Delineation of Molecular Lesions in Acute Myeloid Leukemia Patients at Diagnosis: Integrated Next Generation Sequencing and Cytogenomic Studies
Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by a wide range of genetic defects. Cytogenetics, molecular and genomic technologies have proved to be helpful for deciphering the mutational landscape of AML and impacted clinical practice. Forty-eight new AML patients were inve...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-05-01
|
| Series: | Genes |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4425/12/6/846 |
| _version_ | 1797531974831702016 |
|---|---|
| author | Sorina Mihaela Papuc Alina Erbescu Diana Cisleanu Diana Ozunu Cristina Enache Ion Dumitru Elena Lupoaia Andrus Mihaela Gaman Viola Maria Popov Maria Dobre Oana Stanca Silvana Angelescu Nicoleta Berbec Andrei Colita Ana-Maria Vladareanu Horia Bumbea Aurora Arghir |
| author_facet | Sorina Mihaela Papuc Alina Erbescu Diana Cisleanu Diana Ozunu Cristina Enache Ion Dumitru Elena Lupoaia Andrus Mihaela Gaman Viola Maria Popov Maria Dobre Oana Stanca Silvana Angelescu Nicoleta Berbec Andrei Colita Ana-Maria Vladareanu Horia Bumbea Aurora Arghir |
| author_sort | Sorina Mihaela Papuc |
| collection | DOAJ |
| description | Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by a wide range of genetic defects. Cytogenetics, molecular and genomic technologies have proved to be helpful for deciphering the mutational landscape of AML and impacted clinical practice. Forty-eight new AML patients were investigated with an integrated approach, including classical and molecular cytogenetics, array-based comparative genomic hybridization and targeted next generation sequencing (NGS). Various genetic defects were identified in all the patients using our strategy. Targeted NGS revealed known pathogenic mutations as well as rare or unreported variants with deleterious predictions. The mutational screening of the normal karyotype (NK) group identified clinically relevant variants in 86.2% of the patients; in the abnormal cytogenetics group, the mutation detection rate was 87.5%. Overall, the highest mutation prevalence was observed for the <i>NPM1</i> gene, followed by <i>DNMT3A, FLT3</i> and <i>NRAS</i>. An unexpected co-occurrence of <i>KMT2A</i> translocation and <i>DNMT3A</i>-R882 was identified; alterations of these genes, which are involved in epigenetic regulation, are considered to be mutually exclusive. A microarray analysis detected CNVs in 25% of the NK AML patients. In patients with complex karyotypes, the microarray analysis made a significant contribution toward the accurate characterization of chromosomal defects. In summary, our results show that the integration of multiple investigative strategies increases the detection yield of genetic defects with potential clinical relevance. |
| first_indexed | 2024-03-10T10:52:26Z |
| format | Article |
| id | doaj.art-2d519916b295498a8d18680b4c12e5f0 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T10:52:26Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-2d519916b295498a8d18680b4c12e5f02023-11-21T22:07:46ZengMDPI AGGenes2073-44252021-05-0112684610.3390/genes12060846Delineation of Molecular Lesions in Acute Myeloid Leukemia Patients at Diagnosis: Integrated Next Generation Sequencing and Cytogenomic StudiesSorina Mihaela Papuc0Alina Erbescu1Diana Cisleanu2Diana Ozunu3Cristina Enache4Ion Dumitru5Elena Lupoaia Andrus6Mihaela Gaman7Viola Maria Popov8Maria Dobre9Oana Stanca10Silvana Angelescu11Nicoleta Berbec12Andrei Colita13Ana-Maria Vladareanu14Horia Bumbea15Aurora Arghir16Victor Babes National Institute of Pathology, 050096 Bucharest, RomaniaVictor Babes National Institute of Pathology, 050096 Bucharest, RomaniaCarol Davila University of Medicine and Pharmacy, 050474 Bucharest, RomaniaVictor Babes National Institute of Pathology, 050096 Bucharest, RomaniaCarol Davila University of Medicine and Pharmacy, 050474 Bucharest, RomaniaEmergency Universitary Clinical Hospital, 050098 Bucharest, RomaniaCarol Davila University of Medicine and Pharmacy, 050474 Bucharest, RomaniaCarol Davila University of Medicine and Pharmacy, 050474 Bucharest, RomaniaColentina Clinical Hospital, 020125 Bucharest, RomaniaVictor Babes National Institute of Pathology, 050096 Bucharest, RomaniaCarol Davila University of Medicine and Pharmacy, 050474 Bucharest, RomaniaCarol Davila University of Medicine and Pharmacy, 050474 Bucharest, RomaniaCarol Davila University of Medicine and Pharmacy, 050474 Bucharest, RomaniaCarol Davila University of Medicine and Pharmacy, 050474 Bucharest, RomaniaCarol Davila University of Medicine and Pharmacy, 050474 Bucharest, RomaniaCarol Davila University of Medicine and Pharmacy, 050474 Bucharest, RomaniaVictor Babes National Institute of Pathology, 050096 Bucharest, RomaniaAcute myeloid leukemia (AML) is a heterogeneous disorder characterized by a wide range of genetic defects. Cytogenetics, molecular and genomic technologies have proved to be helpful for deciphering the mutational landscape of AML and impacted clinical practice. Forty-eight new AML patients were investigated with an integrated approach, including classical and molecular cytogenetics, array-based comparative genomic hybridization and targeted next generation sequencing (NGS). Various genetic defects were identified in