B lymphoblastic leukaemia/lymphoma with ETV6::RUNX1 fusion

Revision as of 16:51, 6 September 2024 by Bailey.Glen (talk | contribs)

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent 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:B-Lymphoblastic Leukemia/Lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1.

(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, 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 to a table, click within the table and select the > symbol that appears to be given options. 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 Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support)

Primary Author(s)*

Marilena Melas, PhD; Yassmine Akkari, PhD, FACMG

Cancer Category/Type

B-Lymphoblastic Leukemia/Lymphoma

Cancer Category / Type

Put your text here

Cancer Sub-Classification / Subtype

B-Lymphoblastic Leukemia/Lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1

Definition / Description of Disease

  • 20 - 30% of childhood preB ALL; most common translocation (Chin Med J (Engl) 2003;116:1298) but not infants; also 3% of adult
  • Excellent prognosis due to good response to chemotherapy; 90% remissions; relapses occur later than other ALL

Mihova D. B lymphoblastic leukemia / lymphoma with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/leukemiapreBALLt1221.html. Accessed June 14th, 2020.

Synonyms / Terminology

B- Lymphoblastic Leukemia (B-ALL) is also known as Precursor B-Cell Lymphoblastic Leukemia, B-Cell...The t(12;21)(p13.2;q22.2) results in the in-frame fusion of the amino terminus of ETV6 (formally known as TEL ) with all known functional domains of RUNX1 (formally known as AML1)

Epidemiology / Prevalence

The t(12;21)(p13.2;q22.2) resulting in the ETV6-RUNX1 fusion is the most common chromosomal rearrangement in pediatric B-ALL present in ~25% of patients diagnosed between the ages of 2 and 10 years. The t(12;21) is less prevalent in adult B-ALL with an estimated incidence of ~3%

Clinical Features

Put your text here and fill in the table (Instruction: Can include references in the table. Do not delete table.)

Signs and Symptoms EXAMPLE: Asymptomatic (incidental finding on complete blood counts)

EXAMPLE: B-symptoms (weight loss, fever, night sweats)

EXAMPLE: Fatigue

EXAMPLE: Lymphadenopathy (uncommon)

Laboratory Findings EXAMPLE: Cytopenias

EXAMPLE: Lymphocytosis (low level)


editv4:Clinical Features
The content below was from the old template. Please incorporate above.

The presence of ETV6-RUNX1 alters differentiation and enhances self renewal of hematopoietic progenitor cells, particularly of B-lineage. The expression of ETV6-RUNX1 in human cord blood progenitor cells reportedly caused the expansion of a candidate pre-leukemic population that had a growth advantage in the presence of transforming growth factor-β

Sites of Involvement

bone marrow

Morphologic Features

No distinct morphologic features

Immunophenotype

Finding Marker
Positive (universal) CD10, CD19, CD34
Positive (subset) CD3, CD33
Negative (universal) CD9
Negative (subset) CD20

Chromosomal Rearrangements (Gene Fusions)

Put your text here and fill in the table

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE: t(9;22)(q34;q11.2) EXAMPLE: 3'ABL1 / 5'BCR EXAMPLE: der(22) EXAMPLE: 20% (COSMIC)

EXAMPLE: 30% (add reference)

Yes No Yes EXAMPLE:

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).


editv4:Chromosomal Rearrangements (Gene Fusions)
The content below was from the old template. Please incorporate above.
Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence
t(12;21)(p13.2;q22.1) ETV6-RUNX1 der(21)t(12;21) 25% of B-ALL cases


editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).
Please incorporate this section into the relevant tables found in:
  • Chromosomal Rearrangements (Gene Fusions)
  • Individual Region Genomic Gain/Loss/LOH
  • Characteristic Chromosomal Patterns
  • Gene Mutations (SNV/INDEL)

ETV6-RUNX1-positive ALL cells have distinct biologic features and are reported to have an increased in vitro sensitivity to anti-leukemic drugs such as L-asparaginase, doxorubicin, etoposide and dexamethasone compared with leukemic cells of other cytogenetic subtypes. The presence of ETV6-RUNX1 has been associated with a relatively low rate of relapse in multiple studies.Moreover, relapses tend to occur late and have a better salvage rate than other ALL subtypes. A COG (Children's Oncology Group) study indicated that the presence of ETV6-RUNX1 was an independent predictor of favorable outcome.However, in a study from the (DFCI) Dana Farber Cancer Institute Consortium, ETV6-RUNX1 status was not an independent prognostic factor after accounting for age, initial leukocyte count and treatment group.Thus, it is not clear whether the ETV6-RUNX1 fusion has independent prognostic significance in the context of current risk-adapted therapy and whether the outcome of children with ETV6-RUNX1-positive ALL can be further improved by contemporary therapeutic strategies.

Individual Region Genomic Gain / Loss / LOH

Put your text here and fill in the table (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. Do not delete table.)

Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE:

7

EXAMPLE: Loss EXAMPLE:

chr7:1- 159,335,973 [hg38]

EXAMPLE:

chr7

Yes Yes No EXAMPLE:

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:

8

EXAMPLE: Gain EXAMPLE:

chr8:1-145,138,636 [hg38]

EXAMPLE:

chr8

No No No EXAMPLE:

Common recurrent secondary finding for t(8;21) (add reference).

editv4:Genomic Gain/Loss/LOH
The content below was from the old template. Please incorporate above.

The 12p13 deletion is the most common accompanying abnormality found in approximately 40% of cases resulting in the loss of ETV6 on the chromosome not involved in the rearrangement. In addition, deletion of the CDKN2A/B locus on 9p21 or the PAX5 gene at 9p13 can be both seen in about a quarter of patients [29–32] . These abnormalities, as well as loss of 6q and gain of chromosome 16, are thought to be among the earliest genomic aberrations in t(12;21) positive B-ALL

Chromosome Number Gain/Loss/Amp/LOH Region
EXAMPLE: 8 EXAMPLE: Gain EXAMPLE: chr8:0-1000000
EXAMPLE: 7 EXAMPLE: Loss EXAMPLE: chr7:0-1000000

Characteristic Chromosomal Patterns

Put your text here (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. Do not delete table.)

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE:

Co-deletion of 1p and 18q

Yes No No EXAMPLE:

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 (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well as 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. Do not delete table.)

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; Variable LOF mutations

EXAMPLE:

EGFR; Exon 20 mutations

EXAMPLE: BRAF; Activating mutations

EXAMPLE: TSG EXAMPLE: 20% (COSMIC)

EXAMPLE: 30% (add Reference)

EXAMPLE: IDH1 R123H EXAMPLE: EGFR amplification EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).


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.

Epigenomic Alterations

Put your text here

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Can include references in the table. Do not delete table.)

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations EXAMPLE: MAPK signaling EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations EXAMPLE: Cell cycle regulation EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations EXAMPLE:  Histone modification, chromatin remodeling EXAMPLE:  Abnormal gene expression program

Genetic Diagnostic Testing Methods

FISH (dual and extra signal), RT-PCR. Since this translocation is cryptic, conventional chromosome analysis would not detect it.

Familial Forms

Family predisposition ?

Additional Information

Put your text here

Links

ETV6

RUNX1

Put your links here (use "Link" icon at top of page)

References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted. 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.)

Notes

*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 coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome. *Citation of this Page: “B lymphoblastic leukaemia/lymphoma with ETV6::RUNX1 fusion”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:B_lymphoblastic_leukaemia/lymphoma_with_ETV6::RUNX1_fusion.