Leukemic conversion involving RAS mutations of type 1 CALR-mutated primary myelofibrosis in a patient treated for HCV cirrhosis: a case report
<p>Somatic frameshift mutations in exon 9 of calreticulin (<em>CALR</em>) 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 <em>CALR</em&g...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Frontiers Media
2023
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| _version_ | 1797111480505597952 |
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| author | Gurban, P Mambet, C Botezatu, A Necula, LG Neagu, AI Matei, L Pitica, IM Nedeianu, S Chivu-Economescu, M Bleotu, C Ataman, M Mocanu, G Saguna, C Pavel, AG Stambouli, D Sepulchre, E Anton, G Diaconu, CC Constantinescu, SN |
| author_facet | Gurban, P Mambet, C Botezatu, A Necula, LG Neagu, AI Matei, L Pitica, IM Nedeianu, S Chivu-Economescu, M Bleotu, C Ataman, M Mocanu, G Saguna, C Pavel, AG Stambouli, D Sepulchre, E Anton, G Diaconu, CC Constantinescu, SN |
| author_sort | Gurban, P |
| collection | OXFORD |
| description | <p>Somatic frameshift mutations in exon 9 of calreticulin (<em>CALR</em>) 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 <em>CALR</em> 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 <em>CALR</em> 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 <em>CALR</em>-mutated clone through the acquisition of genetic events in the RAS signaling pathway: an increased variant allele frequency of the germline <em>NRAS</em> Y64D mutation present in the chronic phase (via an acquired uniparental disomy of chromosome 1) and gaining <em>NRAS</em> 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 <em>CALR</em>-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.</p> |
| first_indexed | 2024-03-07T08:11:01Z |
| format | Journal article |
| id | oxford-uuid:60abac84-902f-4da0-8f8a-2edc60fe5efa |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:11:01Z |
| publishDate | 2023 |
| publisher | Frontiers Media |
| record_format | dspace |
| spelling | oxford-uuid:60abac84-902f-4da0-8f8a-2edc60fe5efa2023-11-24T14:42:17ZLeukemic conversion involving RAS mutations of type 1 CALR-mutated primary myelofibrosis in a patient treated for HCV cirrhosis: a case reportJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:60abac84-902f-4da0-8f8a-2edc60fe5efaEnglishSymplectic ElementsFrontiers Media2023Gurban, PMambet, CBotezatu, ANecula, LGNeagu, AIMatei, LPitica, IMNedeianu, SChivu-Economescu, MBleotu, CAtaman, MMocanu, GSaguna, CPavel, AGStambouli, DSepulchre, EAnton, GDiaconu, CCConstantinescu, SN<p>Somatic frameshift mutations in exon 9 of calreticulin (<em>CALR</em>) 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 <em>CALR</em> 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 <em>CALR</em> 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 <em>CALR</em>-mutated clone through the acquisition of genetic events in the RAS signaling pathway: an increased variant allele frequency of the germline <em>NRAS</em> Y64D mutation present in the chronic phase (via an acquired uniparental disomy of chromosome 1) and gaining <em>NRAS</em> 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 <em>CALR</em>-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.</p> |
| spellingShingle | Gurban, P Mambet, C Botezatu, A Necula, LG Neagu, AI Matei, L Pitica, IM Nedeianu, S Chivu-Economescu, M Bleotu, C Ataman, M Mocanu, G Saguna, C Pavel, AG Stambouli, D Sepulchre, E Anton, G Diaconu, CC Constantinescu, SN Leukemic conversion involving RAS mutations of type 1 CALR-mutated primary myelofibrosis in a patient treated for HCV cirrhosis: a case report |
| 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 |
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