HAEM5:Immunoglobulin-related (AL) amyloidosis: Difference between revisions
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<blockquote class= | <blockquote class="blockedit">{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Primary Amyloidosis]]. | ||
}}</blockquote> | }}</blockquote> | ||
<span style="color:#0070C0">(General Instructions – The | <span style="color:#0070C0">(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)</span> | ||
==Primary Author(s)*== | ==Primary Author(s)*== | ||
Heather E. Williams, PhD, MS, PgD, ErCLG | Heather E. Williams, PhD, MS, PgD, ErCLG | ||
==WHO Classification of Disease== | ==WHO Classification of Disease== | ||
| Line 37: | Line 34: | ||
|} | |} | ||
== | ==Related Terminology== | ||
{| class="wikitable" | {| class="wikitable" | ||
| | |+ | ||
| | |Acceptable | ||
|Light chain amyloidosis; AL amyloidosis | |||
|- | |- | ||
| | |Not Recommended | ||
| | |N/A | ||
|} | |} | ||
==Gene Rearrangements== | |||
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> | |||
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
|- | |- | ||
! | !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). | |||
|- | |- | ||
| | |<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> | |||
''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). | |||
|- | |- | ||
|<span class="blue-text">EXAMPLE:</span> ''ALK'' | |||
| | |<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK'' | ||
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> | |||
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 | |||
| | |||
| | |||
|- | |- | ||
| | | | ||
| | |||
| | | | ||
| | | | ||
| | | | ||
| | | | ||
| | |||
| | |||
|} | |} | ||
<blockquote class= | <blockquote class="blockedit">{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}</blockquote> | ||
Overall, the genetic profile of AL amyloidosis is similar to non-IgM Monoclonal Gammopathy of Undetermined Significance (MGUS) and [[Multiple Myeloma]] (MM). However, notably, the frequency of the [t(11;14)(q13;q32), ''IGH-CCND1''] chromosomal rearrangement in AL amyloidosis differs significantly than that of MGUS and [[Multiple Myeloma|MM]]. The [t(11;14)(q13;q32), ''IGH-CCND1''] occurs at higher frequency in AL amyloidosis (~40% of patients) than in MGUS and [[Multiple Myeloma|MM]] (15-20%)<ref name=":0" /><ref name=":9" />. The [t(11;14)(q13;q32), ''IGH-CCND1''] fusion results from the juxtaposition of the ''CCND1'' proto-oncogene at 11q13 with the immunoglobulin heavy chain (''IGH'') locus at 14q32<ref>{{Cite journal|last=Hayman|first=Suzanne R.|last2=Bailey|first2=Richard J.|last3=Jalal|first3=Syed M.|last4=Ahmann|first4=Gregory J.|last5=Dispenzieri|first5=Angela|last6=Gertz|first6=Morie A.|last7=Greipp|first7=Philip R.|last8=Kyle|first8=Robert A.|last9=Lacy|first9=Martha Q.|date=2001|title=Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis|url=https://ashpublications.org/blood/article/98/7/2266/107138/Translocations-involving-the-immunoglobulin|journal=Blood|language=en|volume=98|issue=7|pages=2266–2268|doi=10.1182/blood.V98.7.2266|issn=1528-0020}}</ref><ref>{{Cite journal|last=Fonseca|first=Rafael|last2=Rajkumar|first2=S. Vincent|last3=Ahmann|first3=Gregory J.|last4=Jalal|first4=Syed M.|last5=Hoyer|first5=James D.|last6=Gertz|first6=Morie A.|last7=Kyle|first7=Robert A.|last8=Greipp|first8=Philip R.|last9=Dewald|first9=Gordon W.|date=2000|title=FISH Demonstrates Treatment-Related Chromosome Damage in Myeloid but not Plasma Cells in Primary Systemic Amyloidosis|url=http://www.tandfonline.com/doi/full/10.3109/10428190009065839|journal=Leukemia & Lymphoma|language=en|volume=39|issue=3-4|pages=391–395|doi=10.3109/10428190009065839|issn=1042-8194}}</ref><ref>{{Cite journal|last=Saleem|first=Mohamed|last2=Yusoff|first2=Narazah Mohd|date=2016|title=Fusion genes in malignant neoplastic disorders of haematopoietic system|url=https://www.tandfonline.com/doi/full/10.1080/10245332.2015.1106816|journal=Hematology|language=en|volume=21|issue=9|pages=501–512|doi=10.1080/10245332.2015.1106816|issn=1607-8454}}</ref>. | Overall, the genetic profile of AL amyloidosis is similar to non-IgM Monoclonal Gammopathy of Undetermined Significance (MGUS) and [[Multiple Myeloma]] (MM). However, notably, the frequency of the [t(11;14)(q13;q32), ''IGH-CCND1''] chromosomal rearrangement in AL amyloidosis differs significantly than that of MGUS and [[Multiple Myeloma|MM]]. The [t(11;14)(q13;q32), ''IGH-CCND1''] occurs at higher frequency in AL amyloidosis (~40% of patients) than in MGUS and [[Multiple Myeloma|MM]] (15-20%)<ref name=":0">McKenna RW, et al., (2017). Plasma cell neoplasms: Monoclonal immunoglobulin deposition diseases, 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. IARC Press: Lyon, France, p254-255. </ref><ref name=":9" />. The [t(11;14)(q13;q32), ''IGH-CCND1''] fusion results from the juxtaposition of the ''CCND1'' proto-oncogene at 11q13 with the immunoglobulin heavy chain (''IGH'') locus at 14q32<ref>{{Cite journal|last=Hayman|first=Suzanne R.|last2=Bailey|first2=Richard J.|last3=Jalal|first3=Syed M.|last4=Ahmann|first4=Gregory J.|last5=Dispenzieri|first5=Angela|last6=Gertz|first6=Morie A.|last7=Greipp|first7=Philip R.|last8=Kyle|first8=Robert A.|last9=Lacy|first9=Martha Q.|date=2001|title=Translocations involving the immunoglobulin heavy-chain locus are possible early genetic events in patients with primary systemic amyloidosis|url=https://ashpublications.org/blood/article/98/7/2266/107138/Translocations-involving-the-immunoglobulin|journal=Blood|language=en|volume=98|issue=7|pages=2266–2268|doi=10.1182/blood.V98.7.2266|issn=1528-0020}}</ref><ref>{{Cite journal|last=Fonseca|first=Rafael|last2=Rajkumar|first2=S. Vincent|last3=Ahmann|first3=Gregory J.|last4=Jalal|first4=Syed M.|last5=Hoyer|first5=James D.|last6=Gertz|first6=Morie A.|last7=Kyle|first7=Robert A.|last8=Greipp|first8=Philip R.|last9=Dewald|first9=Gordon W.|date=2000|title=FISH Demonstrates Treatment-Related Chromosome Damage in Myeloid but not Plasma Cells in Primary Systemic Amyloidosis|url=http://www.tandfonline.com/doi/full/10.3109/10428190009065839|journal=Leukemia & Lymphoma|language=en|volume=39|issue=3-4|pages=391–395|doi=10.3109/10428190009065839|issn=1042-8194}}</ref><ref>{{Cite journal|last=Saleem|first=Mohamed|last2=Yusoff|first2=Narazah Mohd|date=2016|title=Fusion genes in malignant neoplastic disorders of haematopoietic system|url=https://www.tandfonline.com/doi/full/10.1080/10245332.2015.1106816|journal=Hematology|language=en|volume=21|issue=9|pages=501–512|doi=10.1080/10245332.2015.1106816|issn=1607-8454}}</ref>. | ||
