Leukemic conversion involving RAS mutations of type 1 CALR-mutated primary myelofibrosis in a patient treated for HCV cirrhosis: a case report
Somatic frameshift mutations in exon 9 of calreticulin (CALR) gene are recognized as disease drivers in primary myelofibrosis (PMF), one of the three classical Philadelphia-negative myeloproliferative neoplasms (MPNs). Type 1/type 1-like CALR mutations particularly confer a favorable prognostic and...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1266996/full |
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| author | Petruta Gurban Petruta Gurban Cristina Mambet Cristina Mambet Cristina Mambet Anca Botezatu Laura G. Necula Ana I. Neagu Ana I. Neagu Lilia Matei Ioana M. Pitica Saviana Nedeianu Mihaela Chivu-Economescu Coralia Bleotu Marius Ataman Gabriela Mocanu Carmen Saguna Carmen Saguna Anca G. Pavel Danae Stambouli Elise Sepulchre Gabriela Anton Carmen C. Diaconu Stefan N. Constantinescu Stefan N. Constantinescu Stefan N. Constantinescu Stefan N. Constantinescu |
| author_facet | Petruta Gurban Petruta Gurban Cristina Mambet Cristina Mambet Cristina Mambet Anca Botezatu Laura G. Necula Ana I. Neagu Ana I. Neagu Lilia Matei Ioana M. Pitica Saviana Nedeianu Mihaela Chivu-Economescu Coralia Bleotu Marius Ataman Gabriela Mocanu Carmen Saguna Carmen Saguna Anca G. Pavel Danae Stambouli Elise Sepulchre Gabriela Anton Carmen C. Diaconu Stefan N. Constantinescu Stefan N. Constantinescu Stefan N. Constantinescu Stefan N. Constantinescu |
| author_sort | Petruta Gurban |
| collection | DOAJ |
| description | Somatic frameshift mutations in exon 9 of calreticulin (CALR) gene are recognized as disease drivers in primary myelofibrosis (PMF), one of the three classical Philadelphia-negative myeloproliferative neoplasms (MPNs). Type 1/type 1-like CALR mutations particularly confer a favorable prognostic and survival advantage in PMF patients. We report an unusual case of PMF incidentally diagnosed in a 68-year-old woman known with hepatitis C virus (HCV) cirrhosis who developed a progressive painful splenomegaly, without anomalies in blood cell counts. While harboring a type 1 CALR mutation, the patient underwent a leukemic transformation in less than 1 year from diagnosis, with a lethal outcome. Analysis of paired DNA samples from chronic and leukemic phases by a targeted next-generation sequencing (NGS) panel and single-nucleotide polymorphism (SNP) microarray revealed that the leukemic clone developed from the CALR-mutated clone through the acquisition of genetic events in the RAS signaling pathway: an increased variant allele frequency of the germline NRAS Y64D mutation present in the chronic phase (via an acquired uniparental disomy of chromosome 1) and gaining NRAS G12D in the blast phase. SNP microarray analysis showed five clinically significant copy number losses at regions 7q22.1, 8q11.1-q11.21, 10p12.1-p11.22, 11p14.1-p11.2, and Xp11.4, revealing a complex karyotype already in the chronic phase. We discuss how additional mutations, detected by NGS, as well as HCV infection and antiviral therapy, might have negatively impacted this type 1 CALR-mutated PMF. We suggest that larger studies are required to determine if more careful monitoring would be needed in MPN patients also carrying HCV and receiving anti-HCV treatment. |
| first_indexed | 2024-03-11T21:03:59Z |
| format | Article |
| id | doaj.art-cab0ef6fb3fd429d81f30f7b95f9c82b |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-03-11T21:03:59Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-cab0ef6fb3fd429d81f30f7b95f9c82b2023-09-29T15:41:58ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-09-011310.3389/fonc.2023.12669961266996Leukemic conversion involving RAS mutations of type 1 CALR-mutated primary myelofibrosis in a patient treated for HCV cirrhosis: a case reportPetruta Gurban0Petruta Gurban1Cristina Mambet2Cristina Mambet3Cristina Mambet4Anca Botezatu5Laura G. Necula6Ana I. Neagu7Ana I. Neagu8Lilia Matei9Ioana M. Pitica10Saviana Nedeianu11Mihaela Chivu-Economescu12Coralia Bleotu13Marius Ataman14Gabriela Mocanu15Carmen Saguna16Carmen Saguna17Anca G. Pavel18Danae Stambouli19Elise Sepulchre20Gabriela Anton21Carmen C. Diaconu22Stefan N. Constantinescu23Stefan N. Constantinescu24Stefan N. Constantinescu25Stefan N. Constantinescu26Cellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Romanian Academy, Bucharest, RomaniaCytogenomic Medical Laboratory Ltd., Bucharest, RomaniaCellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Romanian Academy, Bucharest, RomaniaDepartment of Radiology, Oncology, and Hematology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, RomaniaHematology Department, Emergency University Clinical Hospital, Bucharest, RomaniaMolecular Virology Department, Stefan S. Nicolau Institute of Virology, Romanian Academy, Bucharest, RomaniaCellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Romanian Academy, Bucharest, RomaniaCellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Romanian Academy, Bucharest, RomaniaDepartment of Radiology, Oncology, and Hematology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, RomaniaCellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Romanian Academy, Bucharest, RomaniaCellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Romanian Academy, Bucharest, RomaniaCellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Romanian