fabcb36ea49662e3181f156d82cbccba 292101.pdf a3898595bf4dab57b6494bb9f38f99cc05fc1aed 292101.pdf 059f652baa5cfaf315611bc7ee829436c6666af28dede39032d500ca4d5648a8 292101.pdf Title: Genetics Abnormalities with Clinical Impact in Primary Cutaneous Lymphomas Subject: Primary cutaneous lymphomas comprise a heterogeneous group of extranodal non-Hodgkin lymphomas (NHL) that arise from skin resident lymphoid cells and are manifested by specific lymphomatous cutaneous lesions with no evidence of extracutaneous disease at the time of diagnosis. They may originate from mature T-lymphocytes (70% of all cases), mature B-lymphocytes (25–30%) or, rarely, NK cells. Cutaneous T-cell lymphomas (CTCL) comprise a heterogeneous group of T-cell malignancies including Mycosis Fungoides (MF) the most frequent subtype, accounting for approximately half of CTCL, and Sézary syndrome (SS), which is an erythrodermic and leukemic subtype characterized by significant blood involvement. The mutational landscape of MF and SS by NGS include recurrent genomic alterations in the TCR signaling effectors (i.e., PLCG1), the NF-B elements (i.e., CARD11), DNA damage/repair elements (TP53 or ATM), JAK/STAT pathway elements or epigenetic modifiers (DNMT3). Genomic copy number variations appeared to be more prevalent than somatic mutations. Other CTCL subtypes such as primary cutaneous anaplastic large cell lymphoma also harbor genetic alterations of the JAK/STAT pathway in up to 50% of cases. Recently, primary cutaneous aggressive epidermotropic T-cell lymphoma, a rare fatal subtype, was found to contain a specific profile of JAK2 rearrangements. Other aggressive cytotoxic CTCL (primary cutaneous T-cell lymphomas) also show genetic alterations in the JAK/STAT pathway in a large proportion of patients. Thus, CTCL patients have a heterogeneous genetic/transcriptional and epigenetic background, and there is no uniform treatment for these patients. In this scenario, a pathway-based personalized management is required. Cutaneous B-cell lymphoma (CBCL) subtypes present a variable genetic profile. The genetic heterogeneity parallels the multiple types of specialized B-cells and their specific tissue distribution. Particularly, many recurrent hotspot and damaging mutations in primary cutaneous diffuse large B-cell lymphoma of the leg type, involving MYD88 gene, or BCL6 and MYC translocations and BLIMP1 or CDKN2A deletions are useful for diagnostic and prognostic purposes for this aggressive subtype from other indolent CBCL forms. Keywords: cutaneous lymphoma; genetics Author: Fernando Gallardo and Ramon M. Pujol Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Oct 11 12:14:30 2022 CEST ModDate: Tue Oct 11 12:35:15 2022 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 16 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 338126 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ASHNOE+EURM10 Type 1 Builtin yes yes no 10 0 QKHTZR+URWPalladioL-Bold Type 1 Custom yes yes no 14 0 YPENZT+URWPalladioL-Roma Type 1 Custom yes yes no 19 0 FFQNZB+URWPalladioL-Ital Type 1 Custom yes yes no 23 0 AHRQMW+VnURWPalladioL Type 1 Custom yes yes no 27 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 47 0 BTFGED+VnURWPalladioL-Bold Type 1 Custom yes yes no 64 0 PZSLXK+PazoMath-Italic Type 1 Builtin yes yes no 74 0 FXXUVH+CMSY10 Type 1 Builtin yes yes no 84 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-05-18 03:25:37 CEST RepresentationInformation: 292101.