<blockquote class="blockedit"> | <blockquote class="blockedit"> | ||
<center><span style="color:Maroon">'''End of V4 Section'''</span> | <center><span style="color:Maroon">'''End of V4 Section'''</span> | ||
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<blockquote class= | <blockquote class="blockedit">{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in: | ||
* Chromosomal Rearrangements (Gene Fusions) | * Chromosomal Rearrangements (Gene Fusions) | ||
* Individual Region Genomic Gain/Loss/LOH | * Individual Region Genomic Gain/Loss/LOH | ||
| Line 166: | Line 123: | ||
* Gene Mutations (SNV/INDEL)}}</blockquote> | * Gene Mutations (SNV/INDEL)}}</blockquote> | ||
An early stage diagnosis provides patients with the broadest options for treatment, including eligibility for dose intensive chemotherapy regiments. However, the diagnosis requires a high clinical suspicion in individuals with nephrotic range proteinuria with or without renal insufficiency, non-dilated cardiomyopathy, peripheral neuropathy, hepatomegaly or automatic neuropathy in the presence (or absence) of paraprotein detectable in the serum or urine<ref name=":2" />. Prognosis is highly variable, however, it is extremely poor in the absence of treatment. Nearly twenty years ago, the median survival was dismal at 1-2 years, with less than 5% of all AL amyloidosis patients alive ten or more years following diagnosis, however within the last decade this median survival has changed dramatically, and ~30-40% patients survive more than ten years<ref name=":3" /><ref name=":4" /><ref name=":17" />. The most frequent cause of death (reported in ~40% of cases) is the presence of amyloid-related cardiac disease<ref name=":15" /><ref>{{Cite journal|last=Warsame|first=R|last2=Kumar|first2=S K|last3=Gertz|first3=M A|last4=Lacy|first4=M Q|last5=Buadi|first5=F K|last6=Hayman|first6=S R|last7=Leung|first7=N|last8=Dingli|first8=D|last9=Lust|first9=J A|date=2015|title=Abnormal FISH in patients with immunoglobulin light chain amyloidosis is a risk factor for cardiac involvement and for death|url=http://www.nature.com/articles/bcj201534|journal=Blood Cancer Journal|language=en|volume=5|issue=5|pages=e310–e310|doi=10.1038/bcj.2015.34|issn=2044-5385|pmc=PMC4423220|pmid=25933374}}</ref><ref>{{Cite journal|last=Tahir|first=Usman A.|last2=Doros|first2=Gheorghe|last3=Kim|first3=John S.|last4=Connors|first4=Lawreen H.|last5=Seldin|first5=David C.|last6=Sam|first6=Flora|date=2019|title=Predictors of Mortality in Light Chain Cardiac Amyloidosis with Heart Failure|url=http://www.nature.com/articles/s41598-019-44912-x|journal=Scientific Reports|language=en|volume=9|issue=1|doi=10.1038/s41598-019-44912-x|issn=2045-2322|pmc=PMC6561903|pmid=31189919}}</ref>. | An early stage diagnosis provides patients with the broadest options for treatment, including eligibility for dose intensive chemotherapy regiments. However, the diagnosis requires a high clinical suspicion in individuals with nephrotic range proteinuria with or without renal insufficiency, non-dilated cardiomyopathy, peripheral neuropathy, hepatomegaly or automatic neuropathy in the presence (or absence) of paraprotein detectable in the serum or urine<ref name=":2">{{Cite journal|date=2004|title=Guidelines on the diagnosis and management of AL amyloidosis|url=http://doi.wiley.com/10.1111/j.1365-2141.2004.04970.x|journal=British Journal of Haematology|language=en|volume=125|issue=6|pages=681–700|doi=10.1111/j.1365-2141.2004.04970.x|issn=0007-1048}}</ref>. Prognosis is highly variable, however, it is extremely poor in the absence of treatment. Nearly twenty years ago, the median survival was dismal at 1-2 years, with less than 5% of all AL amyloidosis patients alive ten or more years following diagnosis, however within the last decade this median survival has changed dramatically, and ~30-40% patients survive more than ten years<ref name=":3">{{Cite journal|last=Ra|first=Kyle|last2=Ma|first2=Gertz|date=1995|title=Primary systemic amyloidosis: clinical and laboratory features in 474 cases|url=https://pubmed.ncbi.nlm.nih.gov/7878478/|language=en|pmid=7878478}}</ref><ref name=":4">{{Cite journal|last=G|first=Merlini|date=2017|title=AL amyloidosis: from molecular mechanisms to targeted therapies|url=https://pubmed.ncbi.nlm.nih.gov/29222231/|language=en|doi=10.1182/asheducation-2017.1.1|pmc=PMC6142527|pmid=29222231}}</ref><ref name=":17">{{Cite journal|last=Ra|first=Kyle|last2=Ma|first2=Gertz|last3=Pr|first3=Greipp|last4=Te|first4=Witzig|last5=Ja|first5=Lust|last6=Mq|first6=Lacy|last7=Tm|first7=Therneau|date=1999|title=Long-term survival (10 years or more) in 30 patients with primary amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/9920856/|language=en|pmid=9920856}}</ref>. The most frequent cause of death (reported in ~40% of cases) is the presence of amyloid-related cardiac disease<ref name=":15">{{Cite journal|last=Ra|first=Kyle|last2=Pr|first2=Greipp|last3=Wm|first3=O'Fallon|date=1986|title=Primary systemic amyloidosis: multivariate analysis for prognostic factors in 168 cases|url=https://pubmed.ncbi.nlm.nih.gov/3719098/|language=en|pmid=3719098}}</ref><ref>{{Cite journal|last=Warsame|first=R|last2=Kumar|first2=S K|last3=Gertz|first3=M A|last4=Lacy|first4=M Q|last5=Buadi|first5=F K|last6=Hayman|first6=S R|last7=Leung|first7=N|last8=Dingli|first8=D|last9=Lust|first9=J A|date=2015|title=Abnormal FISH in patients with immunoglobulin light chain amyloidosis is a risk factor for cardiac involvement and for death|url=http://www.nature.com/articles/bcj201534|journal=Blood Cancer Journal|language=en|volume=5|issue=5|pages=e310–e310|doi=10.1038/bcj.2015.34|issn=2044-5385|pmc=PMC4423220|pmid=25933374}}</ref><ref>{{Cite journal|last=Tahir|first=Usman A.|last2=Doros|first2=Gheorghe|last3=Kim|first3=John S.|last4=Connors|first4=Lawreen H.|last5=Seldin|first5=David C.|last6=Sam|first6=Flora|date=2019|title=Predictors of Mortality in Light Chain Cardiac Amyloidosis with Heart Failure|url=http://www.nature.com/articles/s41598-019-44912-x|journal=Scientific Reports|language=en|volume=9|issue=1|doi=10.1038/s41598-019-44912-x|issn=2045-2322|pmc=PMC6561903|pmid=31189919}}</ref>. | ||
