An update of novel identified cytogenetic and molecular biomarkers in the laboratory diagnosis of hematological neoplasia
-
Tanja Hinrichsen
,
Stefanie Kuehner
Abstract
Cancer diagnosis and identification of novel biomarkers are a rapidly changing field and open new doors into personalized medicine. Particularly in the diagnosis of hematological neoplasia, the identification of novel biomarkers has become more important because of biological sub-classification, prognosis and targeted and individualized therapies. Therefore, techniques like blood count, morphology, cytochemistry, histology, immunophenotyping, cytogenetics and molecular genetics are essential and cannot be denied nowadays. In the last years, a broad spectrum of novel molecular biomarkers has been identified in the genetic and molecular characterization of myelodysplastic syndromes. Lots of these novel molecular biomarkers gained entry in the routine diagnostics and provide an excess profit for patients. However, to ensure a cost-effective, targeted and individualized diagnostic testing, application of existing techniques has to be weighed against each other to obtain the best possible combination of targeted diagnostics. This review summarized thus far the diagnostic-relevant morphologic, cytogenetic and molecular biomarkers in the laboratory diagnosis of hematological neoplasia.
Zusammenfassung
Die Krebsdiagnostik und die Identifizierung von neuen Biomarkern ist ein sehr schnelllebiges Feld und öffnet aufgrund neuer Technologien die Türen zur personalisierten Medizin. Besonders in der Diagnostik hämatologischer Neoplasien ist die Identifizierung neuer Biomarker enorm wichtig hinsichtlich der biologischen Subklassifikation, der Prognose und der zielgerichteten individuellen Therapie. Deshalb sind Techniken wie Blutbild, Morphologie, Zytochemie, Histologie, Immunphänotypisierung sowie der Zytogenetik und der Molekulargenetik heutzutage nicht mehr wegzudenken. In den letzten Jahren wurde eine Vielzahl von neuen Biomarkern in der molekulargenetischen Charakterisierung des myelodysplastischen Syndroms (MDS) entdeckt. Viele der neuen Biomarker hielten Einzug in die Routine-Diagnostik und stellen einen enormen Profit für die Patienten dar. Um eine kosten-effektive, zielgerichtete sowie individuelle Diagnostik zu gewährleisten, sollten die bestehenden Methoden gegeneinander abgewogen und eingesetzt werden, um eine bestmögliche Patientenversorgung zu sichern. Dieses Review fasst die bisher diagnostisch relevanten Biomarker von hämatologischen Neoplasien hinsichtlich Morphologie, Zytogenetik und Molekulargenetik zusammen.
Reviewed Publication:
Klein H.-G.
| Classification | B-cell antigenes | T-cell antigenes | Other antigenes | Cytogenetics | Molecular genetics | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CD19 | CD20 | CD22 | CD23 | CD3 | CD5 | CD7 | Karyogram | FISH | |||||
| Precursor B-cell lymphoma | |||||||||||||
| B lymphoblastic leukaemia/lymphoma | + | +/– | + | – | – | – | CD10 +; cyCD79a; CD24; TdT; CD34 + /–; CD45dim; CD13+/–; CD33+/– | Yes | Maybe accordingly subtype (s.b.) del(6q) del(9p) del(12p) t(17;19)(q22;p13) | E2A-HLF | |||
| Mature B-cell neoplasms | |||||||||||||
| Chronic lymphocytic leukaemia/small lymphocytic lymphoma | + | + | +/– | + | – | + | – | FMC7–; CD10–; CD200+; CD79a+; CD43+; sIg(+); prognostisch: CD38; ZAP-70 | Recommended | del(13q) +12 del(17p) del(11q) del(6q) 14q32-rg | IgVH mutation status TP53 BIRC3 NOTCH1 SF3B1 FBXW7 MYD88 XPO1 ATM | ||
