Compendium of Cancer Genome Aberrations

HAEM5:Chronic lymphocytic leukaemia/small lymphocytic lymphoma: Difference between revisions

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{{DISPLAYTITLE:Chronic lymphocytic leukaemia/small lymphocytic lymphoma}}
{{DISPLAYTITLE:Chronic lymphocytic leukaemia/small lymphocytic lymphoma}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]


{{Under Construction}}
<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma]].
}}</blockquote>
==Primary Author(s)*==
==Primary Author(s)*==
Jamie Nagy, PhD, University of Iowa
Jaime Nagy, PhD, University of Iowa


Honey Reddi, PhD
Renee Eigsti, MD, Pathology Services of Kalamazoo
__TOC__


==Cancer Category / Type==
Honey Reddi, PhD, Belay Diagnostics
==WHO Classification of Disease==


Mature B-cell neoplasms
{| class="wikitable"
 
!Structure
==Cancer Sub-Classification / Subtype==
!Disease
 
|-
Put your text here
|Book
|Haematolymphoid Tumours (5th ed.)
|-
|Category
|B-cell lymphoid proliferations and lymphomas
|-
|Family
|Mature B-cell neoplasms
|-
|Type
|Pre-neoplastic and neoplastic small lymphocytic proliferations
|-
|Subtype(s)
|Chronic lymphocytic leukaemia/small lymphocytic lymphoma
|}


==Definition / Description of Disease==
==Related Terminology==


This is a distinct entity in the 2016 World Health Organization (WHO) classification system<ref>Campo E, et al., (2017). Chronic lymphocytic leukemia/small lymphocytic lymphoma, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p216-221.</ref>. Chronic Lymphocytic Leukemia (CLL) is a chronic lymphoproliferative disorder characterized by monoclonal B cell proliferation.   
'''CLL Tables''' - A list of clinically significant and/or recurrent CNAs and CN-LOH with potential or strong diagnostic, prognostic and treatment implications in CLL. Table derived from Chun et al., 2018 [<ref>{{Cite journal|last=K|first=Chun|last2=Gd|first2=Wenger|last3=A|first3=Chaubey|last4=Dp|first4=Dash|last5=R|first5=Kanagal-Shamanna|last6=S|first6=Kantarci|last7=R|first7=Kolhe|last8=Dl|first8=Van Dyke|last9=L|first9=Wang|date=2018|title=Assessing copy number aberrations and copy-neutral loss-of-heterozygosity across the genome as best practice: An evidence-based review from the Cancer Genomics Consortium (CGC) working group for chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/30554732/|language=en|pmid=30554732}}</ref>] with permission from Cancer Genetics. See [[CLL Tables: Regions of Recurrent Copy Number Change and CN-LOH]]. 
==Synonyms / Terminology==
Chronic lymphocytic leukaemia, B―cell type; chronic lymphoid leukaemia; chronic lymphatic leukaemia
==Epidemiology / Prevalence==
It is the most common adult leukemia in Western populations,  comprising 25% to 30% of all leukemias in the United States.  The median age at diagnosis is 70 years. CLL occurrence is more prevalent in anglo americans and much lower in asian populations<ref name=":0">Taneja A, Master SR. (2017) Cancer, Leukemia, Lymphocytic, Chronic (CLL)  SourceStatPearls [I. Treasure Island (FL): StatPearls Publishing. <nowiki>https://www.ncbi.nlm.nih.gov/books/NBK470433/</nowiki>.</ref>.
==Clinical Features==
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|+
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
|Acceptable
 
|B-cell chronic lymphocytic leukaemia / small lymphocytic lymphoma
EXAMPLE B-symptoms (weight loss, fever, night sweats)
 
EXAMPLE Fatigue
 
EXAMPLE Lymphadenopathy (uncommon)
|-
|-
|'''Laboratory Findings'''
|Not Recommended
|EXAMPLE Cytopenias
|N/A
 
EXAMPLE Lymphocytosis (low level)
|}
|}


 
==Gene Rearrangements==
<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
 
Most (90%) patients with CLL are asymptomatic and only 5-10% of patients with CLL present with symptoms of fever, weight loss, night sweats, and/or fatigue<ref name=":0" />.
 
</blockquote>
==Sites of Involvement==
CLL/SLL involves the blood, bone marrow, and secondary lymphoid tissues such as the spleen, lymph nodes, and Waldeyer ring. Extranodal involvement
 
(e.g. of the skin, gastrointestinal tract, or CNS) occurs in a small subset of cases<ref>{{Cite journal|last=M|first=Ratterman|last2=K|first2=Kruczek|last3=S|first3=Sulo|last4=Td|first4=Shanafelt|last5=Ne|first5=Kay|last6=C|first6=Nabhan|date=2014|title=Extramedullary chronic lymphocytic leukemia: systematic analysis of cases reported between 1975 and 2012|url=https://pubmed.ncbi.nlm.nih.gov/24064196/|language=en|pmid=24064196}}</ref>.
 
==Morphologic Features==
 
'''Lymph Nodes:''' Enlarged lymph nodes show diffuse architectural effacement by a proliferation of small lymphocytes with variably prominent scattered paler proliferation centers (pseudofollicles)<ref>Lennert K, editor. (1978). Malignant lymphomas other than Hodgkin’s disease. NewYork: Springer Verlag.</ref>. The predominant cell in the diffuse areas is a '''''typical CLL cell''''' (small lymphocyte with scant cytoplasm, and clumped chromatin). Proliferation centers are composed of small lymphocytes, prolymphocytes, and paraimmunoblasts. Mitotic activity is usually very low.
 