To preserve and improve the function of organs infiltrated by amyloid deposits, treatments focus on substantially reducing the supply of monoclonal immunoglobulin light chains to stabilize or regress existing amyloid deposits<ref name=":16" /><ref>{{Cite journal|last=Jd|first=Gillmore|last2=Pn|first2=Hawkins|last3=Mb|first3=Pepys|date=1997|title=Amyloidosis: a review of recent diagnostic and therapeutic developments|url=https://pubmed.ncbi.nlm.nih.gov/9375734/|language=en|pmid=9375734}}</ref>. Chemotherapies used are based on regimens proven effective in patients with multiple myeloma, however clinical benefits are often delayed for many months to allow for adequate suppression of an underlying plasma cell dyscrasia<ref name=":2" />. These range from low, intermediate, or high dose approaches alone or in combination with other newly emerging novel therapies<ref name=":2" /><ref>National Comprehensive Cancer Network. Systemic Light Chain Amyloidosis (Version 1.2020). <nowiki>https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf</nowiki> Accessed July 20th, 2020.</ref>. More intensive chemotherapies are associated with intense treatment related toxicity. Recent studies have linked the presence of specific genetic profiles (i.e. t(11;14)) to poor outcomes and suggested that the use of specific therapies (i.e. bortezomib) are associated with the poorest of outcomes, however, this link has not been firmly established—inversely patients with 1q deletion have superior outcomes when treated on bortezomib-based regimens<ref name=":14" /><ref name=":4" /><ref>{{Cite journal|last=Bochtler|first=Tilmann|last2=Hegenbart|first2=Ute|last3=Kunz|first3=Christina|last4=Granzow|first4=Martin|last5=Benner|first5=Axel|last6=Seckinger|first6=Anja|last7=Kimmich|first7=Christoph|last8=Goldschmidt|first8=Hartmut|last9=Ho|first9=Anthony D.|date=2015|title=Translocation t(11;14) Is Associated With Adverse Outcome in Patients With Newly Diagnosed AL Amyloidosis When Treated With Bortezomib-Based Regimens|url=http://ascopubs.org/doi/10.1200/JCO.2014.57.4947|journal=Journal of Clinical Oncology|language=en|volume=33|issue=12|pages=1371–1378|doi=10.1200/JCO.2014.57.4947|issn=0732-183X}}</ref>. | To preserve and improve the function of organs infiltrated by amyloid deposits, treatments focus on substantially reducing the supply of monoclonal immunoglobulin light chains to stabilize or regress existing amyloid deposits<ref name=":16">{{Cite journal|last=Mahmood|first=S.|last2=Palladini|first2=G.|last3=Sanchorawala|first3=V.|last4=Wechalekar|first4=A.|date=2014|title=Update on treatment of light chain amyloidosis|url=http://www.haematologica.org/cgi/doi/10.3324/haematol.2013.087619|journal=Haematologica|language=en|volume=99|issue=2|pages=209–221|doi=10.3324/haematol.2013.087619|issn=0390-6078|pmc=PMC3912950|pmid=24497558}}</ref><ref>{{Cite journal|last=Jd|first=Gillmore|last2=Pn|first2=Hawkins|last3=Mb|first3=Pepys|date=1997|title=Amyloidosis: a review of recent diagnostic and therapeutic developments|url=https://pubmed.ncbi.nlm.nih.gov/9375734/|language=en|pmid=9375734}}</ref>. Chemotherapies used are based on regimens proven effective in patients with multiple myeloma, however clinical benefits are often delayed for many months to allow for adequate suppression of an underlying plasma cell dyscrasia<ref name=":2" />. These range from low, intermediate, or high dose approaches alone or in combination with other newly emerging novel therapies<ref name=":2" /><ref>National Comprehensive Cancer Network. Systemic Light Chain Amyloidosis (Version 1.2020). <nowiki>https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf</nowiki> Accessed July 20th, 2020.</ref>. More intensive chemotherapies are associated with intense treatment related toxicity. Recent studies have linked the presence of specific genetic profiles (i.e. t(11;14)) to poor outcomes and suggested that the use of specific therapies (i.e. bortezomib) are associated with the poorest of outcomes, however, this link has not been firmly established—inversely patients with 1q deletion have superior outcomes when treated on bortezomib-based regimens<ref name=":14">{{Cite journal|last=Ah|first=Bryce|last2=Rp|first2=Ketterling|last3=Ma|first3=Gertz|last4=M|first4=Lacy|last5=Ra|first5=Knudson|last6=S|first6=Zeldenrust|last7=S|first7=Kumar|last8=S|first8=Hayman|last9=F|first9=Buadi|date=2009|title=Translocation t(11;14) and survival of patients with light chain (AL) amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/19211640/|language=en|doi=10.3324/haematol.13369|pmc=PMC2649355|pmid=19211640}}</ref><ref name=":4" /><ref>{{Cite journal|last=Bochtler|first=Tilmann|last2=Hegenbart|first2=Ute|last3=Kunz|first3=Christina|last4=Granzow|first4=Martin|last5=Benner|first5=Axel|last6=Seckinger|first6=Anja|last7=Kimmich|first7=Christoph|last8=Goldschmidt|first8=Hartmut|last9=Ho|first9=Anthony D.|date=2015|title=Translocation t(11;14) Is Associated With Adverse Outcome in Patients With Newly Diagnosed AL Amyloidosis When Treated With Bortezomib-Based Regimens|url=http://ascopubs.org/doi/10.1200/JCO.2014.57.4947|journal=Journal of Clinical Oncology|language=en|volume=33|issue=12|pages=1371–1378|doi=10.1200/JCO.2014.57.4947|issn=0732-183X}}</ref>. | ||
<blockquote class="blockedit"> | <blockquote class="blockedit"> | ||
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---- | ---- | ||
</blockquote> | </blockquote> | ||
==Individual Region Genomic Gain / Loss / LOH== | ==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" | {| class="wikitable sortable" | ||
|- | |- | ||
!Chr #!!Gain | !Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s) | ||
!Diagnostic | !Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | ||
!Established Clinical Significance Per Guidelines - Yes or No (Source) | |||
! | !Clinical Relevance Details/Other Notes | ||
!Notes | |||
|- | |- | ||
|<span class="blue-text">EXAMPLE:</span> | |<span class="blue-text">EXAMPLE:</span> | ||
7 | 7 | ||
|<span class="blue-text">EXAMPLE:</span> Loss | |<span class="blue-text">EXAMPLE:</span> Loss | ||
|<span class="blue-text">EXAMPLE:</span> | |<span class="blue-text">EXAMPLE:</span> | ||
chr7 | |||
chr7 | |||
|<span class="blue-text">EXAMPLE:</span> | |<span class="blue-text">EXAMPLE:</span> | ||
Unknown | |||
|<span class="blue-text">EXAMPLE:</span> D, P | |||
|<span class="blue-text">EXAMPLE:</span> No | |||
| | |||
|No | |||
|<span class="blue-text">EXAMPLE:</span> | |<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). | |||
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 | |||
|- | |- | ||
|<span class="blue-text">EXAMPLE:</span> | |<span class="blue-text">EXAMPLE:</span> | ||
8 | 8 | ||
|<span class="blue-text">EXAMPLE:</span> Gain | |<span class="blue-text">EXAMPLE:</span> Gain | ||
|<span class="blue-text">EXAMPLE:</span> | |<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> | |<span class="blue-text">EXAMPLE:</span> | ||