| B-cell prolymphocytic leukaemia | + | + | + | – | – | – | – | FMC7+; CD79a+; sIg+ | Yes | del(13q) del(17p) del(11q) del(6q) +8q24 14q32-rg | TP53 | ||
| Lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia | + | + | + | – | – | – | – | CD38+; sIg +; CD43+/– | Yes | del(6q) +3 +4 +18 14q32-rg del(13q) del(17p) | MYD88 CXCR4 | ||
| Splenic marginal zone lymphoma | + | + | + | – | – | – | – | CD11c+; sIg+ CD103– | Yes | del(7q) del(8p) del(14q) +3q +8q +12q t(11;18)(q21;q21) 14q32-rg del(17p) | NOTCH2 KLF2 TP53 TNFAIP3 MYD88 ARID1A | ||
| Hairy cell leukaemia | + | + | + | – | – | – | – | CD103+; CD11c+; CD123+; CD25+(HCL)/CD25-(HCLv); sIg+ | Recommended | 14q32-rgdel(17p)+5del(6q)del(11q) +12 | BRAF | ||
| Plasma cell myeloma | –/+ | –/+ | CD38+; CD138+; CD56+; CD10–/+; sIg–/+ | Recommended | 14q32-rg t(4;14)(p16;q32) t(6;14)(p21;q32) t(11;14)(q13;q32) t(14;16)(q32;q23) t(14;20)(q32;q12) +5 +7 +11 del(13q)/–13 del(17p) +1q –1p 8q24-rg | NRAS KRAS BRAF TP53 | |||||||
| Monoclonal gammopathy of undetermined significance (MGUS) | – | Monoklonale Zellen: CD56+; CD38(+) | No | 14q32-rg t(4;14)(p16;q32) t(6;14)(p21;q32) t(11;14)(q13;q32) t(14;16)(q32;q23) t(14;20)(q32;q12) +5 +7 +11 del(13q)/–13 del(17p) +1q –1p 8q24-rg | NRAS KRAS BRAF TP53 | ||||||||
| Follicular lymphoma | + | + | + | +/– | – | – | – | CD10+/–; sIg+ | Yes | 14q32-rg t(14;18)(q32;q21) 3q27-rg del(17)(p13) +12 del(6q) 8q24-rg | IGH-BCL2 TP53 EZH2 MLL2 CREBBP TNFRSF14 | ||
| Mantle cell lymphoma | + | + | + | – | – | + | – | FMC7+; CD79a+; sIg+ | Yes | 14q32-rg t(11;14)(q13;q32); +3q del(6q) del(9q) del(17p) del(11q) del(13q) t(8;14)(q24;q32) | CCND1-IGH ATM CCND1 TP53 UBR5 BIRC3 NOTCH1 NOTCH2 | ||
| Diffuse large B-cell lymphoma | + | + | + | +/– | – | – | – | FMC7+/–; CD79a+; CD10+/–; sIg+/– | Yes | 3q27-rg 14q32-rg 8q24-rg t(14;18)(q32;q21) del(17)(p13) | TP53 EZH2 CD79A/B CARD11 MYD88 TNFAIP3 | ||
| Burkitt lymphoma/leukemia | Corresponds to mature B-ALL in terms of immunophenotype | Yes | t(8;14)(q24;q32) 8q24-rg 18q21-rg 3q27-rg | IGH-MYC | |||||||||
| Precursor T-cell neoplasms | |||||||||||||
| T-lymphoblastic leukaemia/lymphoma | – | – | – | – | – | – | + | TdT+; cCD3+ | Yes | 14q11.2-rg 14q32-rg 7q35-rg 7p14-15-rg 11q23-rg | SIL-TAL1 CALM-AF10 NOTCH1 FBXW7 | ||
| Blastic NK-cell lymphoma | – | – | – | – | – | – | +/– | CD2+; CD16+; CD56+; CD57+; CD8+/–; HLA–DR+ | Yes | No specific changes | |||
| Mature T-cell and NK-cell leukaemia/lymphoma | |||||||||||||
| T-cell prolymphocytic leukaemia | – | – | – | – | + | + | + | CD7+; CD4+; CD8–/+; TCRab+prognostisch: CD52+ | Yes | 14q11-rg 14q32-rg Chromosom 8 del(12p) del(11q) del(17p) | TCR rearrangement ATM TP53 JAK3 | ||
| T-cell large granular lymphocytic leukaemia | – | – | – | – | + | + | +/– | CD2+; CD4–/+; CD8+; TCRab+; HLADR+ | No specific change known | TCR rearrangement STAT3 | |||
| Aggressive NK cell leukaemia | – | – | – | – | – | – | – | cCD3+/–; CD4–; CD8–/+; CD2+; CD16+;CD56+; CD57–/+; CD52–/+ | Recommended | del(7p) del(17p) +1q | |||
| Adult T-cell leukaemia/lymphoma | – | – | – | – | + | + | – | CD2+; CD4+; CD8–; TCRab+ | No specific change known | TCR rearrangement | |||