'''Bone Marrow:''' Biopsy may show interstitial, nodular, mixed (nodular and interstitial), or diffuse involvement. Diffuse involvement is usually associated with more advanced disease<ref>{{Cite journal|last=E|first=Montserrat|last2=N|first2=Villamor|last3=Jc|first3=Reverter|last4=Rm|first4=Brugués|last5=D|first5=Tàssies|last6=F|first6=Bosch|last7=Jl|first7=Aguilar|last8=Jl|first8=Vives-Corrons|last9=M|first9=Rozman|date=1996|title=Bone marrow assessment in B-cell chronic lymphocytic leukaemia: aspirate or biopsy? A comparative study in 258 patients|url=https://pubmed.ncbi.nlm.nih.gov/8611442/|language=en|pmid=8611442}}</ref>. Paratrabecular aggregates are not typical. Proliferation centers can be observed, although they are not as prominent as in lymph nodes, and follicular dendritic cells may be present<ref>{{Cite journal|last=M|first=Chilosi|last2=G|first2=Pizzolo|last3=F|first3=Caligaris-Cappio|last4=A|first4=Ambrosetti|last5=F|first5=Vinante|last6=L|first6=Morittu|last7=F|first7=Bonetti|last8=L|first8=Fiore-Donati|last9=G|first9=Janossy|date=1985|title=Immunohistochemical demonstration of follicular dendritic cells in bone marrow involvement of B-cell chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/3891066/|language=en|pmid=3891066}}</ref>. Most cases have > 30% CLL cells in the bone marrow aspirate<ref>{{Cite journal|last=M|first=Hallek|last2=Bd|first2=Cheson|last3=D|first3=Catovsky|last4=F|first4=Caligaris-Cappio|last5=G|first5=Dighiero|last6=H|first6=Döhner|last7=P|first7=Hillmen|last8=Mj|first8=Keating|last9=E|first9=Montserrat|date=2008|title=Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines|url=https://pubmed.ncbi.nlm.nih.gov/18216293/|language=en|doi=10.1182/blood-2007-06-093906|pmc=PMC2972576|pmid=18216293}}</ref>.
 
'''Peripheral Blood''': Smudge or basket cells are typically observed. In most cases, besides typical CLL cells, other lymphoid cells like prolymphocytes are also observed, but they usually constitute < 15% of the lymphoid cells.
 
==Immunophenotype==
Circulating leukemic B cells express CD19, low surface IgM/lgD, CD20, CD22, and CD79b. Additionally the markers below may be strongly expressed or absent.
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Finding!!Marker
!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
!Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''||<span class="blue-text">EXAMPLE:</span> ''BCR::ABL1''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)
|<span class="blue-text">EXAMPLE:</span> Common (CML)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
|<span class="blue-text">EXAMPLE:</span>
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).
|-
|-
|Positive (universal)||CD5, CD43 and strongly positive
|<span class="blue-text">EXAMPLE:</span> ''CIC''
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
|<span class="blue-text">EXAMPLE:</span> Typically, the last exon of ''CIC'' is fused to ''DUX4''. The fusion breakpoint in ''CIC'' is usually intra-exonic and removes an inhibitory sequence, upregulating ''PEA3'' genes downstream of ''CIC'' including ''ETV1'', ''ETV4'', and ''ETV5''.
|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)
|<span class="blue-text">EXAMPLE:</span> D
|
|<span class="blue-text">EXAMPLE:</span>


for CD23 and CD200
''DUX4'' has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
|-
|-
|Negative (universal)||CD10 is negative
|<span class="blue-text">EXAMPLE:</span> ''ALK''
FMC7 is usually negative or
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''


only weakly expressed.
|-
|Subset||CD5― or CD23―, FMC7+,


strong surface immunoglobulin, or
Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
|<span class="blue-text">EXAMPLE:</span> Fusions result in constitutive activation of the ''ALK'' tyrosine kinase. The most common ''ALK'' fusion is ''EML4::ALK'', with breakpoints in intron 19 of ''ALK''. At the transcript level, a variable (5’) partner gene is fused to 3’ ''ALK'' at exon 20. Rarely, ''ALK'' fusions contain exon 19 due to breakpoints in intron 18.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|<span class="blue-text">EXAMPLE:</span>


CD79b+<ref>{{Cite journal|last=A|first=Criel|last2=L|first2=Michaux|last3=C|first3=De Wolf-Peeters|date=1999|title=The concept of typical and atypical chronic lymphocytic leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/10194119/|language=en|pmid=10194119}}</ref>
Both balanced and unbalanced forms are observed by FISH (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Intragenic deletion of exons 2–7 in ''EGFR'' removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|
|-
|
|
|
|
|
|
|
|
|}
|}


==Chromosomal Rearrangements (Gene Fusions)==
Approximately 32-42% of CLL patients are found to have a translocation noted on conventional G-banding cytogenetics<ref name=":3">{{Cite journal|last=Baliakas|first=Panagiotis|last2=Iskas|first2=Michalis|last3=Gardiner|first3=Anne|last4=Davis|first4=Zadie|last5=Plevova|first5=Karla|last6=Nguyen-Khac|first6=Florence|last7=Malcikova|first7=Jitka|last8=Anagnostopoulos|first8=Achilles|last9=Glide|first9=Sharron|date=2014-03|title=Chromosomal translocations and karyotype complexity in chronic lymphocytic leukemia: a systematic reappraisal of classic cytogenetic data|url=https://pubmed.ncbi.nlm.nih.gov/24166834|journal=American Journal of Hematology|volume=89|issue=3|pages=249–255|doi=10.1002/ajh.23618|issn=1096-8652|pmid=24166834}}</ref><ref>{{Cite journal|last=Van Den Neste|first=E.|last2=Robin|first2=V.|last3=Francart|first3=J.|last4=Hagemeijer|first4=A.|last5=Stul|first5=M.|last6=Vandenberghe|first6=P.|last7=Delannoy|first7=A.|last8=Sonet|first8=A.|last9=Deneys|first9=V.|date=2007-08|title=Chromosomal translocations independently predict treatment failure, treatment-free survival and overall survival in B-cell chronic lymphocytic leukemia patients treated with cladribine|url=https://pubmed.ncbi.nlm.nih.gov/17541398|journal=Leukemia|volume=21|issue=8|pages=1715–1722|doi=10.1038/sj.leu.2404764|issn=0887-6924|pmid=17541398}}</ref><ref>{{Cite journal|last=Mayr|first=Christine|last2=Speicher|first2=Michael R.|last3=Kofler|first3=David M.|last4=Buhmann|first4=Raymund|last5=Strehl|first5=John|last6=Busch|first6=Raymonde|last7=Hallek|first7=Michael|last8=Wendtner|first8=Clemens-Martin|date=2006-01-15|title=Chromosomal translocations are associated with poor prognosis in chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/16179374|journal=Blood|volume=107|issue=2|pages=742–751|doi=10.1182/blood-2005-05-2093|issn=0006-4971|pmid=16179374}}</ref>. Balanced translocations involving ''IGH'' are uncommon (4-9% of patients)<ref>{{Cite journal|last=Cavazzini|first=Francesco|last2=Hernandez|first2=Jose Angel|last3=Gozzetti|first3=Alessandro|last4=Russo Rossi|first4=Antonella|last5=De Angeli|first5=Cristiano|last6=Tiseo|first6=Ruana|last7=Bardi|first7=Antonella|last8=Tammiso|first8=Elisa|last9=Crupi|first9=Rosaria|date=2008-08|title=Chromosome 14q32 translocations involving the immunoglobulin heavy chain locus in chronic lymphocytic leukaemia identify a disease subset with poor prognosis|url=https://pubmed.ncbi.nlm.nih.gov/18547320|journal=British Journal of Haematology|volume=142|issue=4|pages=529–537|doi=10.1111/j.1365-2141.2008.07227.x|issn=1365-2141|pmid=18547320}}</ref>.
 
