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Molecular Screening in Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma: Anaplastic Lymphoma Kinase Analysis, Next-Generation Sequencing Fusion Gene Detection, and T-Cell Receptor Immunoprofiling

M. Kalinova, M. Mrhalova, E. Kabickova, M. Svaton, A. Skotnicova, Z. Prouzova, Z. Krenova, A. Kolenova, M. Divoka, E. Fronkova, R. Kodet

. 2024 ; 37 (3) : 100428. [pub] 20240123

Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc24006902

Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL) originates from the T-lineage and is marked by rearrangements of the ALK gene. More than 10 fusion partners with the ALK gene are known, with the most common being the t(2;5)(p23;q35) translocation resulting in the NPM1::ALK fusion. In 10% to 20% of the ALK+ ALCL cases, the ALK gene fuses with various other partners. Modern molecular techniques, especially next-generation sequencing (NGS), have eased the identification of ALK gene fusion partners and have allowed in-depth characterization of the T-cell receptor (TCR) repertoire. We devised a real-time quantitative reverse-transcription polymerase chain reaction to measure the expression of the translocated portion of the ALK gene. Fusion partners for the ALK gene were analyzed using rapid amplification of 5'cDNA ends (RACE) method or NGS. TCR immunoprofiling was performed by amplicon NGS. We studied 96 ALK+ ALCL patients. NPM1::ALK fusion gene was observed in 71 patients, ATIC::ALK in 9, and TPM3::ALK in 3. CLTC::ALK, MYH9::ALK, and RNF213::ALK fusions were identified in 2 patients each. We also discovered the TPM4::ALK and SATB1::ALK fusion genes, plus the following 2 previously unidentified ALK+ ALCL fusions: SQSTM1::ALK and CAPRIN1::ALK. High expression of the translocated ALK gene segment was observed in all 93 analyzed samples. TCR testing was conducted on 23 patients with available DNA. In 18 (78%) patients, we discerned at least one (ranging from 1 to 4) clonal TCR rearrangement. In 59% of the patients, clonal TCR beta junctions corresponded with sequences previously observed in both healthy donors and under various pathological conditions. Reverse-transcriptase quantitative detection of ALK expression is a fast and reliable method for both diagnosing and monitoring treatment response in ALK+ ALCL patients, irrespective of the ALK gene translocation. NGS reveals new ALK translocation partners. Both malignant and reactive TCR repertoires in ALK+ ALCL patients are unique and do not consistently occur among different patients.

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$a Kalinova, Marketa $u Department of Pathology, 3rd Faculty of Medicine, Charles University, Prague, Czech Republic; Central Laboratories, Faculty Hospital Kralovske Vinohrady, Prague, Czech Republic; Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic. Electronic address: marketa.kalinova@fnkv.cz
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$a Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK+ ALCL) originates from the T-lineage and is marked by rearrangements of the ALK gene. More than 10 fusion partners with the ALK gene are known, with the most common being the t(2;5)(p23;q35) translocation resulting in the NPM1::ALK fusion. In 10% to 20% of the ALK+ ALCL cases, the ALK gene fuses with various other partners. Modern molecular techniques, especially next-generation sequencing (NGS), have eased the identification of ALK gene fusion partners and have allowed in-depth characterization of the T-cell receptor (TCR) repertoire. We devised a real-time quantitative reverse-transcription polymerase chain reaction to measure the expression of the translocated portion of the ALK gene. Fusion partners for the ALK gene were analyzed using rapid amplification of 5'cDNA ends (RACE) method or NGS. TCR immunoprofiling was performed by amplicon NGS. We studied 96 ALK+ ALCL patients. NPM1::ALK fusion gene was observed in 71 patients, ATIC::ALK in 9, and TPM3::ALK in 3. CLTC::ALK, MYH9::ALK, and RNF213::ALK fusions were identified in 2 patients each. We also discovered the TPM4::ALK and SATB1::ALK fusion genes, plus the following 2 previously unidentified ALK+ ALCL fusions: SQSTM1::ALK and CAPRIN1::ALK. High expression of the translocated ALK gene segment was observed in all 93 analyzed samples. TCR testing was conducted on 23 patients with available DNA. In 18 (78%) patients, we discerned at least one (ranging from 1 to 4) clonal TCR rearrangement. In 59% of the patients, clonal TCR beta junctions corresponded with sequences previously observed in both healthy donors and under various pathological conditions. Reverse-transcriptase quantitative detection of ALK expression is a fast and reliable method for both diagnosing and monitoring treatment response in ALK+ ALCL patients, irrespective of the ALK gene translocation. NGS reveals new ALK translocation partners. Both malignant and reactive TCR repertoires in ALK+ ALCL patients are unique and do not consistently occur among different patients.
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$a Mrhalova, Marcela $u Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic
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$a Kabickova, Edita $u CLIP, Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
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$a Svaton, Michael $u CLIP, Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
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$a Skotnicova, Aneta $u CLIP, Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
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$a Prouzova, Zuzana $u Department of Pathology, 3rd Faculty of Medicine, Charles University, Prague, Czech Republic; Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic; Department of Pathology, 1st Faculty of Medicine, VFN, Charles University, Prague, Czech Republic
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$a Krenova, Zdenka $u Department of Pediatric Oncology, University Hospital Brno, Brno, Czech Republic; Department of Pediatrics, Faculty of Medicine Masaryk University, Brno, Czech Republic
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$a Kolenova, Alexandra $u Department of Pediatric Hematology and Oncology, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovak Republic
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$a Divoka, Martina $u Department of Hematooncology, Faculty Hospital Olomouc, Olomouc, Czech Republic
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$a Fronkova, Eva $u CLIP, Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic. Electronic address: eva.fronkova@lfmotol.cuni.cz
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$a Kodet, Roman $u Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic
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