''ERBB2'' | |||
|<span class="blue-text">EXAMPLE:</span> D, P, T | |||
| | |||
| | |||
| | |||
|<span class="blue-text">EXAMPLE:</span> | |<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. | |||
|- | |||
| | |||
| | |||
| | |||
| | |||
| | |||
| | |||
| | |||
|} | |} | ||
<blockquote class= | <blockquote class="blockedit">{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote> | ||
Copy number aberrations (CNAs) in AL amyloidosis are recurrent, although a subset (~10%) do not have aberrant chromosomal changes resolvable by CC or FISH (see [[Characteristic chromosomal aberrations /Patterns]])<ref name=":12" />. Overall, genetic profile studies by Paiva et al. (2016) indicate CNA in AL amyloidosis range in frequency, but are similar to those observed in [[Multiple Myeloma|MM]]; the most frequent include 1) gains of (from highest frequency) chromosomes 9, 19, 5, and losses of X and 16; 2) whole arm alterations include gains of (from highest frequency) 15q and 1q, and losses of Yp, 13q, and 22q<ref name=":13">{{Cite journal|last=Paiva|first=Bruno|last2=Martinez-Lopez|first2=Joaquin|last3=Corchete|first3=Luis A.|last4=Sanchez-Vega|first4=Beatriz|last5=Rapado|first5=Inmaculada|last6=Puig|first6=Noemi|last7=Barrio|first7=Santiago|last8=Sanchez|first8=Maria-Luz|last9=Alignani|first9=Diego|date=2016|title=Phenotypic, transcriptomic, and genomic features of clonal plasma cells in light-chain amyloidosis|url=https://ashpublications.org/blood/article/127/24/3035/35439/Phenotypic-transcriptomic-and-genomic-features-of|journal=Blood|language=en|volume=127|issue=24|pages=3035–3039|doi=10.1182/blood-2015-10-673095|issn=0006-4971}}</ref>. Nearly 90% of patients with t(11;14) have concomitant gains of 11q22.3/11q23, a result of an unbalanced translocation der(14)t(11;14)(q13;32)<ref name=":12" />. Copy neutral loss of heterozygosity (CN-LOH) was also observed in 50% of the cohort<ref name=":12" />. Stratifications analogous to those used in MM have been proposed and include: 1) hyperdiploid (HD): a subgroup with concomitant gains of 1q21; 2) t(11;14) 3) non-hyperdiploid (NHD) with deletion of 13q14/t(4;14); 4) t(''v'';14) ''IGH-''unknown partner<ref name=":12" /><ref>{{Cite journal|last=Cremer|first=Friedrich W.|last2=Bila|first2=Jelena|last3=Buck|first3=Isabelle|last4=Kartal|first4=Mutlu|last5=Hose|first5=Dirk|last6=Ittrich|first6=Carina|last7=Benner|first7=Axel|last8=Raab|first8=Marc S.|last9=Theil|first9=Ann-Cathrin|date=2005|title=Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics|url=http://doi.wiley.com/10.1002/gcc.20231|journal=Genes, Chromosomes and Cancer|language=en|volume=44|issue=2|pages=194–203|doi=10.1002/gcc.20231|issn=1045-2257}}</ref>. Furthermore, WES analyses have identified an average of 15 non-recurrent mutations per patient, but have failed to identify a unifying gene mutation specific for AL amyloidosis<ref name=":13" />. Recent genomic profiling using a combined WES and targeted gene sequencing panel approach have identified recurrent mutations in AL amyloidosis (see [[Gene mutations (SNV/INVDEL)]]<ref name=":18">{{Cite journal|last=Huang|first=Xu-Fei|last2=Jian|first2=Sun|last3=Lu|first3=Jun-Liang|last4=Shen|first4=Kai-Ni|last5=Feng|first5=Jun|last6=Zhang|first6=Cong-Li|last7=Tian|first7=Zhuang|last8=Wang|first8=Jia-Li|last9=Lei|first9=Wan-Jun|date=2020|title=Genomic profiling in amyloid light-chain amyloidosis reveals mutation profiles associated with overall survival|url=https://www.tandfonline.com/doi/full/10.1080/13506129.2019.1678464|journal=Amyloid|language=en|volume=27|issue=1|pages=36–44|doi=10.1080/13506129.2019.1678464|issn=1350-6129}}</ref>. | Copy number aberrations (CNAs) in AL amyloidosis are recurrent, although a subset (~10%) do not have aberrant chromosomal changes resolvable by CC or FISH (see [[Characteristic chromosomal aberrations /Patterns]])<ref name=":12" />. Overall, genetic profile studies by Paiva et al. (2016) indicate CNA in AL amyloidosis range in frequency, but are similar to those observed in [[Multiple Myeloma|MM]]; the most frequent include 1) gains of (from highest frequency) chromosomes 9, 19, 5, and losses of X and 16; 2) whole arm alterations include gains of (from highest frequency) 15q and 1q, and losses of Yp, 13q, and 22q<ref name=":13">{{Cite journal|last=Paiva|first=Bruno|last2=Martinez-Lopez|first2=Joaquin|last3=Corchete|first3=Luis A.|last4=Sanchez-Vega|first4=Beatriz|last5=Rapado|first5=Inmaculada|last6=Puig|first6=Noemi|last7=Barrio|first7=Santiago|last8=Sanchez|first8=Maria-Luz|last9=Alignani|first9=Diego|date=2016|title=Phenotypic, transcriptomic, and genomic features of clonal plasma cells in light-chain amyloidosis|url=https://ashpublications.org/blood/article/127/24/3035/35439/Phenotypic-transcriptomic-and-genomic-features-of|journal=Blood|language=en|volume=127|issue=24|pages=3035–3039|doi=10.1182/blood-2015-10-673095|issn=0006-4971}}</ref>. Nearly 90% of patients with t(11;14) have concomitant gains of 11q22.3/11q23, a result of an unbalanced translocation der(14)t(11;14)(q13;32)<ref name=":12" />. Copy neutral loss of heterozygosity (CN-LOH) was also observed in 50% of the cohort<ref name=":12" />. Stratifications analogous to those used in MM have been proposed and include: 1) hyperdiploid (HD): a subgroup with concomitant gains of 1q21; 2) t(11;14) 3) non-hyperdiploid (NHD) with deletion of 13q14/t(4;14); 4) t(''v'';14) ''IGH-''unknown partner<ref name=":12" /><ref>{{Cite journal|last=Cremer|first=Friedrich W.|last2=Bila|first2=Jelena|last3=Buck|first3=Isabelle|last4=Kartal|first4=Mutlu|last5=Hose|first5=Dirk|last6=Ittrich|first6=Carina|last7=Benner|first7=Axel|last8=Raab|first8=Marc S.|last9=Theil|first9=Ann-Cathrin|date=2005|title=Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics|url=http://doi.wiley.com/10.1002/gcc.20231|journal=Genes, Chromosomes and Cancer|language=en|volume=44|issue=2|pages=194–203|doi=10.1002/gcc.20231|issn=1045-2257}}</ref>. Furthermore, WES analyses have identified an average of 15 non-recurrent mutations per patient, but have failed to identify a unifying gene mutation specific for AL amyloidosis<ref name=":13" />. Recent genomic profiling using a combined WES and targeted gene sequencing panel approach have identified recurrent mutations in AL amyloidosis (see [[Gene mutations (SNV/INVDEL)]]<ref name=":18">{{Cite journal|last=Huang|first=Xu-Fei|last2=Jian|first2=Sun|last3=Lu|first3=Jun-Liang|last4=Shen|first4=Kai-Ni|last5=Feng|first5=Jun|last6=Zhang|first6=Cong-Li|last7=Tian|first7=Zhuang|last8=Wang|first8=Jia-Li|last9=Lei|first9=Wan-Jun|date=2020|title=Genomic profiling in amyloid light-chain amyloidosis reveals mutation profiles associated with overall survival|url=https://www.tandfonline.com/doi/full/10.1080/13506129.2019.1678464|journal=Amyloid|language=en|volume=27|issue=1|pages=36–44|doi=10.1080/13506129.2019.1678464|issn=1350-6129}}</ref>. | ||