all the patients using our strategy. Targeted NGS revealed known pathogenic mutations as well as rare or unreported variants with deleterious predictions. The mutational screening of the normal karyotype (NK) group identified clinically relevant variants in 86.2% of the patients; in the abnormal cytogenetics group, the mutation detection rate was 87.5%. Overall, the highest mutation prevalence was observed for the <i>NPM1</i> gene, followed by <i>DNMT3A, FLT3</i> and <i>NRAS</i>. An unexpected co-occurrence of <i>KMT2A</i> translocation and <i>DNMT3A</i>-R882 was identified; alterations of these genes, which are involved in epigenetic regulation, are considered to be mutually exclusive. A microarray analysis detected CNVs in 25% of the NK AML patients. In patients with complex karyotypes, the microarray analysis made a significant contribution toward the accurate characterization of chromosomal defects. In summary, our results show that the integration of multiple investigative strategies increases the detection yield of genetic defects with potential clinical relevance.https://www.mdpi.com/2073-4425/12/6/846somatic mutationscopy number variantschromosomal abnormalitiesmutational screeningdetection yield |
| spellingShingle | Sorina Mihaela Papuc Alina Erbescu Diana Cisleanu Diana Ozunu Cristina Enache Ion Dumitru Elena Lupoaia Andrus Mihaela Gaman Viola Maria Popov Maria Dobre Oana Stanca Silvana Angelescu Nicoleta Berbec Andrei Colita Ana-Maria Vladareanu Horia Bumbea Aurora Arghir Delineation of Molecular Lesions in Acute Myeloid Leukemia Patients at Diagnosis: Integrated Next Generation Sequencing and Cytogenomic Studies Genes somatic mutations copy number variants chromosomal abnormalities mutational screening detection yield |
| title | Delineation of Molecular Lesions in Acute Myeloid Leukemia Patients at Diagnosis: Integrated Next Generation Sequencing and Cytogenomic Studies |
| title_full | Delineation of Molecular Lesions in Acute Myeloid Leukemia Patients at Diagnosis: Integrated Next Generation Sequencing and Cytogenomic Studies |
| title_fullStr | Delineation of Molecular Lesions in Acute Myeloid Leukemia Patients at Diagnosis: Integrated Next Generation Sequencing and Cytogenomic Studies |
| title_full_unstemmed | Delineation of Molecular Lesions in Acute Myeloid Leukemia Patients at Diagnosis: Integrated Next Generation Sequencing and Cytogenomic Studies |
| title_short | Delineation of Molecular Lesions in Acute Myeloid Leukemia Patients at Diagnosis: Integrated Next Generation Sequencing and Cytogenomic Studies |
| title_sort | delineation of molecular lesions in acute myeloid leukemia patients at diagnosis integrated next generation sequencing and cytogenomic studies |
| topic | somatic mutations copy number variants chromosomal abnormalities mutational screening detection yield |
| url | https://www.mdpi.com/2073-4425/12/6/846 |
| work_keys_str_mv | AT sorinamihaelapapuc delineationofmolecularlesionsinacutemyeloidleukemiapatientsatdiagnosisintegratednextgenerationsequencingandcytogenomicstudies AT alinaerbescu delineationofmolecularlesionsinacutemyeloidleukemiapatientsatdiagnosisintegratednextgenerationsequencingandcytogenomicstudies AT dianacisleanu delineationofmolecularlesionsinacutemyeloidleukemiapatientsatdiagnosisintegratednextgenerationsequencingandcytogenomicstudies AT dianaozunu delineationofmolecularlesionsinacutemyeloidleukemiapatientsatdiagnosisintegratednextgenerationsequencingandcytogenomicstudies AT cristinaenache delineationofmolecularlesionsinacutemyeloidleukemiapatientsatdiagnosisintegratednextgenerationsequencingandcytogenomicstudies AT iondumitru delineationofmolecularlesionsinacutemyeloidleukemiapatientsatdiagnosisintegratednextgenerationsequencingandcytogenomicstudies AT elenalupoaiaandrus delineationofmolecularlesionsinacutemyeloidleukemiapatientsatdiagnosisintegratednextgenerationsequencingandcytogenomicstudies AT mihaelagaman delineationofmolecularlesionsinacutemyeloidleukemiapatientsatdiagnosisintegratednextgenerationsequencingandcytogenomicstudies AT violamariapopov delineationofmolecularlesionsinacutemyeloidleukemiapatientsatdiagnosisintegratednextgenerationsequencingandcytogenomicstudies AT mariadobre delineationofmolecularlesionsinacutemyeloidleukemiapatientsatdiagnosisintegratednextgenerationsequencingandcytogenomicstudies AT oanastanca delineationofmolecularlesionsinacutemyeloidleukemiapatientsatdiagnosisintegratednextgenerationsequencingandcytogenomicstudies AT silvanaangelescu delineationofmolecularlesionsinacutemyeloidleukemiapatientsatdiagnosisintegratednextgenerationsequencingandcytogenomicstudies AT nicoletaberbec delineationofmolecularlesionsinacutemyeloidleukemiapatientsatdiagnosisintegratednextgenerationsequencingandcytogenomicstudies AT andreicolita delineationofmolecularlesionsinacutemyeloidleukemiapatientsatdiagnosisintegratednextgenerationsequencingandcytogenomicstudies AT anamariavladareanu delineationofmolecularlesionsinacutemyeloidleukemiapatientsatdiagnosisintegratednextgenerationsequencingandcytogenomicstudies AT horiabumbea delineationofmolecularlesionsinacutemyeloidleukemiapatientsatdiagnosisintegratednextgenerationsequencingandcytogenomicstudies AT auroraarghir delineationofmolecularlesionsinacutemyeloidleukemiapatientsatdiagnosisintegratednextgenerationsequencingandcytogenomicstudies |