Put your text here and fill in the table


{| class="wikitable sortable"
{| class="wikitable sortable"
Line 105: Line 112:
!Notes
!Notes
|-
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
|t(14;19)
EXAMPLE 30% (add reference)
|''IGH::BCL3''
| ||
|No
|Yes
|Yes
|No
|Inferior prognosis
|-
|t(14;18)
|''IGH::BCL2''
|
|
|No
|No
|No
|No negative effect on outcome observed<ref>{{Cite journal|last=Put|first=N.|last2=Meeus|first2=P.|last3=Chatelain|first3=B.|last4=Rack|first4=K.|last5=Boeckx|first5=N.|last6=Nollet|first6=F.|last7=Graux|first7=C.|last8=Van Den Neste|first8=E.|last9=Janssens|first9=A.|date=2009-06|title=Translocation t(14;18) is not associated with inferior outcome in chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/19295547|journal=Leukemia|volume=23|issue=6|pages=1201–1204|doi=10.1038/leu.2009.44|issn=1476-5551|pmid=19295547}}</ref>
|-
|t(8;14)
|''IGH::MYC''
|
|<1%
|No
|No
|Yes
|Yes
|EXAMPLE
|No
|Prolymphocytes are detected in most of these cases. MYC translocations are associated with an inferior prognosis<ref>{{Cite journal|last=Put|first=Natalie|last2=Van Roosbroeck|first2=Katrien|last3=Konings|first3=Peter|last4=Meeus|first4=Peter|last5=Brusselmans|first5=Caroline|last6=Rack|first6=Katrina|last7=Gervais|first7=Carine|last8=Nguyen-Khac|first8=Florence|last9=Chapiro|first9=Elise|date=2012-06|title=Chronic lymphocytic leukemia and prolymphocytic leukemia with MYC translocations: a subgroup with an aggressive disease course|url=https://pubmed.ncbi.nlm.nih.gov/22205151|journal=Annals of Hematology|volume=91|issue=6|pages=863–873|doi=10.1007/s00277-011-1393-y|issn=1432-0584|pmid=22205151}}</ref><ref>{{Cite journal|last=Huh|first=Yang O.|last2=Lin|first2=Katherine I.-Chun|last3=Vega|first3=Francisco|last4=Schlette|first4=Ellen|last5=Yin|first5=C. Cameron|last6=Keating|first6=Michael J.|last7=Luthra|first7=R.|last8=Medeiros|first8=L. Jeffrey|last9=Abruzzo|first9=Lynne V.|date=2008-07|title=MYC translocation in chronic lymphocytic leukaemia is associated with increased prolymphocytes and a poor prognosis|url=https://pubmed.ncbi.nlm.nih.gov/18477041|journal=British Journal of Haematology|volume=142|issue=1|pages=36–44|doi=10.1111/j.1365-2141.2008.07152.x|issn=1365-2141|pmid=18477041}}</ref>.
|}


The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).
==Individual Region Genomic Gain/Loss/LOH==
|}
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.'') </span>
{| class="wikitable sortable"
==Individual Region Genomic Gain / Loss / LOH==
|-
!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|<span class="blue-text">EXAMPLE:</span>
7
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span>
chr7
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span>
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).
|-
|<span class="blue-text">EXAMPLE:</span>
8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>
chr8
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|
|<span class="blue-text">EXAMPLE:</span>
Common recurrent secondary finding for t(8;21) (add references).
|-
|<span class="blue-text">EXAMPLE:</span>
17
|<span class="blue-text">EXAMPLE:</span> Amp
|<span class="blue-text">EXAMPLE:</span>
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
|<span class="blue-text">EXAMPLE:</span>
''ERBB2''
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|<span class="blue-text">EXAMPLE:</span>
Amplification of ''ERBB2'' is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
|-
|
|
|
|
|
|
|
|}


Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.'') </span>
*Approximately 80% of CLL patients have a cytogenetic abnormality detectable by fluorescence ''in situ'' hybridization (FISH)
*Deletion of chromosome 13q14 detected by FISH is the most common cytogenetic abnormality in CLL. The deleted region includes two microRNAs, ''miR15A'' and ''miR16-1''<ref name=":4">{{Cite journal|last=Liew|first=Danny|last2=Krum|first2=Henry|date=2002-10|title=The role of aldosterone receptor blockade in the management of cardiovascular disease|url=https://pubmed.ncbi.nlm.nih.gov/12431020|journal=Current Opinion in Investigational Drugs (London, England: 2000)|volume=3|issue=10|pages=1468–1473|issn=1472-4472|pmid=12431020}}</ref>. These microRNAs inhibit the expression of genes involved in apoptosis and cell cycle regulation. Deletion of miR15A and miR16-1 leads to upregulation of BCL2<ref>{{Cite journal|last=Cimmino|first=Amelia|last2=Calin|first2=George Adrian|last3=Fabbri|first3=Muller|last4=Iorio|first4=Marilena V.|last5=Ferracin|first5=Manuela|last6=Shimizu|first6=Masayoshi|last7=Wojcik|first7=Sylwia E.|last8=Aqeilan|first8=Rami I.|last9=Zupo|first9=Simona|date=2005-09-27|title=miR-15 and miR-16 induce apoptosis by targeting BCL2|url=https://pubmed.ncbi.nlm.nih.gov/16166262|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=102|issue=39|pages=13944–13949|doi=10.1073/pnas.0506654102|issn=0027-8424|pmc=1236577|pmid=16166262}}</ref>. Deletion of 13q14 as the sole cytogenetic abnormality is associated with a favorable prognosis. Deletions may be heterozygous or homozygous with a similar prognosis. Individuals with a high percentage of nuclei with 13q deletion (>65%) may have a less favorable prognosis<ref>{{Cite journal|last=Van Dyke|first=Daniel L.|last2=Shanafelt|first2=Tait D.|last3=Call|first3=Timothy G.|last4=Zent|first4=Clive S.|last5=Smoley|first5=Stephanie A.|last6=Rabe|first6=Kari G.|last7=Schwager|first7=Susan M.|last8=Sonbert|first8=Jessica C.|last9=Slager|first9=Susan L.|date=2010-02|title=A comprehensive evaluation of the prognostic significance of 13q deletions in patients with B-chronic lymphocytic leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/19895615|journal=British Journal of Haematology|volume=148|issue=4|pages=544–550|doi=10.1111/j.1365-2141.2009.07982.x|issn=1365-2141|pmc=2866061|pmid=19895615}}</ref>
*Deletion of 17p, which includes ''TP53'', is associated with poor prognosis and resistance to standard chemotherapy regimens<ref name=":5">{{Cite journal|last=Döhner|first=H.|last2=Stilgenbauer|first2=S.|last3=Benner|first3=A.|last4=Leupolt|first4=E.|last5=Kröber|first5=A.|last6=Bullinger|first6=L.|last7=Döhner|first7=K.|last8=Bentz|first8=M.|last9=Lichter|first9=P.|date=2000-12-28|title=Genomic aberrations and survival in chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/11136261|journal=The New England Journal of Medicine|volume=343|issue=26|pages=1910–1916|doi=10.1056/NEJM200012283432602|issn=0028-4793|pmid=11136261}}</ref>.


