Compendium of Cancer Genome Aberrations

Polymorphic lymphoproliferative disorders arising in immune deficiency / dysregulation

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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:Polymorphic Post-Transplant Lymphoproliferative Disorders.

Note: encompassing polymorphic PTLD, other iatrogenic immunodef-assoc lympho disorders, among others

(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 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 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 Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

Anna Shestakova, MD, PhD, Fellow, University of Utah/ARUP Laboratories

Fabiola Quintero-Rivera, MD, Professor, University of California Irvine (UCI)

WHO Essential and Desirable Genetic Diagnostic Criteria

(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)

WHO Essential Criteria (Genetics)*
WHO Desirable Criteria (Genetics)*
Other Classification

*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.

Related Terminology

(Instructions: The table will have the related terminology from the WHO autocompleted.)

Acceptable
Not Recommended

Gene Rearrangements

Cytogenetic abnormalities are uncommon in P-PTLD being present in approximately 15% of cases. [1]

Clonally rearranged Immunoglobulin (IG) genes IGH / IGK / IGL may be detected.

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
IGH (heavy chain on chromosome 14q32.13)     IGH Yes Unknown Unknown
IGK (kappa light chain on chromosome 2p11) IGK Yes Unknown Unknown
IGL (lambda light chain on chromosome 22q11) IGL Yes Unknown Unknown
t(1;3)(p36;p21) Unknown Unknown Unknown [2]
ins(11;?)(q23.1;?) Unknown Unknown Unknown [2]
t(1;17)(q21.3;p13) Unknown Unknown Unknown [1]
Inv(9)(p11q13) Unknown Unknown Unknown [1]

Individual Region Genomic Gain/Loss/LOH

Cytogenetic abnormalities are rare in P-PTLD. Trisomy X and trisomy 3 have been reported in the context of P-PTLD.

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
1 Loss 1q31-q44 [3]
3 trisomy Whole chromosome Possibly a recurrent finding Favorable, possibly Favorable, possibly [4] [5]
5 Gain 5p Unknown Unknown Unknown [3]
17 Loss 17q23-q25 [3]
X Loss Xp Unknown Unknown Unknown [3]
X trisomy Whole chromosome Unknown Unknown Unknown [1]

Characteristic Chromosomal or Other Global Mutational Patterns

Trisomy 3 may be a recurrent aberration.

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
Trisomy 3 Unknown Favorable, possibly Favorable, possibly [5][4]

Gene Mutations (SNV/INDEL)

The frequency of mutations in P-PTLD is lower, and variants seen are less deleterious, when compared to those seen in monomorphic PTLD. [6] [7] Mutations in BCL6 are reported in up to 50% of P-PTLD cases. [8]

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
BCL6 Oncogene NM_001130845.1

449T>C, 645G>C, 823T>A, 978G>A, 445C>G, 477T>C, 564T>C, 863A>G ,

443A>T, 506A>G, 668A>G, 802A>G, 803C>G, 837T>G  

Unknown Aggressive disease Aggressive disease [9] [10] [11]
BCL11B NM_0138576.3 H317Y Unknown Unknown Unknown [12]
IRS4 NM_003604.2 P930Q Unknown Unknown Unknown [13]
PAX5 Oncogene Unknown Unknown Unknown [14]
NOTCH1 Oncogene Unknown Unknown Unknown [15]
KRAS Oncogene Unknown Unknown Unknown [16]
JAK3 Oncogene Unknown Unknown Unknown [17]
TET2 TSG Unknown Unknown Unknown [18]
PTPN1 TSG Unknown Unknown Unknown [19]

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

Hypermethylation of O6-Methylguanine-DNA Methyl-Transferase (MGMT) is reported in 75% of P-PTLD [20]. MGMT is involved in DNA repair.

Hypermethylation of SHP1 is observed in 75% of P-PTLD. [20] The SHP1 gene is located on chromosome 12p13 and encodes the SHP1 protein. The protein is expressed in hematopoietic cells and potentiates its negative effect on cell cycle regulation by inhibiting the JAK/STAT pathway.

