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DNA Copy Number Imbalances in Primary Cutaneous Lymphomas (PCL)

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DNA Copy Number Imbalances in Primary Cutaneous Lymphomas (PCL) bioRxiv preprint doi: https://doi.org/10.1101/417766; this version posted September 14, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. DNA copy number imbalances in primary cutaneous lymphomas (PCL) Georgiana Gug1 , Qingyao Huang2,3, Elena Chiticariu1, Caius Solovan1,4, and Michael Baudis2,3 1 University of Medicine and Pharmacy "Victor Babes, " Timis, oara, România 2Institute of Molecular Life Sciences, University of Zurich, Switzerland 3Swiss Institute of Bioinformatics, Zurich, Switzerland 4 Emergency City Hospital, University Clinic of Dermatology and Venereology, Timis, oara, România Cutaneous lymphomas (CL) represent a clinically defined group (CTCLs) in approximately 65% of cases and in a smaller per- of extranodal non-Hodgkin lymphomas harboring heteroge- centage by primary cutaneous B cell lymphomas (CBCL). neous and incompletely delineated molecular aberrations. Over Although a large number of clinicopathologic variants are the past decades, molecular studies have identified several chro- being acknowledged in the WHO classification, a clear, bi- mosomal aberrations, but the interpretation of individual ge- ologically supported definition of specific entities is missing nomic studies can be challenging. so far. We conducted a meta-analysis to delineate genomic alterations for different types of PCL. Searches of PubMed and ISI Web of CTCL identifies a group of extranodal T-cell lymphomas Knowledge for the years 1996 to 2016 identified 32 publications characterized by the infiltration of malignant CD4+ T-cells reporting the investigation of PCL for genome-wide copy num- in the skin (5). Among those, mycosis fungoides (MF) repre- ber alterations, by means of comparative genomic hybridiza- sents the most common diagnosis (44% of CL) (6). MFs are tion techniques and whole genome and exome sequencing. For neoplasms of skin-homing T cells with CD4+ T-helper phe- 449 samples from 22 publications, copy number variation data notype and Th2 pattern which commonly behave as a low- was accessible for sample based meta-analysis. Summary pro- grade lymphoma with a protracted clinical evolution; how- files for genomic imbalances, generated from case-specific data, ever, a subset of patients progress rapidly to severe forms, re- identified complex genomic imbalances, which could discrimi- fractory to current treatment modalities (7). For MF, a wide nate between different subtypes of CL and promise a more ac- spectrum of subtypes has been described, such as follicu- curate classification. The collected data presented in this study are publicly available through the "Progenetix" online reposi- lotropic, pagetoid reticulosis and granulomatous slack skin tory. (8). In contrast to the frequently indolent MF, Sézary syn- drome (SS) represents a rare aggressive subtype of CTCL de- Cutaneous lymphoma | Genomics | Copy number fined by diffuse pruritic rash, lymphadenopathy and the early Correspondence: [email protected] and [email protected] appearance of malignant T-cells in the peripheral blood. The mechanisms underlying the proliferation of neoplastic CD4+ Introduction T-cells in SS are not fully understood. Cutaneous lymphomas (CL) represent a complex group of Lymphomatoid papulosis and primary cutaneous anaplastic extranodal non-Hodgkin lymphomas for which the underly- large cell lymphoma are part of a spectrum of CD30+ cu- ing molecular events are incompletely understood. So far, taneous lymphoproliferative diseases, the second most com- the classification of cutaneous lymphoma remains oneDRAFT of the mon group of CTCL. They have similar morphologic and most challenging areas of oncologic dermato-pathology. The immunophenotypic characteristics, with differentiation rely- first widely accepted classification, which emphasizes the ing predominantly on the clinical representation. Adult T- features of cutaneous lymphomas as primary tumors of the cell leukaemia / lymphoma is an aggressive peripheral T- skin, was the "WHO / EORTC classification (2005)", rep- lymphocytic neoplasm caused by a human retrovirus, human resenting a consensus based on the European Organization T-cell lymphotropic virus type 1 (HTLV-1). Skin involve- for Research and Treatment of Cancer (EORTC) and World ment is generally a manifestation of disseminated disease, Health Organization (WHO) classifications (1)(2). All forms but a slowly progressive form which may have primary cuta- of primary CL found in the WHO / EORTC consensus have neous involvement has been described (smoldering