| Extranodal NK/T cell lymphoma, nasal type | – | – | – | – | – | – | – | cCD3+; CD4–; CD8–/+; CD2+; CD56+; CD57– | Only at leuc. course | evtl. del(6q) | |||
| Hepatosplenic T-cell lymphoma | – | – | – | – | + | – | + | CD4–; CD8+/–; CD2+; CD56+; CD57– | Only at leuc. course | i(7)(q10) 7q-changes +8 | TCR rearrangement | ||
| Sézary syndrome | – | – | – | – | + | + | – | CD2+; CD4+; CD8– TCRab+; CD52+ | Recommended | del(9p) del(17p) | TCR rearrangement TP53 | ||
| Peripheral T-cell lymphoma, unspecified | – | – | – | – | + | –/+ | –/+ | CD4+/–; CD8–/+; CD2+ | Yes | del(5q) del(10q) del(12q) | TCR rearrangement | ||
| Acute myeloid leukemia | CD13 | CD33 | CD65 | cMPO | CD117 | CD34 | CD64 | ||||||
| M 0 | +/– | +/– | – | –/+ | +/– | +/– | – | Yes | del(5q)/–5 del(7q)/–7 +8 del(11q) | At inconspicuous bzw. intermediate karyotype, count for all subgroups: FLT3-ITD NPM1 CEBPA RUNX1 MLL-PTD ASXL1 BCOR DNMT3A FLT3-TKD GATA2 IDH1 IDH2 | |||
| M 1 | +/– | +/– | – | +/– | +/– | +/– | – | Yes | del(5q)/–5 del(7q)/–7 +8 | ||||
| M 2 | + | +/– | – | + | + | +/– | – | Yes | t(8;21)(q22,q22) t(6;9)(p23;q34) | RUNX1-RUNX1T1 DEK-NUP214 | |||
| M 3 M 3v | +/– | + | – | + | +/– | +/– | – | HLA-DR- | Yes Yes | t(15;17)(q22;q12) 17q–rg +8 | PML-RARa | ||
| M 4 | + | + | + | + | +/– | +/– | + | Yes | inv(16)(p13.1q22) t(16;16)(p13.1;q22) t(6;9)(p23;q34) +22 +8 del(7q) +21 | CBFB-MYH11 DEK-NUP214 KIT | |||
| M 4 Eo | Yes | KIT | |||||||||||
| M 5a | +/– | + | +/– | –/+ | +/– | – | + | Yes | t(9;11)(p22;q23) 11q23-rg t(8;16)(p11.2;p13.3)? | KMT2A rearrangement | KRAS NRAS PTPN11 TET2 TP53 WT1 | ||
| M 5b | +/– | + | +/– | +/– | +/– | – | + | Yes | |||||
| M 6 | +/– | +/– | – | – | +/– | – | – | Yes | del(5q)/–5 del(7q)/–7 +8 | ||||
| M 7 | +/– | +/– | – | – | – | –/+ | – | Yes | t(1;22)(p13;q13) t(3;3)(q21;q26.2) inv(3)(q21;q26.2) | RBM15-MKL1 RPN1-EVI1 | |||
| Acute lymphocytic leukaemia (ALL) | CD19 | CD20 | CD22 | cCD79a | cCD22 | CD34 | CD10 | ||||||
| B-cell precursor ALL | |||||||||||||
| Pro-B-ALL | + | – | +/– | + | +/– | +/– | – | TdT+ | Yes | t(4;11)(q21;q23) 11q23-rg | MLL-MLLT2 MLL-MLLT1 | ||
| Common-ALL | + | –/+ | +/– | + | + | +/– | + | TdT+ | Yes | t(9;22)(q34;q11.2) del(6q) | BCR-ABL1 ABL1 | ||
| Pre-B-All | + | –/+ | +/– | + | + | +/– | +/– | TdT+; cIgM+ | Yes | t(1;19)(q23;p13) t(12;21)(p13;q22) del(9p) del(6q) | E2A-PBX ETV6-RUNX1 | ||
| Mature B-ALL | + | + | + | + | + | – | +/– | sIg+; c/sIgM+ | Yes | t(8;14)(q24;q32) | IGH-MYC | ||
| T-cell precursor ALL | CD3 | CD2 | CD5 | CD7 | cCD3 | CD34 | CD10 | ||||||
| Pro-T-ALL | – | – | – | + | + | –/+ | –/+ | Yes | 14q11.2-rg del(6q) del(9p) 1p32-rg 5q35-rg 7q34-rg 10q24-rg 11q23-rg | HOX11-TCR SIL-TAL1 CALM-AF10 NOTCH1 FBXW7 DNMT3A IDH1 IDH2 RUNX1 PHF6 | |||
| Pre-T-ALL | – | +/– | +/– | + | + | –/+ | –/+ | Yes | |||||
| Cortical T-ALL | –/+ | + | + | + | +/– | – | –/+ | CD1a + | Yes | ||||
| Mature T-ALL | + | + | + | + | – | – | –/+ | Yes | |||||
| Myeloproliferative neoplasms | |||||||||||||
| Chronic myelogenous leukaemia (CML) | Yes | t(9;22)(q34;q11.2) +8 i(17q) +19 | BCR-ABL1 ABL1 | ||||||||||
| Chronic neutrophilic leukaemia | Recommended | Maybe for exclusion | CSF3R ASXL1 SETBP1 ELANE (discrimination SCN) BCR-ABL (discrimination CML) | ||||||||||
| Polycythaemia vera | Recommended during course | +8 +9 del(20q) del(13q) | JAK2 EZH2 TET2 PRV1 expression | ||||||||||