Genes and Main Pathways Involved

Put your text here and fill in the table

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
BCL6, mutation BCL6 is a transcription factor, prevents apoptosis Lymphoma, shuts of normal differentiation in B-cells.
Hypermethylation of O6-Methylguanine-DNA Methyl-Transferase (MGMT) MGMT is one of the DNA repair genes that serves to protect against DNA damage Damage of DNA.
Hypermethylation of SHP1


The SHP1 protein is expressed in hematopoietic cells and potentiates its negative effect on cell cycle regulation by inhibiting the JAKs/STATs pathway Activation of JAK/STAT pathway

Genetic Diagnostic Testing Methods

Conventional cytogenetics, FISH, NGS

Familial Forms

Not known

Additional Information

Separate lesions may contain distinct and different clonal populations. [21]

Significant T-cell clones are not expected.

EBV terminal repeat analysis is the most sensitive method for detection of clonal populations in EBV+ cases.

P-PTLD is similar to non-germinal center monomorphic PTLD, when assessed using gene expression profiling. [1][2]

Links

Note: A more extensive list of mutations can be found in:

cBioportal https://www.cbioportal.org/(https://www.cbioportal.org/),

COSMIC (https://cancer.sanger.ac.uk/cosmic),

ICGC [1] (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

BCL6 https://cancer.sanger.ac.uk/cosmic/gene/analysis?all_data=y&coords=AA%3AAA&dr=&end=707&gd=&genome=37&id=1369&ln=BCL6&seqlen=707&sn=large_intestine&src=gene&start=1