'''CLL Tables''' - A list of clinically significant and/or recurrent CNAs and CN-LOH with potential or strong diagnostic, prognostic and treatment implications in CLL. Table derived from Chun et al., 2018 [<ref>{{Cite journal|last=K|first=Chun|last2=Gd|first2=Wenger|last3=A|first3=Chaubey|last4=Dp|first4=Dash|last5=R|first5=Kanagal-Shamanna|last6=S|first6=Kantarci|last7=R|first7=Kolhe|last8=Dl|first8=Van Dyke|last9=L|first9=Wang|date=2018|title=Assessing copy number aberrations and copy-neutral loss-of-heterozygosity across the genome as best practice: An evidence-based review from the Cancer Genomics Consortium (CGC) working group for chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/30554732/|language=en|pmid=30554732}}</ref>] with permission from Cancer Genetics. See [[CLL Tables: Regions of Recurrent Copy Number Change and CN-LOH]].
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
Line 127: Line 206:
!Notes
!Notes
|-
|-
|EXAMPLE
|13
 
|Loss
7
|
|EXAMPLE Loss
|13q14
|EXAMPLE
|No
 
chr7:1- 159,335,973 [hg38]
|EXAMPLE
 
chr7
|Yes
|Yes
|Yes
|No
|No
|EXAMPLE
|Most common cytogenetic abnormality. Isolated 13q deletion is associated with favorable prognosis<ref name=":4" />.
 
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
|-
|-
|EXAMPLE
|11
 
|Loss
8
|
|EXAMPLE Gain
|11q22.3
|EXAMPLE
 
chr8:1-145,138,636 [hg38]
|EXAMPLE
 
chr8
|No
|No
|Yes
|No
|No
|Deletion of ''ATM''. Associated with a poor prognosis.
|-
|17
|Loss
|
|17p13.1
|No
|No
|EXAMPLE
|Yes
 
|Yes
Common recurrent secondary finding for t(8;21) (add reference).
|Deletion of ''TP53''. Patients with 17p deletion show resistance to genotoxic chemotherapies. ''TP53'' deletion is associated with a poor prognosis<ref name=":5" />.
|}
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}
==Characteristic Chromosomal or Other Global Mutational Patterns==
 
Put your text here and fill in the table <span style="color:#0070C0">(I''nstructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
!Chromosomal Pattern
!Molecular Pathogenesis
!Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|<span class="blue-text">EXAMPLE:</span>
Co-deletion of 1p and 18q
|<span class="blue-text">EXAMPLE:</span> See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|<span class="blue-text">EXAMPLE:</span> D, P
|
|
|-
|-
|EXAMPLE 8||EXAMPLE Gain||EXAMPLE chr8:0-1000000
|<span class="blue-text">EXAMPLE:</span>
Microsatellite instability - hypermutated
|
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|<span class="blue-text">EXAMPLE:</span> P, T
|
|
|-
|-
|EXAMPLE 7||EXAMPLE Loss||EXAMPLE chr7:0-1000000
|
|
|
|
|
|
|}
|}


Put your text here and/or fill in the table
Common cytogenetic abnormalities include deletions of 13q, 11q, 6q, and 17p, and trisomy 12. Complex karyotypes (three or more chromosomal abnormalities) are detected in approximately 16% of patients<ref name=":3" /><ref name=":6">{{Cite journal|last=Haferlach|first=C.|last2=Dicker|first2=F.|last3=Schnittger|first3=S.|last4=Kern|first4=W.|last5=Haferlach|first5=T.|date=2007-12|title=Comprehensive genetic characterization of CLL: a study on 506 cases analysed with chromosome banding analysis, interphase FISH, IgV(H) status and immunophenotyping|url=https://pubmed.ncbi.nlm.nih.gov/17805327|journal=Leukemia|volume=21|issue=12|pages=2442–2451|doi=10.1038/sj.leu.2404935|issn=1476-5551|pmid=17805327}}</ref>.
 
'''CLL Tables''' - A list of clinically significant and/or recurrent CNAs and CN-LOH with potential or strong diagnostic, prognostic and treatment implications in CLL.  Table derived from Chun et al., 2018 [<nowiki>PMID 30554732</nowiki>] with permission from Cancer Genetics. See [[CLL Tables: Regions of Recurrent Copy Number Change and CN-LOH]].
 
</blockquote>
==Characteristic Chromosomal Patterns==
 
Put your text here <span style="color:#0070C0">(''EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis'')</span>


