30cec3901d59ba065666841818d8ad85 289532.pdf e0ac55d4d3c9ed5f5daf9e012d976c12d4a5af34 289532.pdf 79c121ae6851fd8b61ae1c7142842637b776f746a6b04f8126f7e6ee1bff5504 289532.pdf Title: Mutational Profile Enables the Identification of a High-Risk Subgroup in Myelodysplastic Syndromes with Isolated Trisomy 8 Subject: Trisomy 8 (+8) is the most frequent trisomy in myelodysplastic syndromes (MDS) and is associated with clinical heterogeneity and intermediate cytogenetic risk when found in isolation. The presence of gene mutations in this group of patients and the prognostic significance has not been extensively analyzed. Targeted deep sequencing was performed in a cohort of 79 MDS patients showing isolated +8. The most frequently mutated genes were: TET2 (38%), STAG2 (34.2%), SRSF2 (29.1%) and RUNX1 (26.6%). The mutational profile identified a high-risk subgroup with mutations in STAG2, SRSF2 and/or RUNX1, resulting in shorter time to acute myeloid leukemia progression (14 months while not reached in patients without these mutations, p < 0.0001) and shorter overall survival (23.7 vs. 46.3 months, p = 0.001). Multivariate analyses revealed the presence of mutations in these genes as an independent prognostic factor in MDS showing +8 isolated (HR: 3.1; p < 0.01). Moreover, 39.5% and 15.4% of patients classified as low/intermediate risk by the IPSS-R and IPSS-M, respectively, were re-stratified as a high-risk subgroup based on the mutational status of STAG2, SRSF2 and RUNX1. Results were validated in an external cohort (n = 2494). In summary, this study validates the prognosis significance of somatic mutations shown in IPSS-M and adds STAG2 as an important mutated gene to consider in this specific subgroup of patients. The mutational profile in isolated +8 MDS patients could, therefore, offer new insights for the correct management of patients with a higher risk of leukemic transformation. Keywords: myelodysplastic syndromes; NGS; isolated trisomy 8; prognostic stratification; AML progression Author: Sofía Toribio-Castelló, Sandra Castaño, Ángela Villaverde-Ramiro, Esperanza Such, Montserrat Arnán, Francesc Solé, Marina Díaz-Beyá, María Díez-Campelo, Mónica del Rey, Teresa González and Jesús María Hernández-Rivas Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Fri Jul 28 10:40:52 2023 CEST ModDate: Tue Aug 1 08:22:10 2023 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 13 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1651059 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- OECJXL+VnURWPalladioL Type 1 Custom yes yes no 10 0 FMYAHI+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 RTXZLP+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 SAHWST+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 WIRPUU+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 47 0 QLBIEB+URWPalladioL-BoldItal Type 1 Custom yes yes no 72 0 HCPSKZ+CMSY10 Type 1 Builtin yes yes no 79 0 JLZORU+EURM10 Type 1 Builtin yes yes no 83 0 CBACON+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 97 0 CBACOO+PalatinoLinotype CID TrueType Identity-H yes yes yes 100 0 CBACOP+PalatinoLinotype TrueType WinAnsi yes yes no 106 0 CBACPA+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 109 0 CBACPB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 115 0 CBADMO+PalatinoLinotype TrueType MacRoman yes yes no 118 0 CBACON+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 133 0 CBACOP+PalatinoLinotype TrueType WinAnsi yes yes no 136 0 CBACPB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 139 0 CBAGJA+PalatinoLinotype,Italic TrueType MacRoman yes yes no 157 0 CBACON+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 160 0 CBACOO+PalatinoLinotype CID TrueType Identity-H yes yes yes 163 0 CBACOP+PalatinoLinotype TrueType WinAnsi yes yes no 169 0 CBACPA+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 172 0 CBACPB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 178 0 CBADMO+PalatinoLinotype TrueType MacRoman yes yes no 181 0 NJWNDJ+VnURWPalladioL-Italic Type 1 Custom yes yes no 194 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-02-29 02:34:16 CET RepresentationInformation: 289532.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-02-28 11:12:41 CET Size: 1651059 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 342 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Patients and Methods Destination: section.2 Children: Item: Title: Patients Cohort and Validation Cohort Destination: subsection.2.1 Item: Title: Sample Procedure and DNA Extraction Destination: subsection.2.2 Item: Title: Cytogenetics and FISH Destination: subsection.2.3 Item: Title: Next-Generation Sequencing Destination: subsection.2.4 Item: Title: Statistical Analysis Destination: subsection.2.5 Item: Title: Results Destination: section.3 Children: Item: Title: MDS with Isolated Trisomy 8 Have a Differential Mutational Pattern Destination: subsection.3.1 Item: Title: Mutational Profile Allows the Distinction of a Worse Prognosis High-Risk-Like Subgroup in MDS with Isolated Trisomy 8 Destination: subsection.3.2 Item: Title: Mutational Status of STAG2, SRSF2 and/or RUNX1 Is an Independent Prognostic Factor Associated with Shorter Time to Progression to AML and Overall Survival in MDS with Isolated Trisomy 8 Destination: subsection.3.3 Item: Title: The Newly Defined Prognostic Mutations Could Refine Prognosis of Patients with Isolated Trisomy 8 within the IPSS-R and the IPSS-M Systems Destination: subsection.3.4 Item: Title: STAG2, SRSF2 and RUNX1 Differentiate a Subgroup of Isolated Trisomy 8 MDS with Worse Outcome in an Independent Validation Cohort Destination: subsection.3.5 Item: Title: Discussion Destination: section.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.A. Info: Title: Mutational Profile Enables the Identification of a High-Risk Subgroup in Myelodysplastic Syndromes with Isolated Trisomy 8 Author: Sofía Toribio-Castelló, Sandra Castaño, Ángela Villaverde-Ramiro, Esperanza Such, Montserrat Arnán, Francesc Solé, Marina Díaz-Beyá, María Díez-Campelo, Mónica del Rey, Teresa González and Jesús María Hernández-Rivas Subject: Trisomy 8 (+8) is the most frequent trisomy in myelodysplastic syndromes (MDS) and is associated with clinical heterogeneity and intermediate cytogenetic risk when found in isolation. The presence of gene mutations in this group of patients and the prognostic significance has not been extensively analyzed. Targeted deep sequencing was performed in a cohort of 79 MDS patients showing isolated +8. The most frequently mutated genes were: TET2 (38%), STAG2 (34.2%), SRSF2 (29.1%) and RUNX1 (26.6%). The mutational profile identified a high-risk subgroup with mutations in STAG2, SRSF2 and/or RUNX1, resulting in shorter time to acute myeloid leukemia progression (14 months while not reached in patients without these mutations, p < 0.0001) and shorter overall survival (23.7 vs. 46.3 months, p = 0.001). Multivariate analyses revealed the presence of mutations in these genes as an independent prognostic factor in MDS showing +8 isolated (HR: 3.1; p < 0.01). Moreover, 39.5% and 15.4% of patients classified as low/intermediate risk by the IPSS-R and IPSS-M, respectively, were re-stratified as a high-risk subgroup based on the mutational status of STAG2, SRSF2 and RUNX1. Results were validated in an external cohort (n = 2494). In summary, this study validates the prognosis significance of somatic mutations shown in IPSS-M and adds STAG2 as an important mutated gene to consider in this specific subgroup of patients. The mutational profile in isolated +8 MDS patients could, therefore, offer new insights for the correct management of patients with a higher risk of leukemic transformation. 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