| Line 228: | Line 194: | ||
---- | ---- | ||
</blockquote> | </blockquote> | ||
==Characteristic Chromosomal Patterns== | ==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" | ||
|- | |- | ||
!Chromosomal Pattern | !Chromosomal Pattern | ||
! | !Molecular Pathogenesis | ||
!Prognostic Significance | !Prevalence - | ||
! | Common >20%, Recurrent 5-20% or Rare <5% (Disease) | ||
!Notes | !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> | |<span class="blue-text">EXAMPLE:</span> | ||
Co-deletion of 1p and 18q | 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 | ||
| | |||
| | |||
|- | |||
|<span class="blue-text">EXAMPLE:</span> | |<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 | |||
| | |||
| | |||
|- | |||
| | |||
| | |||
| | |||
| | |||
| | |||
| | |||
|} | |} | ||
<blockquote class= | <blockquote class="blockedit">{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}</blockquote> | ||
Intra-clonal genetic heterogeneity, i.e. the phenomenon by which malignant cells within an individual may share common cytogenetic aberrations is variable in AL amyloidosis, and there is not strict genetic uniformity within the clones and subclones, rather some tumor cells harbor additional, unique aberrations<ref name=":9">{{Cite journal|last=Bochtler|first=Tilmann|last2=Merz|first2=Maximilian|last3=Hielscher|first3=Thomas|last4=Granzow|first4=Martin|last5=Hoffmann|first5=Korbinian|last6=Krämer|first6=Alwin|last7=Raab|first7=Marc-Steffen|last8=Hillengass|first8=Jens|last9=Seckinger|first9=Anja|date=2018|title=Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma|url=https://ashpublications.org/bloodadvances/article/2/20/2607/16105/Cytogenetic-intraclonal-heterogeneity-of-plasma|journal=Blood Advances|language=en|volume=2|issue=20|pages=2607–2618|doi=10.1182/bloodadvances.2018023200|issn=2473-9529|pmc=PMC6199662|pmid=30327369}}</ref>. Cytogenetic analysis can profile the genetic heterogeneity within the underlying plasma cell dyscrasia in AL and provide prognostic information. These cytogenetic findings rely on Fluorescence ''in situ'' Hybridization (FISH) as conventional cytogenetics (CC), which requires the capture of cells in metaphase, has a poor karyotype yield in plasma cell dyscrasias with detection limited to a mere 15-20% of cases<ref>{{Cite journal|last=Bochtler|first=Tilmann|last2=Stölzel|first2=Friedrich|last3=Heilig|first3=Christoph E.|last4=Kunz|first4=Christina|last5=Mohr|first5=Brigitte|last6=Jauch|first6=Anna|last7=Janssen|first7=Johannes W.G.|last8=Kramer|first8=Michael|last9=Benner|first9=Axel|date=2013|title=Clonal Heterogeneity As Detected by Metaphase Karyotyping Is an Indicator of Poor Prognosis in Acute Myeloid Leukemia|url=http://ascopubs.org/doi/10.1200/JCO.2013.50.7921|journal=Journal of Clinical Oncology|language=en|volume=31|issue=31|pages=3898–3905|doi=10.1200/JCO.2013.50.7921|issn=0732-183X}}</ref><ref>{{Cite journal|last=Gw|first=Dewald|last2=Ra|first2=Kyle|last3=Ga|first3=Hicks|last4=Pr|first4=Greipp|date=1985|title=The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/3926026/|language=en|pmid=3926026}}</ref>. Following enrichment of plasma cells using magnetic activated cell sorting with CD138 immunobeads, interphase FISH analysis can be performed with [[Multiple Myeloma|MM]] specific probe sets or panels. These panels vary, but may include enumeration of ''CKS1B'' (1q21), ''CDKN2C'' (1p32), D9Z1/D15Z4 (CEN9, CEN15), ''RB1'' (13q14), ''TP53'' (17p13), and break-apart probes for ''MYC'' (8q24.1) or ''IGH'' (14q32.3) translocations, often with sequential reflex testing with dual-fusion FISH probes for the five common ''IGH'' partners: [t(4;14)(p16.3;q32); ''IGH-FGFR3''], [t(6;14)(p21;q32); ''IGH-CCND3''], [t(11;14)(q13;q32); ''IGH-CCND1''], [t(14;16)(q32;q23); ''IGH-MAF''], [t(14;20)(q32;q12); ''IGH-MAFB'']. Common cytogenetic aberrations overlap with those found in MM and MUGS, although frequencies differ; the aberrations include the t(11;14)(q13;q32), ''CCND1-IGH'' aberration that predominates (and as such a FISH panel may be tailored specifically for AL amyloidosis), with fewer cases of hyperdiploid and high-risk karyotypes<ref name=":10">{{Cite journal|last=Bochtler|first=Tilmann|last2=Hegenbart|first2=Ute|last3=Cremer|first3=Friedrich W.|last4=Heiss|first4=Christiane|last5=Benner|first5=Axel|last6=Hose|first6=Dirk|last7=Moos|first7=Marion|last8=Bila|first8=Jelena|last9=Bartram|first9=Claus R.|date=2008|title=Evaluation of the cytogenetic aberration pattern in amyloid light chain amyloidosis as compared with monoclonal gammopathy of undetermined significance reveals common pathways of karyotypic instability|url=https://ashpublications.org/blood/article/111/9/4700/24510/Evaluation-of-the-cytogenetic-aberration-pattern|journal=Blood|language=en|volume=111|issue=9|pages=4700–4705|doi=10.1182/blood-2007-11-122101|issn=0006-4971}}</ref><ref name=":11">{{Cite journal|last=Bochtler|first=Tilmann|last2=Hegenbart|first2=Ute|last3=Heiss|first3=Christiane|last4=Benner|first4=Axel|last5=Moos|first5=Marion|last6=Seckinger|first6=Anja|last7=Pschowski-Zuck|first7=Stephanie|last8=Kirn|first8=Désirée|last9=Neben|first9=Kai|date=2011|title=Hyperdiploidy is less frequent in AL amyloidosis compared with monoclonal gammopathy of undetermined significance and inversely associated with translocation t(11;14)|url=https://ashpublications.org/blood/article/117/14/3809/20514/Hyperdiploidy-is-less-frequent-in-AL-amyloidosis|journal=Blood|language=en|volume=117|issue=14|pages=3809–3815|doi=10.1182/blood-2010-02-268987|issn=0006-4971}}</ref><ref>{{Cite journal|last=Cj|first=Harrison|last2=H|first2=Mazzullo|last3=Fm|first3=Ross|last4=Kl|first4=Cheung|last5=G|first5=Gerrard|last6=L|first6=Harewood|last7=A|first7=Mehta|last8=Hj|first8=Lachmann|last9=Pn|first9=Hawkins|date=2002|title=Translocations of 14q32 and deletions of 13q14 are common chromosomal abnormalities in systemic amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/11972529/|language=en|pmid=11972529}}</ref><ref>{{Cite journal|last=Kobayashi|first=Hiroki|last2=Abe|first2=Yoshiaki|last3=Miura|first3=Daisuke|last4=Narita|first4=Kentaro|last5=Kitadate|first5=Akihiro|last6=Takeuchi|first6=Masami|last7=Matsue|first7=Kosei|date=2019|title=Prevalence and clinical implications of t(11;14) in patients with amyloid light-chain amyloidosis with or without concurrent multiple myeloma|url=https://academic.oup.com/jjco/article/49/2/195/5272727|journal=Japanese Journal of Clinical Oncology|language=en|volume=49|issue=2|pages=195–198|doi=10.1093/jjco/hyy202|issn=1465-3621}}</ref>. Hyperdiploidy and t(11;14) are mutually exclusive in AL amyloidosis<ref name=":10" /><ref name=":11" /><ref name=":12">{{Cite journal|last=Granzow|first=Martin|last2=Hegenbart|first2=Ute|last3=Hinderhofer|first3=Katrin|last4=Hose|first4=Dirk|last5=Seckinger|first5=Anja|last6=Bochtler|first6=Tilmann|last7=Hemminki|first7=Kari|last8=Goldschmidt|first8=Hartmut|last9=Schönland|first9=Stefan O.