01b0947b6bf640fb8421b50c64c3303f 286338.pdf 0993258bb218b1d3532da38ebf1748d5213847ce 286338.pdf 5f8f30e5a2fbe7bbfcf2a027bcefe7010fddd9d81d645effcc4940cc544c25a8 286338.pdf Title: TP53 Abnormalities Are Underlying the Poor Outcome Associated with Chromothripsis in Chronic Lymphocytic Leukemia Patients with Complex Karyotype Subject: Chromothripsis (cth) has been associated with a dismal outcome and poor prognosis factors in patients with chronic lymphocytic leukemia (CLL). Despite being correlated with high genome instability, previous studies have not assessed the role of cth in the context of genomic complexity. Herein, we analyzed a cohort of 33 CLL patients with cth and compared them against a cohort of 129 non-cth cases with complex karyotypes. Nine cth cases were analyzed using optical genome mapping (OGM). Patterns detected by genomic microarrays were compared and the prognostic value of cth was analyzed. Cth was distributed throughout the genome, with chromosomes 3, 6 and 13 being those most frequently affected. OGM detected 88.1% of the previously known copy number alterations and several additional cth-related rearrangements (median: 9, range: 3–26). Two patterns were identified: one with rearrangements clustered in the region with cth (3/9) and the other involving both chromothriptic and non-chromothriptic chromosomes (6/9). Cases with cth showed a shorter time to first treatment (TTFT) than non-cth patients (median TTFT: 2 m vs. 15 m; p = 0.013). However, when stratifying patients based on TP53 status, cth did not affect TTFT. Only TP53 maintained its significance in the multivariate analysis for TTFT, including cth and genome complexity defined by genomic microarrays (HR: 1.60; p = 0.029). Our findings suggest that TP53 abnormalities, rather than cth itself, underlie the poor prognosis observed in this subset. Keywords: chronic lymphocytic leukemia; genomic complexity; chromothripsis; TP53; genomic microarrays; optical genome mapping Author: Silvia Ramos-Campoy, Anna Puiggros, Joanna Kamaso, Sílvia Beà, Sandrine Bougeon, María José Larráyoz, Dolors Costa, Helen Parker, Gian Matteo Rigolin, María Laura Blanco, Rosa Collado, Idoya Ancín, Rocío Salgado, Marco A. Moro-García, Tycho Baumann, Eva Gimeno, Carol Moreno, Marta Salido, Xavier Calvo, María José Calasanz, Antonio Cuneo, Florence Nguyen-Khac, David Oscier, Claudia Haferlach, Jonathan C. Strefford, Jacqueline Schoumans and Blanca Espinet Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Aug 2 11:34:05 2022 CEST ModDate: Tue Aug 2 12:40:05 2022 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 18 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 4585981 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- VJNASK+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 LGKYZF+VnURWPalladioL Type 1 Custom yes yes no 15 0 BYXGSC+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 QJDQON+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 SWBBUD+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 BEKLKZ+URWPalladioL-BoldItal Type 1 Custom yes yes no 32 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 51 0 VCVPZQ+CMSY10 Type 1 Builtin yes yes no 76 0 JJIEJG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 95 0 JJIEJI+PalatinoLinotype TrueType WinAnsi yes yes no 98 0 JJIEJK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 101 0 JJIEJG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 113 0 JJIEJI+PalatinoLinotype TrueType WinAnsi yes yes no 116 0 JJIEJK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 119 0 JJIEJG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 130 0 JJIEJI+PalatinoLinotype TrueType WinAnsi yes yes no 133 0 JJIEJK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 136 0 JJIEJG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 146 0 JJIEJH+PalatinoLinotype CID TrueType Identity-H yes yes yes 149 0 JJIEJI+PalatinoLinotype TrueType WinAnsi yes yes no 155 0 JJIEJK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 158 0 JJIEJG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 168 0 JJIEJH+PalatinoLinotype CID TrueType Identity-H yes yes yes 171 0 JJIEJI+PalatinoLinotype TrueType WinAnsi yes yes no 177 0 JJIEJK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 180 0 JJIEJG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 188 0 JJIEJH+PalatinoLinotype CID TrueType Identity-H yes yes yes 191 0 JJIEJI+PalatinoLinotype TrueType WinAnsi yes yes no 197 0 JJIEJK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 200 0 JJIEJG+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 212 0 JJIEJH+PalatinoLinotype CID TrueType Identity-H yes yes yes 215 0 JJIEJI+PalatinoLinotype TrueType WinAnsi yes yes no 221 0 JJIEJK+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 224 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-03-21 02:36:53 CET RepresentationInformation: 286338.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-03-20 13:38:38 CET Size: 4585981 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 435 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Children: Item: Title: Patient Cohort Destination: subsection.2.1 Item: Title: Genomic Microarray Analyses Destination: subsection.2.2 Item: Title: Optical Genome Mapping Destination: subsection.2.3 Item: Title: Whole Chromosome FISH Painting Destination: subsection.2.4 Item: Title: Statistical Analyses Destination: subsection.2.5 Item: Title: Results Destination: section.3 Children: Item: Title: Identification of Chromothripsis Patterns by Genomic Microarrays Destination: subsection.3.1 Item: Title: Detection of Different Chromothripsis Patterns by Optical Genome Mapping Destination: subsection.3.2 Item: Title: Association of Chromothripsis with Other Clinical Characteristics and Prognostic Impact Destination: subsection.3.3 Item: Title: Discussion Destination: section.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.5 Info: Title: TP53 Abnormalities Are Underlying the Poor Outcome Associated with Chromothripsis in Chronic Lymphocytic Leukemia Patients with Complex Karyotype Author: Silvia Ramos-Campoy, Anna Puiggros, Joanna Kamaso, Sílvia Beà, Sandrine Bougeon, María José Larráyoz, Dolors Costa, Helen Parker, Gian Matteo Rigolin, María Laura Blanco, Rosa Collado, Idoya Ancín, Rocío Salgado, Marco A. Moro-García, Tycho Baumann, Eva Gimeno, Carol Moreno, Marta Salido, Xavier Calvo, María José Calasanz, Antonio Cuneo, Florence Nguyen-Khac, David Oscier, Claudia Haferlach, Jonathan C. Strefford, Jacqueline Schoumans and Blanca Espinet Subject: Chromothripsis (cth) has been associated with a dismal outcome and poor prognosis factors in patients with chronic lymphocytic leukemia (CLL). Despite being correlated with high genome instability, previous studies have not assessed the role of cth in the context of genomic complexity. Herein, we analyzed a cohort of 33 CLL patients with cth and compared them against a cohort of 129 non-cth cases with complex karyotypes. Nine cth cases were analyzed using optical genome mapping (OGM). Patterns detected by genomic microarrays were compared and the prognostic value of cth was analyzed. Cth was distributed throughout the genome, with chromosomes 3, 6 and 13 being those most frequently affected. OGM detected 88.1% of the previously known copy number alterations and several additional cth-related rearrangements (median: 9, range: 3 26). Two patterns were identified: one with rearrangements clustered in the region with cth (3/9) and the other involving both chromothriptic and non-chromothriptic chromosomes (6/9). Cases with cth showed a shorter time to first treatment (TTFT) than non-cth patients (median TTFT: 2 m vs. 15 m; p = 0.013). However, when stratifying patients based on TP53 status, cth did not affect TTFT. Only TP53 maintained its significance in the multivariate analysis for TTFT, including cth and genome complexity defined by genomic microarrays (HR: 1.60; p = 0.029). Our findings suggest that TP53 abnormalities, rather than cth itself, underlie the poor prognosis observed in this subset. 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