| Essential thrombocythaemia (ET) | No | Maybe for exclusion | JAK2 MPL CALR TET2 PRV1 expression | ||||||||||
| Primary myelofibrosis | Recommended | del(13q) der(6)t(1;6) del(20q) +1q +9 +8 | JAK2 MPL CALR ASXL1 EZH2 IDH1 IDH2 SRSF2 TET2 PRV1 expression | ||||||||||
| Chronic eosinophilic leukaemia/Hypereosinophilic syndrome | Yes | del(4)(q12) 5q31-31-rg 8p11-rg +8 –7 del(12p) i(17q) | FIP1L1-PDGFRA ETV6-PDGFRB ZNF198-FGFR1 | ||||||||||
| Mastocytosis | Yes | – | KIT | ||||||||||
| Myelodysplastic/myeloproliferative neoplasms | |||||||||||||
| Chronic myelomonocytic leukaemia | Recommended | +8 –7/del(7q) 12p-rg t(9;22)(q34;q11.2) 5q31-q33-rg | ASXL1 CBL EZH2 JAK2 KIT | ||||||||||
| del(4q) del(20q) | KRAS NRAS RUNX1 SRSF2 TET2 | ||||||||||||
| Atypical chronic myeloid leukaemia | Yes | +8 del(20q) | ASXL1 CBL CSF3R KRAS NRAS SETBP1 | ||||||||||
| Juvenile myelomonocytic leukaemia | Yes | –7 | PTPN11NRASKRASNF1 | ||||||||||
| Myelodysplastic syndrome | |||||||||||||
| Myelodysplastic syndrome | Yes | 3q26-rg del(4q) del(5q)/–5 del(7q)/–7 +8 del(17p) del(20q) –Y | ASXL1 DNMT3A ETV6 EZH2 NRAS RUNX1 SF3B1 SRSF2 TET2 TP53 U2AF1 ZRSR2 BCOR CBL CEBPa KIT KRAS NPM1 PTEN PTPN11 | ||||||||||
Conclusions
In conclusion, molecular biomarkers are essential for the sub-classification of patients suffering from hematological neoplasia to save diagnosis. Therefore, it is important to steadily indentify novel biomarkers concerning immunophenotypes, cytogenetics and molecular genetics to increase basic understanding of the molecular mechanisms of hematological neoplasia and to relieve sub-classification to manage the patients at the best possible rate.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
©2015 by De Gruyter
This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Articles in the same Issue
- Frontmatter
- Editorial
- Aktuelle Diagnostik in der Hämatologie
- Hämatologie/Hematology
- Stufendiagnostik zur Abklärung von krankhaften Veränderungen der Leukozyten
- Rationale Anämieabklärung
- Diagnostik von myelodysplastischen Syndromen (MDS) und akuten myeloischen Leukämien (AML)
- Differenzialdiagnose BCR-ABL1-negativer myeloproliferativer Neoplasien
- Hämoglobinvarianten – Pathomechanismus, Symptome und Diagnostik
- Molekulargenetische und zytogenetische Diagnostik/Molecular-Genetic and Cytogenetic Diagnostics
- An update of novel identified cytogenetic and molecular biomarkers in the laboratory diagnosis of hematological neoplasia
- Stufendiagnostik der Hämoglobinopathien
- Rational laboratory diagnostics of primary immunodeficiency disorders
Articles in the same Issue
- Frontmatter
- Editorial
- Aktuelle Diagnostik in der Hämatologie
- Hämatologie/Hematology
- Stufendiagnostik zur Abklärung von krankhaften Veränderungen der Leukozyten
- Rationale Anämieabklärung
- Diagnostik von myelodysplastischen Syndromen (MDS) und akuten myeloischen Leukämien (AML)
- Differenzialdiagnose BCR-ABL1-negativer myeloproliferativer Neoplasien
- Hämoglobinvarianten – Pathomechanismus, Symptome und Diagnostik
- Molekulargenetische und zytogenetische Diagnostik/Molecular-Genetic and Cytogenetic Diagnostics
- An update of novel identified cytogenetic and molecular biomarkers in the laboratory diagnosis of hematological neoplasia
- Stufendiagnostik der Hämoglobinopathien
- Rational laboratory diagnostics of primary immunodeficiency disorders