|date=2017|title=Novel recurrent chromosomal aberrations detected in clonal plasma cells of light chain amyloidosis patients show potential adverse prognostic effect: first results from a genome-wide copy number array analysis|url=http://www.haematologica.org/lookup/doi/10.3324/haematol.2016.160721|journal=Haematologica|language=en|volume=102|issue=7|pages=1281–1290|doi=10.3324/haematol.2016.160721|issn=0390-6078|pmc=PMC5566044|pmid=28341732}}</ref>. Recent studies have further characterized the clonal distribution of these aberrations: main clones are likely to contain the t(11;14) or t(''v'';14) ''IGH-v'' translocations, and hyperdiploidy, whereas subclones similar to those in Monoclonal gammopathy of undetermined significance (MGUS) and [[Multiple Myeloma|MM]] often carry gain of ''CKS1B'' (1q21), and deletions of 8p21 (''PNOC''), ''RB1'' (13q14), and ''TP53'' (17p13)<ref name=":9" />. Of note, the frequency of the t(11;14) aberration has been shown to decrease with the progression of the plasma cell dyscrasia<ref name=":9" />. However, the impact of plasma cell FISH on the outcomes of AL amyloidosis remains uncertain, with some well characterized genotype-outcome associations recently reported<ref name=":4" /><ref>{{Cite journal|last=Muchtar|first=E|last2=Dispenzieri|first2=A|last3=Kumar|first3=S K|last4=Ketterling|first4=R P|last5=Dingli|first5=D|last6=Lacy|first6=M Q|last7=Buadi|first7=F K|last8=Hayman|first8=S R|last9=Kapoor|first9=P|date=2017|title=Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category|url=http://www.nature.com/articles/leu2016369|journal=Leukemia|language=en|volume=31|issue=7|pages=1562–1569|doi=10.1038/leu.2016.369|issn=0887-6924}}</ref>. | Intra-clonal genetic heterogeneity, i.e. the phenomenon by which malignant cells within an individual may share common cytogenetic aberrations is variable in AL amyloidosis, and there is not strict genetic uniformity within the clones and subclones, rather some tumor cells harbor additional, unique aberrations<ref name=":9">{{Cite journal|last=Bochtler|first=Tilmann|last2=Merz|first2=Maximilian|last3=Hielscher|first3=Thomas|last4=Granzow|first4=Martin|last5=Hoffmann|first5=Korbinian|last6=Krämer|first6=Alwin|last7=Raab|first7=Marc-Steffen|last8=Hillengass|first8=Jens|last9=Seckinger|first9=Anja|date=2018|title=Cytogenetic intraclonal heterogeneity of plasma cell dyscrasia in AL amyloidosis as compared with multiple myeloma|url=https://ashpublications.org/bloodadvances/article/2/20/2607/16105/Cytogenetic-intraclonal-heterogeneity-of-plasma|journal=Blood Advances|language=en|volume=2|issue=20|pages=2607–2618|doi=10.1182/bloodadvances.2018023200|issn=2473-9529|pmc=PMC6199662|pmid=30327369}}</ref>. Cytogenetic analysis can profile the genetic heterogeneity within the underlying plasma cell dyscrasia in AL and provide prognostic information. These cytogenetic findings rely on Fluorescence ''in situ'' Hybridization (FISH) as conventional cytogenetics (CC), which requires the capture of cells in metaphase, has a poor karyotype yield in plasma cell dyscrasias with detection limited to a mere 15-20% of cases<ref>{{Cite journal|last=Bochtler|first=Tilmann|last2=Stölzel|first2=Friedrich|last3=Heilig|first3=Christoph E.|last4=Kunz|first4=Christina|last5=Mohr|first5=Brigitte|last6=Jauch|first6=Anna|last7=Janssen|first7=Johannes W.G.|last8=Kramer|first8=Michael|last9=Benner|first9=Axel|date=2013|title=Clonal Heterogeneity As Detected by Metaphase Karyotyping Is an Indicator of Poor Prognosis in Acute Myeloid Leukemia|url=http://ascopubs.org/doi/10.1200/JCO.2013.50.7921|journal=Journal of Clinical Oncology|language=en|volume=31|issue=31|pages=3898–3905|doi=10.1200/JCO.2013.50.7921|issn=0732-183X}}</ref><ref>{{Cite journal|last=Gw|first=Dewald|last2=Ra|first2=Kyle|last3=Ga|first3=Hicks|last4=Pr|first4=Greipp|date=1985|title=The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/3926026/|language=en|pmid=3926026}}</ref>. Following enrichment of plasma cells using magnetic activated cell sorting with CD138 immunobeads, interphase FISH analysis can be performed with [[Multiple Myeloma|MM]] specific probe sets or panels. These panels vary, but may include enumeration of ''CKS1B'' (1q21), ''CDKN2C'' (1p32), D9Z1/D15Z4 (CEN9, CEN15), ''RB1'' (13q14), ''TP53'' (17p13), and break-apart probes for ''MYC'' (8q24.1) or ''IGH'' (14q32.3) translocations, often with sequential reflex testing with dual-fusion FISH probes for the five common ''IGH'' partners: [t(4;14)(p16.3;q32); ''IGH-FGFR3''], [t(6;14)(p21;q32); ''IGH-CCND3''], [t(11;14)(q13;q32); ''IGH-CCND1''], [t(14;16)(q32;q23); ''IGH-MAF''], [t(14;20)(q32;q12); ''IGH-MAFB'']. Common cytogenetic aberrations overlap with those found in MM and MUGS, although frequencies differ; the aberrations include the t(11;14)(q13;q32), ''CCND1-IGH'' aberration that predominates (and as such a FISH panel may be tailored specifically for AL amyloidosis), with fewer cases of hyperdiploid and high-risk karyotypes<ref name=":10">{{Cite journal|last=Bochtler|first=Tilmann|last2=Hegenbart|first2=Ute|last3=Cremer|first3=Friedrich W.|last4=Heiss|first4=Christiane|last5=Benner|first5=Axel|last6=Hose|first6=Dirk|last7=Moos|first7=Marion|last8=Bila|first8=Jelena|last9=Bartram|first9=Claus R.