{| class="wikitable sortable"
{| class="wikitable sortable"
Line 190: Line 280:
!Notes
!Notes
|-
|-
|EXAMPLE
|13q14 deletion
 
|No
Co-deletion of 1p and 18q
|Yes
|No
|Can also be detected in the homozygous state. Biallelic deletions are often cryptic and not cytogenetically visible<ref>{{Cite journal|last=Migliazza|first=A.|last2=Bosch|first2=F.|last3=Komatsu|first3=H.|last4=Cayanis|first4=E.|last5=Martinotti|first5=S.|last6=Toniato|first6=E.|last7=Guccione|first7=E.|last8=Qu|first8=X.|last9=Chien|first9=M.|date=2001-04-01|title=Nucleotide sequence, transcription map, and mutation analysis of the 13q14 chromosomal region deleted in B-cell chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/11264177|journal=Blood|volume=97|issue=7|pages=2098–2104|doi=10.1182/blood.v97.7.2098|issn=0006-4971|pmid=11264177}}</ref>. 13q deletion as the sole abnormality is typically associated with a good prognosis, however, CLL with a high percentage of nuclei with 13q deletion may have a more aggressive clinical course<ref>{{Cite journal|last=Dal Bo|first=Michele|last2=Rossi|first2=Francesca Maria|last3=Rossi|first3=Davide|last4=Deambrogi|first4=Clara|last5=Bertoni|first5=Francesco|last6=Del Giudice|first6=Ilaria|last7=Palumbo|first7=Giuseppe|last8=Nanni|first8=Mauro|last9=Rinaldi|first9=Andrea|date=2011-08|title=13q14 deletion size and number of deleted cells both influence prognosis in chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/21563234|journal=Genes, Chromosomes & Cancer|volume=50|issue=8|pages=633–643|doi=10.1002/gcc.20885|issn=1098-2264|pmid=21563234}}</ref>
|-
|11q22.3 deletion
|No
|Yes
|No
|11q deletions are most often seen in patients with advanced CLL and are associated with more rapid disease progression<ref>{{Cite journal|last=Döhner|first=H.|last2=Stilgenbauer|first2=S.|last3=James|first3=M. R.|last4=Benner|first4=A.|last5=Weilguni|first5=T.|last6=Bentz|first6=M.|last7=Fischer|first7=K.|last8=Hunstein|first8=W.|last9=Lichter|first9=P.|date=1997-04-01|title=11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis|url=https://pubmed.ncbi.nlm.nih.gov/9116297|journal=Blood|volume=89|issue=7|pages=2516–2522|issn=0006-4971|pmid=9116297}}</ref><ref name=":5" />
|-
|Trisomy 12
|No
|Unknown
|No
|Conflicting evidence on prognostic significance. As a sole abnormality may be associated with low risk. Associated with intermediate risk if ''NOTCH1'' mutation is present<ref name=":8" />
|-
|6q21 deletion
|No
|Yes
|No
|Intermediate risk<ref>{{Cite journal|last=Cuneo|first=A.|last2=Rigolin|first2=G. M.|last3=Bigoni|first3=R.|last4=De Angeli|first4=C.|last5=Veronese|first5=A.|last6=Cavazzini|first6=F.|last7=Bardi|first7=A.|last8=Roberti|first8=M. G.|last9=Tammiso|first9=E.|date=2004-03|title=Chronic lymphocytic leukemia with 6q- shows distinct hematological features and intermediate prognosis|url=https://pubmed.ncbi.nlm.nih.gov/14712287|journal=Leukemia|volume=18|issue=3|pages=476–483|doi=10.1038/sj.leu.2403242|issn=0887-6924|pmid=14712287}}</ref>
|-
|17p13 deletion
|No
|Yes
|Yes
|Yes
|poor prognosis<ref name=":5" />
|-
|Complex karyotype
|No
|No
|Yes
|No
|No
|EXAMPLE:
|Patients with a complex karyotype have a shortened overall survival and are associated with 11q and/or 17p deletions<ref name=":6" /><ref>{{Cite journal|last=Jaglowski|first=Samantha M.|last2=Ruppert|first2=Amy S.|last3=Heerema|first3=Nyla A.|last4=Bingman|first4=Anissa|last5=Flynn|first5=Joseph M.|last6=Grever|first6=Michael R.|last7=Jones|first7=Jeffrey A.|last8=Elder|first8=Patrick|last9=Devine|first9=Steven M.|date=2012-10|title=Complex karyotype predicts for inferior outcomes following reduced-intensity conditioning allogeneic transplant for chronic lymphocytic leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/22831395|journal=British Journal of Haematology|volume=159|issue=1|pages=82–87|doi=10.1111/j.1365-2141.2012.09239.x|issn=1365-2141|pmc=3719859|pmid=22831395}}</ref>.
 
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|}
|}
==Gene Mutations (SNV / INDEL)==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity.'') </span>


==Gene Mutations (SNV/INDEL)==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
!'''Diagnostic Significance (Yes, No or Unknown)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Prognostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!Therapeutic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Notes
!Clinical Relevance Details/Other Notes
|-
|-
|EXAMPLE: TP53; Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span>''EGFR''


EXAMPLE:
<br />
 
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
EGFR; Exon 20 mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
 
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
EXAMPLE: BRAF; Activating mutations
|<span class="blue-text">EXAMPLE:</span> T
|EXAMPLE: TSG
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|EXAMPLE: 20% (COSMIC)
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
 
|-
EXAMPLE: 30% (add Reference)
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|EXAMPLE: IDH1 R123H
<br />
|EXAMPLE: EGFR amplification
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|<span class="blue-text">EXAMPLE:</span> P
|
|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|
|-
|
|
|
|
|
|
|
|
|
|
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
<br />
|}
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.


 
*IGHV genes are mutated in 50-70% of cases and unmutated in 30-50%.
<blockquote class='blockedit'>{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}
*Unmutated IGHV genes have been shown to have a poorer prognosis, along with ''TP53'', ''BIRC3'', ''NOTCH1'', and ''SF3B1'' mutations.
 
Prevalence (COSMIC, May 2018)
NOTCH1 12%
SF3B1 12%
ATM 12%
TP53 11%
NFKBIE 4%
XPO1 4%
BTK 4%
MED12 3%
BIRC3 3%
MYD88 3%
LRP1b 3%
POT1 3%
BRAF 2%
FAT1 2%