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-05-17 20:36:43 CEST Size: 338126 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 396 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Primary Cutaneous T-Cell Lymphomas: Mycosis Fungoides and Sézary Syndrome Destination: section.2 Children: Item: Title: Genetic and Epigenetics Abnormalitites in MF/SS Destination: subsection.2.1 Children: Item: Title: Spectrum of Somatic Point Mutations Destination: subsubsection.2.1.1 Item: Title: Genomic Copy Number Variants Destination: subsubsection.2.1.2 Item: Title: Complex Chromosomal Rearrangements Destination: subsubsection.2.1.3 Item: Title: Epigenetics in CTCL Destination: subsubsection.2.1.4 Item: Title: Current and Potential Therapeutic Implications: Towards a Personalized Medicine in CTCL Destination: subsubsection.2.1.5 Item: Title: Other Cutaneous T-Cell Lymphomas Distinct from Mycosis Fungoides and Sézary Syndrome Destination: section.3 Children: Item: Title: Cutaneous CD30(+) Lymphoproliferative Disorders Destination: subsection.3.1 Item: Title: Subcutaneous Panniculitis-like T-Cell Lymphoma Destination: subsection.3.2 Item: Title: Primary Cutaneous T-Cell Lymphoma Destination: subsection.3.3 Item: Title: Primary Cutaneous CD8(+) Aggressive Epidermotropic Cytotoxic T-Cell Lymphoma Destination: subsection.3.4 Item: Title: Extranodal NK/T-Cells Lymphoma, Nasal Type Destination: subsection.3.5 Item: Title: Primary Cutaneous T-Cell Lymphoma, Not Otherwise Specified Destination: subsection.3.6 Item: Title: Primary Cutaneous B-Cell Lymphomas Destination: section.4 Children: Item: Title: Primary Cutaneous FollicularB-Cell Lymphoma Destination: subsection.4.1 Item: Title: Primary Cutaneous Lymphoma of Marginal Zone Cells (Cutaneous Lymphoproliferative Disorder of the Marginal Zone Cells) Destination: subsection.4.2 Item: Title: Diffuse Large B-Cell Lymphoma of the Leg Type Destination: subsection.4.3 Item: Title: Concluding Remarks Destination: section.5 Item: Title: References Destination: section.5 Info: Title: Genetics Abnormalities with Clinical Impact in Primary Cutaneous Lymphomas Author: Fernando Gallardo and Ramon M. Pujol Subject: Primary cutaneous lymphomas comprise a heterogeneous group of extranodal non-Hodgkin lymphomas (NHL) that arise from skin resident lymphoid cells and are manifested by specific lymphomatous cutaneous lesions with no evidence of extracutaneous disease at the time of diagnosis. They may originate from mature T-lymphocytes (70% of all cases), mature B-lymphocytes (25 30%) or, rarely, NK cells. Cutaneous T-cell lymphomas (CTCL) comprise a heterogeneous group of T-cell malignancies including Mycosis Fungoides (MF) the most frequent subtype, accounting for approximately half of CTCL, and Sézary syndrome (SS), which is an erythrodermic and leukemic subtype characterized by significant blood involvement. The mutational landscape of MF and SS by NGS include recurrent genomic alterations in the TCR signaling effectors (i.e., PLCG1), the NF-B elements (i.e., CARD11), DNA damage/repair elements (TP53 or ATM), JAK/STAT pathway elements or epigenetic modifiers (DNMT3). Genomic copy number variations appeared to be more prevalent than somatic mutations. Other CTCL subtypes such as primary cutaneous anaplastic large cell lymphoma also harbor genetic alterations of the JAK/STAT pathway in up to 50% of cases. Recently, primary cutaneous aggressive epidermotropic T-cell lymphoma, a rare fatal subtype, was found to contain a specific profile of JAK2 rearrangements. Other aggressive cytotoxic CTCL (primary cutaneous T-cell lymphomas) also show genetic alterations in the JAK/STAT pathway in a large proportion of patients. Thus, CTCL patients have a heterogeneous genetic/transcriptional and epigenetic background, and there is no uniform treatment for these patients. In this scenario, a pathway-based personalized management is required. Cutaneous B-cell lymphoma (CBCL) subtypes present a variable genetic profile. The genetic heterogeneity parallels the multiple types of specialized B-cells and their specific tissue distribution. Particularly, many recurrent hotspot and damaging mutations in primary cutaneous diffuse large B-cell lymphoma of the leg type, involving MYD88 gene, or BCL6 and MYC translocations and BLIMP1 or CDKN2A deletions are useful for diagnostic and prognostic purposes for this aggressive subtype from other indolent CBCL forms. 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