|date=2008|title=Evaluation of the cytogenetic aberration pattern in amyloid light chain amyloidosis as compared with monoclonal gammopathy of undetermined significance reveals common pathways of karyotypic instability|url=https://ashpublications.org/blood/article/111/9/4700/24510/Evaluation-of-the-cytogenetic-aberration-pattern|journal=Blood|language=en|volume=111|issue=9|pages=4700–4705|doi=10.1182/blood-2007-11-122101|issn=0006-4971}}</ref><ref name=":11">{{Cite journal|last=Bochtler|first=Tilmann|last2=Hegenbart|first2=Ute|last3=Heiss|first3=Christiane|last4=Benner|first4=Axel|last5=Moos|first5=Marion|last6=Seckinger|first6=Anja|last7=Pschowski-Zuck|first7=Stephanie|last8=Kirn|first8=Désirée|last9=Neben|first9=Kai|date=2011|title=Hyperdiploidy is less frequent in AL amyloidosis compared with monoclonal gammopathy of undetermined significance and inversely associated with translocation t(11;14)|url=https://ashpublications.org/blood/article/117/14/3809/20514/Hyperdiploidy-is-less-frequent-in-AL-amyloidosis|journal=Blood|language=en|volume=117|issue=14|pages=3809–3815|doi=10.1182/blood-2010-02-268987|issn=0006-4971}}</ref><ref>{{Cite journal|last=Cj|first=Harrison|last2=H|first2=Mazzullo|last3=Fm|first3=Ross|last4=Kl|first4=Cheung|last5=G|first5=Gerrard|last6=L|first6=Harewood|last7=A|first7=Mehta|last8=Hj|first8=Lachmann|last9=Pn|first9=Hawkins|date=2002|title=Translocations of 14q32 and deletions of 13q14 are common chromosomal abnormalities in systemic amyloidosis|url=https://pubmed.ncbi.nlm.nih.gov/11972529/|language=en|pmid=11972529}}</ref><ref>{{Cite journal|last=Kobayashi|first=Hiroki|last2=Abe|first2=Yoshiaki|last3=Miura|first3=Daisuke|last4=Narita|first4=Kentaro|last5=Kitadate|first5=Akihiro|last6=Takeuchi|first6=Masami|last7=Matsue|first7=Kosei|date=2019|title=Prevalence and clinical implications of t(11;14) in patients with amyloid light-chain amyloidosis with or without concurrent multiple myeloma|url=https://academic.oup.com/jjco/article/49/2/195/5272727|journal=Japanese Journal of Clinical Oncology|language=en|volume=49|issue=2|pages=195–198|doi=10.1093/jjco/hyy202|issn=1465-3621}}</ref>. Hyperdiploidy and t(11;14) are mutually exclusive in AL amyloidosis<ref name=":10" /><ref name=":11" /><ref name=":12">{{Cite journal|last=Granzow|first=Martin|last2=Hegenbart|first2=Ute|last3=Hinderhofer|first3=Katrin|last4=Hose|first4=Dirk|last5=Seckinger|first5=Anja|last6=Bochtler|first6=Tilmann|last7=Hemminki|first7=Kari|last8=Goldschmidt|first8=Hartmut|last9=Schönland|first9=Stefan O.|date=2017|title=Novel recurrent chromosomal aberrations detected in clonal plasma cells of light chain amyloidosis patients show potential adverse prognostic effect: first results from a genome-wide copy number array analysis|url=http://www.haematologica.org/lookup/doi/10.3324/haematol.2016.160721|journal=Haematologica|language=en|volume=102|issue=7|pages=1281–1290|doi=10.3324/haematol.2016.160721|issn=0390-6078|pmc=PMC5566044|pmid=28341732}}</ref>. Recent studies have further characterized the clonal distribution of these aberrations: main clones are likely to contain the t(11;14) or t(''v'';14) ''IGH-v'' translocations, and hyperdiploidy, whereas subclones similar to those in Monoclonal gammopathy of undetermined significance (MGUS) and [[Multiple Myeloma|MM]] often carry gain of ''CKS1B'' (1q21), and deletions of 8p21 (''PNOC''), ''RB1'' (13q14), and ''TP53'' (17p13)<ref name=":9" />. Of note, the frequency of the t(11;14) aberration has been shown to decrease with the progression of the plasma cell dyscrasia<ref name=":9" />. However, the impact of plasma cell FISH on the outcomes of AL amyloidosis remains uncertain, with some well characterized genotype-outcome associations recently reported<ref name=":4" /><ref>{{Cite journal|last=Muchtar|first=E|last2=Dispenzieri|first2=A|last3=Kumar|first3=S K|last4=Ketterling|first4=R P|last5=Dingli|first5=D|last6=Lacy|first6=M Q|last7=Buadi|first7=F K|last8=Hayman|first8=S R|last9=Kapoor|first9=P|date=2017|title=Interphase fluorescence in situ hybridization in untreated AL amyloidosis has an independent prognostic impact by abnormality type and treatment category|url=http://www.nature.com/articles/leu2016369|journal=Leukemia|language=en|volume=31|issue=7|pages=1562–1569|doi=10.1038/leu.2016.369|issn=0887-6924}}</ref>. | ||
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</blockquote> | </blockquote> | ||
==Gene Mutations (SNV / INDEL)== | ==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 | !Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!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) | ||
!Notes | !Clinical Relevance Details/Other Notes | ||
|- | |- | ||
|<span class="blue-text">EXAMPLE:</span> | |<span class="blue-text">EXAMPLE:</span>''EGFR'' | ||
<span class="blue-text">EXAMPLE:</span> | <br /> | ||
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations | |||
|<span class="blue-text">EXAMPLE:</span> Oncogene | |||
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer) | |||
<span class="blue-text">EXAMPLE:</span> | |<span class="blue-text">EXAMPLE:</span> T | ||
|<span class="blue-text">EXAMPLE:</span> | |<span class="blue-text">EXAMPLE:</span> Yes (NCCN) | ||
|<span class="blue-text">EXAMPLE:</span> | |<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). | ||
|- | |||
<span class="blue-text">EXAMPLE:</span> | |<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations | ||
|<span class="blue-text">EXAMPLE:</span> | <br /> | ||
|<span class="blue-text">EXAMPLE:</span> | |<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 | |||
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|- | |||
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|}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. | |||
|} | |||
Note: A more extensive list of mutations can be found in | |||
<blockquote class= | <blockquote class="blockedit">{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote> | ||
Few studies have evaluated the genetic profile of bone marrow plasma cells from AL amyloidosis patients<ref name=":12" /><ref>{{Cite journal|last=López-Corral|first=L|last2=Sarasquete|first2=M E|last3=Beà|first3=S|last4=García-Sanz|first4=R|last5=Mateos|first5=M V|last6=Corchete|first6=L A|last7=Sayagués|first7=J M|last8=García|first8=E M|last9=Bladé|first9=J|date=2012|title=SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status|url=http://www.nature.com/articles/leu2012128|journal=Leukemia|language=en|volume=26|issue=12|pages=2521–2529|doi=10.1038/leu.2012.128|issn=0887-6924}}</ref><ref name=":13" /><ref>{{Cite journal|last=Weinhold|first=N|last2=Försti|first2=A|last3=da Silva Filho|first3=M I|last4=Nickel|first4=J|last5=Campo|first5=C|last6=Hoffmann|first6=P|last7=Nöthen|first7=M M|last8=Hose|first8=D|last9=Goldschmidt|first9=H|date=2014|title=Immunoglobulin light-chain amyloidosis shares genetic susceptibility with multiple myeloma|url=http://www.nature.com/articles/leu2014208|journal=Leukemia|language=en|volume=28|issue=11|pages=2254–2256|doi=10.1038/leu.2014.208|issn=0887-6924}}</ref>. A comprehensive evaluation by Paiva et al. (2016) identified 38 significantly deregulated (3 upregulated/35 downregulated) genes in AL amyloidosis plasma cells. Specifically, the tumor suppressor genes cadherin 1 (''CDH1'') and RCAN family member 3 (''RCAN''), and the pro-apoptotic genes GLI pathogenesis related 1 (''GLIPR1'') and Fas cell surface death receptor (''FAS'') were downregulated, whereas significant overexpression of the interferon induced transmembrane protein 1 (''IFITM1'') gene known to be associated with the development of aggressive solid tumors was observed<ref name=":13" /><ref>{{Cite journal|last=Yu|first=Fang|last2=Xie|first2=Dan|last3=Ng|first3=Samuel S.