{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
!Gene; Genetic Alteration!!Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)!!Prevalence (COSMIC / TCGA / Other)!!Concomitant Mutations!!Mutually Exclusive Mutations
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|-
|EXAMPLE TP53||EXAMPLE R273H||EXAMPLE Tumor Suppressor||EXAMPLE LOF||EXAMPLE 20%
|IGHV mutations
|}
|Other (IGVH unmutated B lymphocytes are naïve cells. IGHV mutated B lymphocytes are previously-triggered, postgerminal center “memory" cells)
|50-70%
===Other Mutations===
|
{| class="wikitable sortable"
|
|No
|Yes
|Yes
|Unmutated IGHV genes have a poor prognosis and respond poorly to continuous multiregimen chemotherapy<ref>{{Cite journal|last=Damle|first=R. N.|last2=Wasil|first2=T.|last3=Fais|first3=F.|last4=Ghiotto|first4=F.|last5=Valetto|first5=A.|last6=Allen|first6=S. L.|last7=Buchbinder|first7=A.|last8=Budman|first8=D.|last9=Dittmar|first9=K.|date=1999-09-15|title=Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/10477712|journal=Blood|volume=94|issue=6|pages=1840–1847|issn=0006-4971|pmid=10477712}}</ref><ref>{{Cite journal|last=Hamblin|first=T. J.|last2=Davis|first2=Z.|last3=Gardiner|first3=A.|last4=Oscier|first4=D. G.|last5=Stevenson|first5=F. K.|date=1999-09-15|title=Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/10477713|journal=Blood|volume=94|issue=6|pages=1848–1854|issn=0006-4971|pmid=10477713}}</ref>
<br />
|-
|-
!Type!!Gene/Region/Other
|''NOTCH1''; frameshift, nonsense, and missense mutations
|Other (may be important for follicular differentiation and possible cell fate selection within the follicle)
|5-12.3%
|''FBXW7'' mutation and trisomy 12
|''SF3B1'' mutation
|No
|Yes
|No
|intermediate risk<ref name=":7">{{Cite journal|last=Jeromin|first=S.|last2=Weissmann|first2=S.|last3=Haferlach|first3=C.|last4=Dicker|first4=F.|last5=Bayer|first5=K.|last6=Grossmann|first6=V.|last7=Alpermann|first7=T.|last8=Roller|first8=A.|last9=Kohlmann|first9=A.|date=2014-01|title=SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients|url=https://pubmed.ncbi.nlm.nih.gov/24113472|journal=Leukemia|volume=28|issue=1|pages=108–117|doi=10.1038/leu.2013.263|issn=1476-5551|pmid=24113472}}</ref><ref name=":8">{{Cite journal|last=Rossi|first=Davide|last2=Rasi|first2=Silvia|last3=Spina|first3=Valeria|last4=Bruscaggin|first4=Alessio|last5=Monti|first5=Sara|last6=Ciardullo|first6=Carmela|last7=Deambrogi|first7=Clara|last8=Khiabanian|first8=Hossein|last9=Serra|first9=Roberto|date=2013-02-21|title=Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/23243274|journal=Blood|volume=121|issue=8|pages=1403–1412|doi=10.1182/blood-2012-09-458265|issn=1528-0020|pmc=3578955|pmid=23243274}}</ref>
|-
|-
|Concomitant Mutations||EXAMPLE IDH1 R123H
|''SF3B1''; missense (most)
|Other (part of the spliceosome machinery)
|9-10%
|Del(11q)
|''NOTCH1'' and ''FBXW7'' mutations
|No
|Yes
|No
|intermediate risk<ref name=":7" /><ref name=":8" />
|-
|-
|Secondary Mutations||EXAMPLE Trisomy 7
|''TP53''; missense (most)
|Tumor suppressor gene
|7.1%
|
|
|No
|Yes
|No
|High risk<ref name=":7" /><ref name=":8" />
|-
|-
|Mutually Exclusive||EXAMPLE EGFR Amplification
|''BIRC3''; frameshift and nonsense
|Tumor suppressor gene
|7.2%
|
|
|No
|Yes
|Yes
|High risk and subject to failure of FCR chemoimmunotherapy<ref name=":8" /><ref name=":9">{{Cite journal|last=Diop|first=Fary|last2=Moia|first2=Riccardo|last3=Favini|first3=Chiara|last4=Spaccarotella|first4=Elisa|last5=De Paoli|first5=Lorenzo|last6=Bruscaggin|first6=Alessio|last7=Spina|first7=Valeria|last8=Terzi-di-Bergamo|first8=Lodovico|last9=Arruga|first9=Francesca|date=2020|title=Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/31371416|journal=Haematologica|volume=105|issue=2|pages=448–456|doi=10.3324/haematol.2019.219550|issn=1592-8721|pmc=7012473|pmid=31371416}}</ref><ref>{{Cite journal|last=Blakemore|first=Stuart J.|last2=Clifford|first2=Ruth|last3=Parker|first3=Helen|last4=Antoniou|first4=Pavlos|last5=Stec-Dziedzic|first5=Ewa|last6=Larrayoz|first6=Marta|last7=Davis|first7=Zadie|last8=Kadalyayil|first8=Latha|last9=Colins|first9=Andrew|date=2020-07|title=Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial|url=https://pubmed.ncbi.nlm.nih.gov/32015491|journal=Leukemia|volume=34|issue=7|pages=1760–1774|doi=10.1038/s41375-020-0723-2|issn=1476-5551|pmc=7326706|pmid=32015491}}</ref>
|}
|}
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.


</blockquote>
==Epigenomic Alterations==
==Epigenomic Alterations==
 
Whole genome methylation studies have identified three epigenetic subgroups of CLL<ref name=":10">{{Cite journal|last=Queirós|first=A. C.|last2=Villamor|first2=N.|last3=Clot|first3=G.|last4=Martinez-Trillos|first4=A.|last5=Kulis|first5=M.|last6=Navarro|first6=A.|last7=Penas|first7=E. M. M.|last8=Jayne|first8=S.|last9=Majid|first9=A.|date=2015-03|title=A B-cell epigenetic signature defines three biologic subgroups of chronic lymphocytic leukemia with clinical impact|url=https://pubmed.ncbi.nlm.nih.gov/25151957|journal=Leukemia|volume=29|issue=3|pages=598–605|doi=10.1038/leu.2014.252|issn=1476-5551|pmid=25151957}}</ref>. These subgroups are related to different stages of B-cell maturation and include naïve B-cell like, intermediate, and memory B-cell like CLL. Naïve B-cell like epigenetic subgroup mainly has unmutated IGHV, whereas the memory B-like subgroup mainly have mutated IGHV genes. The intermediate epigenetic subgroup was also found to have mainly mutated IGHV, however, is associated with a worse prognosis than the memory B-like subgroup. The epigenetic classification was found to be an independent prognostic factor for time to first treatment<ref name=":10" /><ref>{{Cite journal|last=Oakes|first=Christopher C.|last2=Seifert|first2=Marc|last3=Assenov|first3=Yassen|last4=Gu|first4=Lei|last5=Przekopowitz|first5=Martina|last6=Ruppert|first6=Amy S.|last7=Wang|first7=Qi|last8=Imbusch|first8=Charles D.|last9=Serva|first9=Andrius|date=2016-03|title=DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/26780610|journal=Nature Genetics|volume=48|issue=3|pages=253–264|doi=10.1038/ng.3488|issn=1546-1718|pmc=4963005|pmid=26780610}}</ref>.
Put your text here