Academy, Bucharest, RomaniaCellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Romanian Academy, Bucharest, RomaniaCellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Romanian Academy, Bucharest, RomaniaCellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Romanian Academy, Bucharest, RomaniaDepartment of Hematology, Coltea Clinical Hospital, Bucharest, RomaniaDepartment of Radiology, Oncology, and Hematology, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, RomaniaDepartment of Hematology, Coltea Clinical Hospital, Bucharest, RomaniaCytogenomic Medical Laboratory Ltd., Bucharest, RomaniaCytogenomic Medical Laboratory Ltd., Bucharest, RomaniaDe Duve Institute, Université Catholique de Louvain, Brussels, BelgiumMolecular Virology Department, Stefan S. Nicolau Institute of Virology, Romanian Academy, Bucharest, RomaniaCellular and Molecular Pathology Department, Stefan S. Nicolau Institute of Virology, Romanian Academy, Bucharest, RomaniaDe Duve Institute, Université Catholique de Louvain, Brussels, BelgiumSIGN (Cell Signalling and Molecular Hematology), Ludwig Institute for Cancer Research Brussels, Brussels, BelgiumWalloon Excellence in Life Sciences and Biotechnology (WELBIO) Department, WEL Research Institute, Wavre, Belgium0Nuffield Department of Medicine, Ludwig Institute for Cancer Research, Oxford University, Oxford, United KingdomSomatic frameshift mutations in exon 9 of calreticulin (CALR) gene are recognized as disease drivers in primary myelofibrosis (PMF), one of the three classical Philadelphia-negative myeloproliferative neoplasms (MPNs). Type 1/type 1-like CALR mutations particularly confer a favorable prognostic and survival advantage in PMF patients. We report an unusual case of PMF incidentally diagnosed in a 68-year-old woman known with hepatitis C virus (HCV) cirrhosis who developed a progressive painful splenomegaly, without anomalies in blood cell counts. While harboring a type 1 CALR mutation, the patient underwent a leukemic transformation in less than 1 year from diagnosis, with a lethal outcome. Analysis of paired DNA samples from chronic and leukemic phases by a targeted next-generation sequencing (NGS) panel and single-nucleotide polymorphism (SNP) microarray revealed that the leukemic clone developed from the CALR-mutated clone through the acquisition of genetic events in the RAS signaling pathway: an increased variant allele frequency of the germline NRAS Y64D mutation present in the chronic phase (via an acquired uniparental disomy of chromosome 1) and gaining NRAS G12D in the blast phase. SNP microarray analysis showed five clinically significant copy number losses at regions 7q22.1, 8q11.1-q11.21, 10p12.1-p11.22, 11p14.1-p11.2, and Xp11.4, revealing a complex karyotype already in the chronic phase. We discuss how additional mutations, detected by NGS, as well as HCV infection and antiviral therapy, might have negatively impacted this type 1 CALR-mutated PMF. We suggest that larger studies are required to determine if more careful monitoring would be needed in MPN patients also carrying HCV and receiving anti-HCV treatment.https://www.frontiersin.org/articles/10.3389/fonc.2023.1266996/fullprimary myelofibrosis (PMF)hepatitis C virus (HCV) cirrhosistype 1 calreticulin (CALR)targeted next-generation sequencing (NGS)NRASacquired uniparental disomy (aUPD) |
| spellingShingle | Petruta Gurban Petruta Gurban Cristina Mambet Cristina Mambet Cristina Mambet Anca Botezatu Laura G. Necula Ana I. Neagu Ana I. Neagu Lilia Matei Ioana M. Pitica Saviana Nedeianu Mihaela Chivu-Economescu Coralia Bleotu Marius Ataman Gabriela Mocanu Carmen Saguna Carmen Saguna Anca G. Pavel Danae Stambouli Elise Sepulchre Gabriela Anton Carmen C. Diaconu Stefan N. Constantinescu Stefan N. Constantinescu Stefan N. Constantinescu Stefan N. Constantinescu Leukemic conversion involving RAS mutations of type 1 CALR-mutated primary myelofibrosis in a patient treated for HCV cirrhosis: a case report Frontiers in Oncology primary myelofibrosis (PMF) hepatitis C virus (HCV) cirrhosis type 1 calreticulin (CALR) targeted next-generation sequencing (NGS) NRAS acquired uniparental disomy (aUPD) |
| title | Leukemic conversion involving RAS mutations of type 1 CALR-mutated primary myelofibrosis in a patient treated for HCV cirrhosis: a case report |
| title_full | Leukemic conversion involving RAS mutations of type 1 CALR-mutated primary myelofibrosis in a patient treated for HCV cirrhosis: a case report |
| title_fullStr | Leukemic conversion involving RAS mutations of type 1 CALR-mutated primary myelofibrosis in a patient treated for HCV cirrhosis: a case report |
| title_full_unstemmed | Leukemic conversion involving RAS mutations of type 1 CALR-mutated primary myelofibrosis in a patient treated for HCV cirrhosis: a case report |
| title_short | Leukemic conversion involving RAS mutations of type 1 CALR-mutated primary myelofibrosis in a patient treated for HCV cirrhosis: a case report |
| title_sort | leukemic conversion involving ras mutations of type 1 calr mutated primary myelofibrosis in a patient treated for hcv cirrhosis a case report |
| topic | primary myelofibrosis (PMF) hepatitis C virus (HCV) cirrhosis type 1 calreticulin (CALR) targeted next-generation sequencing (NGS) NRAS acquired uniparental disomy (aUPD) |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1266996/full |
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