|last4=Lum|first4=Ching Tung|last5=Cai|first5=Mu-Yan|last6=Cheung|first6=William K.|last7=Kung|first7=Hsiang-Fu|last8=Lin|first8=Guimiao|last9=Wang|first9=Xiaomei|date=2015|title=IFITM1 promotes the metastasis of human colorectal cancer via CAV-1|url=https://linkinghub.elsevier.com/retrieve/pii/S0304383515005005|journal=Cancer Letters|language=en|volume=368|issue=1|pages=135–143|doi=10.1016/j.canlet.2015.07.034}}</ref> | Few studies have evaluated the genetic profile of bone marrow plasma cells from AL amyloidosis patients<ref name=":12" /><ref>{{Cite journal|last=López-Corral|first=L|last2=Sarasquete|first2=M E|last3=Beà|first3=S|last4=García-Sanz|first4=R|last5=Mateos|first5=M V|last6=Corchete|first6=L A|last7=Sayagués|first7=J M|last8=García|first8=E M|last9=Bladé|first9=J|date=2012|title=SNP-based mapping arrays reveal high genomic complexity in monoclonal gammopathies, from MGUS to myeloma status|url=http://www.nature.com/articles/leu2012128|journal=Leukemia|language=en|volume=26|issue=12|pages=2521–2529|doi=10.1038/leu.2012.128|issn=0887-6924}}</ref><ref name=":13" /><ref>{{Cite journal|last=Weinhold|first=N|last2=Försti|first2=A|last3=da Silva Filho|first3=M I|last4=Nickel|first4=J|last5=Campo|first5=C|last6=Hoffmann|first6=P|last7=Nöthen|first7=M M|last8=Hose|first8=D|last9=Goldschmidt|first9=H|date=2014|title=Immunoglobulin light-chain amyloidosis shares genetic susceptibility with multiple myeloma|url=http://www.nature.com/articles/leu2014208|journal=Leukemia|language=en|volume=28|issue=11|pages=2254–2256|doi=10.1038/leu.2014.208|issn=0887-6924}}</ref>. A comprehensive evaluation by Paiva et al. (2016) identified 38 significantly deregulated (3 upregulated/35 downregulated) genes in AL amyloidosis plasma cells. Specifically, the tumor suppressor genes cadherin 1 (''CDH1'') and RCAN family member 3 (''RCAN''), and the pro-apoptotic genes GLI pathogenesis related 1 (''GLIPR1'') and Fas cell surface death receptor (''FAS'') were downregulated, whereas significant overexpression of the interferon induced transmembrane protein 1 (''IFITM1'') gene known to be associated with the development of aggressive solid tumors was observed<ref name=":13" /><ref>{{Cite journal|last=Yu|first=Fang|last2=Xie|first2=Dan|last3=Ng|first3=Samuel S.|last4=Lum|first4=Ching Tung|last5=Cai|first5=Mu-Yan|last6=Cheung|first6=William K.|last7=Kung|first7=Hsiang-Fu|last8=Lin|first8=Guimiao|last9=Wang|first9=Xiaomei|date=2015|title=IFITM1 promotes the metastasis of human colorectal cancer via CAV-1|url=https://linkinghub.elsevier.com/retrieve/pii/S0304383515005005|journal=Cancer Letters|language=en|volume=368|issue=1|pages=135–143|doi=10.1016/j.canlet.2015.07.034}}</ref> | ||
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==Genes and Main Pathways Involved== | ==Genes and Main Pathways Involved== | ||
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: | |||
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span> | |||
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
|- | |- | ||
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome | !Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome | ||
|- | |- | ||
|<span class="blue-text">EXAMPLE:</span> BRAF and MAP2K1; Activating mutations | |<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations | ||
|<span class="blue-text">EXAMPLE:</span> MAPK signaling | |<span class="blue-text">EXAMPLE:</span> MAPK signaling | ||
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation | |<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation | ||
|- | |- | ||
|<span class="blue-text">EXAMPLE:</span> CDKN2A; Inactivating mutations | |<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations | ||
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation | |<span class="blue-text">EXAMPLE:</span> Cell cycle regulation | ||
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division | |<span class="blue-text">EXAMPLE:</span> Unregulated cell division | ||
|- | |- | ||
|<span class="blue-text">EXAMPLE:</span> | |<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations | ||
|<span class="blue-text">EXAMPLE:</span> | |<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling | ||
|<span class="blue-text">EXAMPLE:</span> | |<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program | ||
|- | |||
| | |||
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|} | |} | ||
==Genetic Diagnostic Testing Methods== | ==Genetic Diagnostic Testing Methods== | ||
Put your text here <span style="color:#0070C0">(''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')</span> | |||
==Familial Forms== | ==Familial Forms== | ||
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> | 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> | ||
==Additional Information== | ==Additional Information== | ||
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==References== | ==References== | ||
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking | (use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span> <references /> | ||
<br /> | |||
==Notes== | ==Notes== | ||
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA | <nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative. When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author. | ||
Prior Author(s): | |||
<nowiki>*</nowiki>''Citation of this Page'': “Immunoglobulin-related (AL) amyloidosis”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Immunoglobulin-related_(AL)_amyloidosis</nowiki>. | <nowiki>*</nowiki>''Citation of this Page'': “Immunoglobulin-related (AL) amyloidosis”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Immunoglobulin-related_(AL)_amyloidosis</nowiki>. | ||
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases I]] | [[Category:HAEM5]] | ||
[[Category:DISEASE]] | |||
[[Category:Diseases I]] | |||