subtype) been adopted by the WHO classifications (3). Updates which (9). integrate these nosological entities into a larger classification, Other recognized CTCLs include subcutaneous panniculitis- containing both nodal and extranodal lymphomas as different like T-cell lymphoma, extranodal NK / T-cell lymphoma, categories, are made periodical, with currently active classi- and peripheral T-cell lymphomas, rare subtypes (Cutaneous fication having been published in 2016 (4). Since our meta- gamma/delta T Cell Lymphoma, Primary cutaneous CD4+ analysis is based on data spanning the period from 1996 to small-medium sized pleomorphic T-Cell lymphoma, Primary 2016, we decided to follow the 2008 classification to avoid cutaneous aggressive epidermotropic CD8+) (3). discrepancies and ambiguities in code assignment. The class of cutaneous B cell lymphomas (CBCL) have pro- CLs are represented by primary cutaneous T cell lymphomas vided cause for debate for a long time, and present a com- Gug et al. | bioRχiv | September 14, 2018 | 1–13 bioRxiv preprint doi: https://doi.org/10.1101/417766; this version posted September 14, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. pelling reason for developing a new classification. Currently variably combined: "lymphoma", "cutaneous lymphoma", recognized categories include Primary Cutaneous Marginal "skin lymphoma", "CTCL", "mycosis fungoides", "sezary", Zone B-cell lymphoma, Primary Cutaneous Follicle Cen- "leukaemia", "leukemia", "lymphomatoid papulosis", and tre Lymphoma, primary cutaneous diffuse large B-cell lym- "cgh" or "CGH" or "aCGH" or "comparative genomic hy- phoma, and primary cutaneous intravascular large B-cell bridisation" or "snp" or "SNP" or "array" or "genomic ar- lymphoma (3). ray" or "genome" or "copy number" or "dna microarray" or To date, little is known about the underlying molecular events "amplification". Additional, we followed up on references in CL, both because of the limited ability to extrapolate from the selected articles for possibly relevant publications lessons learnt from the nodal counterpart (similar pathologi- followed by evaluation of the abstracts. If more than one arti- cal entities with different biological behavior, prognosis and cle was published using the same series of subjects, we chose treatment) and also the difficulty to conduct studies address- the latest or the most complete study for this meta-analysis. ing CL (overall low incidence together with high clinico- pathologic heterogeneity) (10). Over the past decade, molec- Inclusion and exclusion criteria. For selection of the stud- ular studies have identified several molecular events such as ies we followed the guidelines of the critical checklist pro- gene specific mutations, aberrant gene expression profiles, posed by the Dutch Cochrane Centre Meta-analysis of Ob- upregulated micro-RNAs, telomere shortening, and chromo- servational Studies in Epidemiology (MOOSE) (20). Articles somal aberrations (11–18). However, the etiology remains were identified as eligible when they fit the following crite- unknown for the majority of cases, with a set of common ria: i. they contain genomic copy number data with whole pathways or initiating events in different stages of lympho- genome coverage and access to this information; ii. diagno- cyte maturation to be identified. Importantly, the behavior sis of Primary Cutaneous Lymphoma (PCL) with equivalent of a malignant clone of lymphocytes is not only the result of terminology in EORTC-WHO (2005) and WHO (2008) clas- its uncontrolled proliferation but also may depend on factors sifications (Table1); iii. matching available or convincingly and stimulants from the cutaneous microenviroment. inferred locus information. A number of studies have been investigating structural The process of study retrieval is presented in Table 2 accord- genome variants in CL, such as chromosomal copy number ing to PRISMA (preferred reporting items for systematic re- alterations, localized copy number variations, deletions, am- views and meta-analyses) statement. plifications and insertions. While these genome variants may be based on different rearrangement mechanisms, the com- mon end point of somatic copy number variations/alterations Data extraction and quality assessment. For each of the (CNV) is a potential gene dosage effect, promoting over- or identified studies, the following information was extracted: underrepresentation of the transcripts and proteins derived first author, year of publication, population demographics, from genes in the affected regions. While large CNVs make it clinical characteristics, follow-up data where available, and difficult to identify the possible
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