BCLB11B https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=BCL11B

IRS4 https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=irs4

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Djokic, Miroslav; et al. (2005). "Post-transplant lymphoproliferative disorder subtypes correlate with different recurring chromosomal abnormalities". Genes, Chromosomes and Cancer. 45 (3): 313–318. doi:10.1002/gcc.20287. ISSN 1045-2257.
  2. ↑ 2.0 2.1 2.2 Vakiani, Efsevia; et al. (2008-12). "Genetic and phenotypic analysis of B-cell post-transplant lymphoproliferative disorders provides insights into disease biology". Hematological Oncology. 26 (4): 199–211. doi:10.1002/hon.859. ISSN 0278-0232. Check date values in: |date= (help)
  3. ↑ 3.0 3.1 3.2 3.3 Poirel, Hélène A.; et al. (2005-07-27). "Characteristic Pattern of Chromosomal Imbalances in Posttransplantation Lymphoproliferative Disorders: Correlation with Histopathological Subcategories and EBV Status". Transplantation. 80 (2): 176–184. doi:10.1097/01.tp.0000163288.98419.0d. ISSN 0041-1337.
  4. ↑ 4.0 4.1 Gallego, Marta S.; et al. (2002-05-19). "Trisomy 3 in two paediatric post-transplant lymphomas". British Journal of Haematology. 117 (3): 558–562. doi:10.1046/j.1365-2141.2002.03481.x. ISSN 0007-1048.
  5. ↑ 5.0 5.1 Shestakova, Anna; et al. (2020-10). "Trisomy 3, a sole recurrent cytogenetic abnormality in pediatric polymorphic post-transplant lymphoproliferative disorder (PTLD)". Cancer Genetics. 248-249: 39–48. doi:10.1016/j.cancergen.2020.09.006. ISSN 2210-7762. Check date values in: |date= (help)
  6. ↑ Menter, Thomas; et al. (2017-04-17). "Mutational landscape of B-cell post-transplant lymphoproliferative disorders". British Journal of Haematology. 178 (1): 48–56. doi:10.1111/bjh.14633. ISSN 0007-1048.
  7. ↑ Butzmann, Alexandra; et al. (2022-01-17). "Mutations in JAK/STAT and NOTCH1 Genes Are Enriched in Post-Transplant Lymphoproliferative Disorders". Frontiers in Oncology. 11. doi:10.3389/fonc.2021.790481. ISSN 2234-943X.
  8. ↑ Cesarman, E.; et al. (1998-10-01). "BCL-6 gene mutations in posttransplantation lymphoproliferative disorders predict response to therapy and clinical outcome". Blood. 92 (7): 2294–2302. ISSN 0006-4971. PMID 9746767.
  9. ↑ Capello, D. (2003-07-31). "Molecular histogenesis of posttransplantation lymphoproliferative disorders". Blood. 102 (10): 3775–3785. doi:10.1182/blood-2003-05-1683. ISSN 0006-4971.
  10. ↑ Cesarman, Ethel; et al. (1998-10-01). "BCL-6 Gene Mutations in Posttransplantation Lymphoproliferative Disorders Predict Response to Therapy and Clinical Outcome". Blood. 92 (7): 2294–2302. doi:10.1182/blood.v92.7.2294. ISSN 1528-0020.
  11. ↑ Morscio, J.; et al. (2013). "Molecular Pathogenesis of B-Cell Posttransplant Lymphoproliferative Disorder: What Do We Know So Far?". Clinical and Developmental Immunology. 2013: 1–13. doi:10.1155/2013/150835. ISSN 1740-2522.
  12. ↑ Butzmann, Alexandra; et al. (2022-01-17). "Mutations in JAK/STAT and NOTCH1 Genes Are Enriched in Post-Transplant Lymphoproliferative Disorders". Frontiers in Oncology. 11. doi:10.3389/fonc.2021.790481. ISSN 2234-943X.
  13. ↑ Butzmann, Alexandra; et al. (2022-01-17). "Mutations in JAK/STAT and NOTCH1 Genes Are Enriched in Post-Transplant Lymphoproliferative Disorders". Frontiers in Oncology. 11. doi:10.3389/fonc.2021.790481. ISSN 2234-943X.
  14. ↑ Menter, Thomas; et al. (2017-04-17). "Mutational landscape of B-cell post-transplant lymphoproliferative disorders". British Journal of Haematology. 178 (1): 48–56. doi:10.1111/bjh.14633. ISSN 0007-1048.
  15. ↑ Menter, Thomas; et al. (2017-04-17). "Mutational landscape of B-cell post-transplant lymphoproliferative disorders". British Journal of Haematology. 178 (1): 48–56. doi:10.1111/bjh.14633. ISSN 0007-1048.
  16. ↑ Menter, Thomas; et al. (2017-04-17). "Mutational landscape of B-cell post-transplant lymphoproliferative disorders". British Journal of Haematology. 178 (1): 48–56. doi:10.1111/bjh.14633. ISSN 0007-1048.
  17. ↑ Menter, Thomas; et al. (2017-04-17). "Mutational landscape of B-cell post-transplant lymphoproliferative disorders". British Journal of Haematology. 178 (1): 48–56. doi:10.1111/bjh.14633. ISSN 0007-1048.
  18. ↑ Menter, Thomas; et al. (2017-04-17). "Mutational landscape of B-cell post-transplant lymphoproliferative disorders". British Journal of Haematology. 178 (1): 48–56. doi:10.1111/bjh.14633. ISSN 0007-1048.
  19. ↑ Menter, Thomas; et al. (2017-04-17). "Mutational landscape of B-cell post-transplant lymphoproliferative disorders". British Journal of Haematology. 178 (1): 48–56. doi:10.1111/bjh.14633. ISSN 0007-1048.
  20. ↑ 20.0 20.1 Ibrahim, Hazem A. H.; et al. (2012). "Posttransplant Lymphoproliferative Disorders". Advances in Hematology. 2012: 1–11. doi:10.1155/2012/230173. ISSN 1687-9104.
  21. ↑ Chadburn, Amy; et al. (1995-06-01). <2747::aid-cncr2820751119>3.0.co;2-3 "Molecular genetic analysis demonstrates that multiple posttransplantation lymphoproliferative disorders occurring in one anatomic site in a single patient represent distinct primary lymphoid neoplasms". Cancer. 75 (11): 2747–2756. doi:10.1002/1097-0142(19950601)75:11<2747::aid-cncr2820751119>3.0.co;2-3. ISSN 0008-543X.

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: “Polymorphic lymphoproliferative disorders arising in immune deficiency / dysregulation”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/12/2025, https://ccga.io/index.php/HAEM5:Polymorphic_lymphoproliferative_disorders_arising_in_immune_deficiency_/_dysregulation.

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