genetic differences between Asian and Caucasian chronic lymphocytic leukemia". doi:10.3892/ijo.2013.1966. PMC 3775563. PMID 23708256.CS1 maint: PMC format (link)
- ↑ K, Tsukasaki; et al. (2006). "Comparative genomic hybridization analysis of Japanese B-cell chronic lymphocytic leukemia: correlation with clinical course". PMID 16321855.
- ↑ 18.0 18.1 R, Gunnarsson; et al. (2011). "Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia". doi:10.3324/haematol.2010.039768. PMC 3148910. PMID 21546498.CS1 maint: PMC format (link)
- ↑ A, Cuneo; et al. (2004). "Chronic lymphocytic leukemia with 6q- shows distinct hematological features and intermediate prognosis". PMID 14712287.
- ↑ Dm, Wang; et al. (2011). "Intermediate prognosis of 6q deletion in chronic lymphocytic leukemia". PMID 21281237.
- ↑ M, Jarosova; et al. (2017). "Chromosome 6q deletion correlates with poor prognosis and low relative expression of FOXO3 in chronic lymphocytic leukemia patients". PMID 28699185.
- ↑ C, Nabhan; et al. (2015). "Predicting Prognosis in Chronic Lymphocytic Leukemia in the Contemporary Era". PMID 26181643.
- ↑ V, Grubor; et al. (2009). "Novel genomic alterations and clonal evolution in chronic lymphocytic leukemia revealed by representational oligonucleotide microarray analysis (ROMA)". PMID 18922857.
- ↑ 24.0 24.1 C, Schwaenen; et al. (2004). "Automated array-based genomic profiling in chronic lymphocytic leukemia: development of a clinical tool and discovery of recurrent genomic alterations". doi:10.1073/pnas.0304717101. PMC 327147. PMID 14730057.CS1 maint: PMC format (link)
- ↑ 25.0 25.1 25.2 25.3 Wg, Wierda; et al. (2017). "NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 1.2017". PMID 28275031.
- ↑ M, Dal Bo; et al. (2011). "13q14 deletion size and number of deleted cells both influence prognosis in chronic lymphocytic leukemia". PMID 21563234.
- ↑ 27.0 27.1 Sn, Malek (2013). "The biology and clinical significance of acquired genomic copy number aberrations and recurrent gene mutations in chronic lymphocytic leukemia". doi:10.1038/onc.2012.411. PMC 3676480. PMID 23001040.CS1 maint: PMC format (link)
- ↑ Pt, Greipp; et al. (2013). "Patients with chronic lymphocytic leukaemia and clonal deletion of both 17p13.1 and 11q22.3 have a very poor prognosis". doi:10.1111/bjh.12534. PMC 3907074. PMID 24032430.CS1 maint: PMC format (link)
- ↑ A, Cosson; et al. (2014). "14q deletions are associated with trisomy 12, NOTCH1 mutations and unmutated IGHV genes in chronic lymphocytic leukemia and small lymphocytic lymphoma". PMID 24729385.
- ↑ 30.0 30.1 R, Ibbotson; et al. (2012). "Coexistence of trisomies of chromosomes 12 and 19 in chronic lymphocytic leukemia occurs exclusively in the rare IgG-positive variant". PMID 21788947.
- ↑ Sr, Gunn; et al. (2008). "The HemeScan test for genomic prognostic marker assessment in chronic lymphocytic leukemia". PMID 23495782.