==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|EXAMPLE: BRAF and MAP2K1; Activating mutations
|''NOTCH1''; PEST domain truncation
|EXAMPLE: MAPK signaling
|Notch signaling
|EXAMPLE: Increased cell growth and proliferation
|Abnormally stabilized Notch signaling<ref>{{Cite journal|last=Mesini|first=Nicolò|last2=Fiorcari|first2=Stefania|last3=Atene|first3=Claudio Giacinto|last4=Maffei|first4=Rossana|last5=Potenza|first5=Leonardo|last6=Luppi|first6=Mario|last7=Marasca|first7=Roberto|date=2022|title=Role of Notch2 pathway in mature B cell malignancies|url=https://pubmed.ncbi.nlm.nih.gov/36686759|journal=Frontiers in Oncology|volume=12|pages=1073672|doi=10.3389/fonc.2022.1073672|issn=2234-943X|pmc=9846264|pmid=36686759}}</ref>
|-
|-
|EXAMPLE: CDKN2A; Inactivating mutations
|''TP53''; deletion and mutations
|EXAMPLE: Cell cycle regulation
|DNA damage response
|EXAMPLE: Unregulated cell division
|Cell proliferation and reduced response to cytotoxic chemotherapy<ref>{{Cite journal|last=Aitken|first=Marisa J. L.|last2=Lee|first2=Hun J.|last3=Post|first3=Sean M.|date=2019|title=Emerging treatment options for patients with p53-pathway-deficient CLL|url=https://pubmed.ncbi.nlm.nih.gov/31839919|journal=Therapeutic Advances in Hematology|volume=10|pages=2040620719891356|doi=10.1177/2040620719891356|issn=2040-6207|pmc=6896129|pmid=31839919}}</ref>
|-
|-
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
|''BIRC3''; mutations
|EXAMPLE:  Histone modification, chromatin remodeling
|NF-kB signaling
|EXAMPLE:  Abnormal gene expression program
|Activation of non-canonical NF-kB signaling<ref name=":9" />
|}
|}
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
Cytogenetics (FISH, CpG-stimulated Karyotype, SNP microarray)


Put your text here
Immunoglobulin Heavy Chain Variable Region Gene (IGHV) mutation status


==Familial Forms==
==Familial Forms==
Familial predisposition is found in 5-10% of patients with CLL<ref>{{Cite journal|last=Goldin|first=Lynn R.|last2=Pfeiffer|first2=Ruth M.|last3=Li|first3=Xinjun|last4=Hemminki|first4=Kari|date=2004-09-15|title=Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database|url=https://pubmed.ncbi.nlm.nih.gov/15161669|journal=Blood|volume=104|issue=6|pages=1850–1854|doi=10.1182/blood-2004-01-0341|issn=0006-4971|pmid=15161669}}</ref>. The overall risk of developing CLL is 2-7 times higher in first-degree relatives of individuals with CLL.
==Additional Information==
This disease is <u>defined/characterized</u> as detailed below:
*This is a distinct entity in the [https://tumourclassification.iarc.who.int/welcome/ 5th edition World Health Organization (WHO) classification system].  It was also a distinct entity in the 2016 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues revised 4th edition<ref name=":1">Campo E, et al., (2017). Chronic lymphocytic leukemia/small lymphocytic lymphoma, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p216-221.</ref>. Chronic Lymphocytic Leukemia (CLL) is a chronic lymphoproliferative disorder characterized by monoclonal B cell proliferation. CLL is defined by the presence of >5x10<sup>9</sup>/L monoclonal B-cells in the peripheral blood. Cells are small, mature appearing lymphocytes with light chain restriction by flow cytometry. The term small lymphocytic lymphoma (SLL) is used for cases with <5x10<sup>9</sup>/L circulating monoclonal B-cells and documented nodal, splenic, or other extramedullary involvement<ref name=":2">{{Cite journal|last=Hallek|first=Michael|last2=Cheson|first2=Bruce D.|last3=Catovsky|first3=Daniel|last4=Caligaris-Cappio|first4=Federico|last5=Dighiero|first5=Guillaume|last6=Döhner|first6=Hartmut|last7=Hillmen|first7=Peter|last8=Keating|first8=Michael J.|last9=Montserrat|first9=Emili|date=2008-06-15|title=Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines|url=https://pubmed.ncbi.nlm.nih.gov/18216293|journal=Blood|volume=111|issue=12|pages=5446–5456|doi=10.1182/blood-2007-06-093906|issn=1528-0020|pmc=2972576|pmid=18216293}}</ref>.
The <u>epidemiology/prevalence</u> of this disease is detailed below:
*CLL is the most common leukemia in the Western world with an annual incidence of approximately 5/100,000, comprising 25% to 30% of all leukemias in the United States. The incidence increases with age with a median age at diagnosis of 70 years. CLL can also present in younger individuals with approximately 10% of cases diagnosed in individuals less than 55 years of age<ref>{{Cite journal|last=Parikh|first=Sameer A.|last2=Rabe|first2=Kari G.|last3=Kay|first3=Neil E.|last4=Call|first4=Timothy G.|last5=Ding|first5=Wei|last6=Schwager|first6=Susan M.|last7=Bowen|first7=Deborah A.|last8=Conte|first8=Michael|last9=Jelinek|first9=Diane F.|date=2014-01|title=Chronic lymphocytic leukemia in young (≤ 55 years) patients: a comprehensive analysis of prognostic factors and outcomes|url=https://pubmed.ncbi.nlm.nih.gov/23911703|journal=Haematologica|volume=99|issue=1|pages=140–147|doi=10.3324/haematol.2013.086066|issn=1592-8721|pmc=4007929|pmid=23911703}}</ref>. CLL occurrence is more prevalent in anglo americans and much lower in asian populations<ref name=":0">Taneja A, Master SR. (2017) Cancer, Leukemia, Lymphocytic, Chronic (CLL)  SourceStatPearls [I. Treasure Island (FL): StatPearls Publishing. <nowiki>https://www.ncbi.nlm.nih.gov/books/NBK470433/</nowiki>.</ref>.
The <u>clinical features</u> of this disease are detailed below:


Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
*Most (90%) patients with CLL are asymptomatic and are diagnosed based on routine blood tests<ref name=":1" />. Only 5-10% of patients with CLL present with symptoms of fever, weight loss, night sweats, and/or fatigue<ref name=":0" />.
*Signs and symptoms - Asymptomatic (incidental finding on complete blood counts); Weight loss, fever, night sweats; Fatigue; Lymphadenopathy, splenomegaly (less common)
*Laboratory findings - Absolute lymphocytosis' Anemia; Thrombocytopenia; Paraprotein, usually IgM type (~10% of patients) hypogammaglobulinemia (~30% of patients at diagnosis)


==Additional Information==
The <u>sites of involvement</u> of this disease are detailed below:
 
*CLL/SLL involves the blood, bone marrow, and secondary lymphoid tissues such as the spleen, lymph nodes, and Waldeyer ring. Extranodal involvement (e.g. of the skin, gastrointestinal tract, or CNS) occurs in a small subset of cases<ref>{{Cite journal|last=M|first=Ratterman|last2=K|first2=Kruczek|last3=S|first3=Sulo|last4=Td|first4=Shanafelt|last5=Ne|first5=Kay|last6=C|first6=Nabhan|date=2014|title=Extramedullary chronic lymphocytic leukemia: systematic analysis of cases reported between 1975 and 2012|url=https://pubmed.ncbi.nlm.nih.gov/24064196/|language=en|pmid=24064196}}</ref>.
 