- ↑ H, Parker; et al. (2016). "Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia". doi:10.1038/leu.2016.134. PMC 5023049. PMID 27282254.CS1 maint: PMC format (link)
- ↑ 33.0 33.1 Hagenkord, Jill M.; et al. (2010-03). "Array-based karyotyping for prognostic assessment in chronic lymphocytic leukemia: performance comparison of Affymetrix 10K2.0, 250K Nsp, and SNP6.0 arrays". The Journal of molecular diagnostics: JMD. 12 (2): 184–196. doi:10.2353/jmoldx.2010.090118. ISSN 1943-7811. PMC 2871725. PMID 20075210. Check date values in:
|date=
(help) - ↑ Pfeifer, Dietmar; et al. (2007-02-01). "Genome-wide analysis of DNA copy number changes and LOH in CLL using high-density SNP arrays". Blood. 109 (3): 1202–1210. doi:10.1182/blood-2006-07-034256. ISSN 0006-4971. PMID 17053054.
- ↑ 35.0 35.1 35.2 35.3 Edelmann, Jennifer; et al. (2012-12-06). "High-resolution genomic profiling of chronic lymphocytic leukemia reveals new recurrent genomic alterations". Blood. 120 (24): 4783–4794. doi:10.1182/blood-2012-04-423517. ISSN 1528-0020. PMID 23047824.
- ↑ Grygalewicz, Beata; et al. (2016). "Monoallelic and biallelic deletions of 13q14 in a group of CLL/SLL patients investigated by CGH Haematological Cancer and SNP array (8x60K)". Molecular Cytogenetics. 9: 1. doi:10.1186/s13039-015-0212-x. ISSN 1755-8166. PMC 4702365. PMID 26740820.
- ↑ Gunnarsson, Rebeqa; et al. (2011-08). "Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia". Haematologica. 96 (8): 1161–1169. doi:10.3324/haematol.2010.039768. ISSN 1592-8721. PMC 3148910. PMID 21546498. Check date values in:
|date=
(help) - ↑ 38.0 38.1 38.2 Parker, H.; et al. (2011-03). "13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia". Leukemia. 25 (3): 489–497. doi:10.1038/leu.2010.288. ISSN 1476-5551. PMID 21151023. Check date values in:
|date=
(help) - ↑ Lehmann, Sören; et al. (2008-03-15). "Molecular allelokaryotyping of early-stage, untreated chronic lymphocytic leukemia". Cancer. 112 (6): 1296–1305. doi:10.1002/cncr.23270. ISSN 0008-543X. PMID 18246537.
- ↑ Ouillette, Peter; et al. (2011-11-01). "The prognostic significance of various 13q14 deletions in chronic lymphocytic leukemia". Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 17 (21): 6778–6790. doi:10.1158/1078-0432.CCR-11-0785. ISSN 1078-0432. PMC 3207001. PMID 21890456.
- ↑ 41.0 41.1 Stevens-Kroef, Marian Jpl; et al. (2014-01-09). "Identification of prognostic relevant chromosomal abnormalities in chronic lymphocytic leukemia using microarray-based genomic profiling". Molecular Cytogenetics. 7 (1): 3. doi:10.1186/1755-8166-7-3. ISSN 1755-8166. PMC 3905918. PMID 24401281.
- ↑ Saddler, Chris; et al. (2008-02-01). "Comprehensive biomarker and genomic analysis identifies p53 status as the major determinant of response to MDM2 inhibitors in chronic lymphocytic leukemia". Blood. 111 (3): 1584–1593. doi:10.1182/blood-2007-09-112698. ISSN 0006-4971. PMID 17971485.
- ↑ Pei, Jianming; et al. (2014-03). "Copy neutral loss of heterozygosity in 20q in chronic lymphocytic leukemia/small lymphocytic lymphoma". Cancer Genetics. 207 (3): 98–102. doi:10.1016/j.cancergen.2014.02.005. ISSN 2210-7762. PMC 4010307. PMID 24704113. Check date values in:
|date=
(help) - ↑ Xu, Xinjie; et al. (2013-09). "The advantage of using SNP array in clinical testing for hematological malignancies--a comparative study of three genetic testing methods". Cancer Genetics. 206 (9–10): 317–326. doi:10.1016/j.cancergen.2013.09.001. ISSN 2210-7762. PMID 24269304. Check date values in:
|date=
(help)