The <u>morphologic features</u> of this disease are detailed below:
 
*Lymph Nodes: Enlarged lymph nodes show diffuse architectural effacement by a proliferation of small lymphocytes with variably prominent scattered paler proliferation centers (pseudofollicles)<ref>Lennert K, editor. (1978). Malignant lymphomas other than Hodgkin’s disease. NewYork: Springer Verlag.</ref>. The predominant cell in the diffuse areas is a ''typical CLL cell'' (small lymphocyte with scant cytoplasm, and clumped chromatin). Proliferation centers are composed of small lymphocytes, prolymphocytes, and paraimmunoblasts. Mitotic activity is usually very low.
*Bone Marrow: Biopsy may show interstitial, nodular, mixed (nodular and interstitial), or diffuse involvement. Diffuse involvement is usually associated with more advanced disease<ref>{{Cite journal|last=E|first=Montserrat|last2=N|first2=Villamor|last3=Jc|first3=Reverter|last4=Rm|first4=Brugués|last5=D|first5=Tàssies|last6=F|first6=Bosch|last7=Jl|first7=Aguilar|last8=Jl|first8=Vives-Corrons|last9=M|first9=Rozman|date=1996|title=Bone marrow assessment in B-cell chronic lymphocytic leukaemia: aspirate or biopsy? A comparative study in 258 patients|url=https://pubmed.ncbi.nlm.nih.gov/8611442/|language=en|pmid=8611442}}</ref>. Paratrabecular aggregates are not typical. Proliferation centers can be observed, although they are not as prominent as in lymph nodes, and follicular dendritic cells may be present<ref>{{Cite journal|last=M|first=Chilosi|last2=G|first2=Pizzolo|last3=F|first3=Caligaris-Cappio|last4=A|first4=Ambrosetti|last5=F|first5=Vinante|last6=L|first6=Morittu|last7=F|first7=Bonetti|last8=L|first8=Fiore-Donati|last9=G|first9=Janossy|date=1985|title=Immunohistochemical demonstration of follicular dendritic cells in bone marrow involvement of B-cell chronic lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/3891066/|language=en|pmid=3891066}}</ref>. Most cases have > 30% CLL cells in the bone marrow aspirate<ref name=":2" />.
*Peripheral Blood: Smudge or basket cells are typically observed. In most cases, besides typical CLL cells, other lymphoid cells like prolymphocytes are also observed, but they usually constitute < 15% of the lymphoid cells.
 
The <u>immunophenotype</u> of this disease is detailed below:
 
*CLL cells express CD19, CD20, CD5, CD23, CD43, CD200, and LEF1<ref>{{Cite journal|last=Dorfman|first=David M.|last2=Shahsafaei|first2=Aliakbar|date=2010-11|title=CD200 (OX-2 membrane glycoprotein) expression in b cell-derived neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/20959655|journal=American Journal of Clinical Pathology|volume=134|issue=5|pages=726–733|doi=10.1309/AJCP38XRRUGSQOVC|issn=1943-7722|pmid=20959655}}</ref><ref>{{Cite journal|last=Matutes|first=E.|last2=Owusu-Ankomah|first2=K.|last3=Morilla|first3=R.|last4=Garcia Marco|first4=J.|last5=Houlihan|first5=A.|last6=Que|first6=T. H.|last7=Catovsky|first7=D.|date=1994-10|title=The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL|url=https://pubmed.ncbi.nlm.nih.gov/7523797|journal=Leukemia|volume=8|issue=10|pages=1640–1645|issn=0887-6924|pmid=7523797}}</ref>. The levels of surface CD20, surface immunoglobulin and CD79b is low compared to normal B-cells<ref>{{Cite journal|last=Moreau|first=E. J.|last2=Matutes|first2=E.|last3=A'Hern|first3=R. P.|last4=Morilla|first4=A. M.|last5=Morilla|first5=R. M.|last6=Owusu-Ankomah|first6=K. A.|last7=Seon|first7=B. K.|last8=Catovsky|first8=D.|date=1997-10|title=Improvement of the chronic lymphocytic leukemia scoring system with the monoclonal antibody SN8 (CD79b)|url=https://pubmed.ncbi.nlm.nih.gov/9322589|journal=American Journal of Clinical Pathology|volume=108|issue=4|pages=378–382|doi=10.1093/ajcp/108.4.378|issn=0002-9173|pmid=9322589}}</ref>. Cells have kappa or lambda restricted Ig light chain expression.
 
Positive (universal) - CD5, CD43 and strongly positive for CD23 and CD200
 
Negative (universal) - CD10 is negative, FMC7 is usually negative or only weakly expressed.


Put your text here
Subset - CD5- or CD23-, FMC7+, strong surface immunoglobulin, or CD79b+<ref>{{Cite journal|last=A|first=Criel|last2=L|first2=Michaux|last3=C|first3=De Wolf-Peeters|date=1999|title=The concept of typical and atypical chronic lymphocytic leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/10194119/|language=en|pmid=10194119}}</ref>


==Links==
==Links==


[[HAEM5:Monoclonal B-cell lymphocytosis]]
Not Applicable


==References==
==References==
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==Notes==
==Notes==
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<nowiki>*</nowiki>''Citation of this Page'': “Chronic lymphocytic leukaemia/small lymphocytic lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Chronic_lymphocytic_leukaemia/small_lymphocytic_lymphoma</nowiki>.
<nowiki>*</nowiki>''Citation of this Page'': “Chronic lymphocytic leukaemia/small lymphocytic lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Chronic_lymphocytic_leukaemia/small_lymphocytic_lymphoma</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases C]]
[[Category:HAEM5]]
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[[Category:Diseases C]]
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