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THE LANDSCAPE OF SOMATIC MUTATIONS OF PRIMARY CUTANEOUS DIFFUSE LARGE B-CELL LYMPHOMA, LEG-TYPE

Abstract : Introduction: Primary cutaneous diffuse large B‐cell lymphoma leg‐type (PCLBCL‐LT) is recognized by the World Health Organization (WHO) classification as a rare and aggressive disease accounting for 5 to 10% of primary cutaneous lymphoma. It displays original clinical features occurring mostly in the elderly and preferentially involving the legs but date the genetic specificities of this entities, as compared to other B‐cell aggressive lymphoma is unknown. Methods: To determine whether the mutational profile of primary cutaneous diffuse large B‐cell lymphoma leg‐type (PCLBCL‐LT) is unique by comparison with other diffuse large B‐cell lymphoma (DLBCL) subtypes, we analyzed a total cohort of 28 PCLBCL‐LT cases by next generation sequencing with a Lymphopanel designed for DLBCL. We also analyzed 12 pairs of tumor and control DNA samples by whole exome sequencing which led us to perform resequencing of three selected genes not included in the Lymphopanel: TBL1XR1, KLHL6 and IKZF3. To pinpoint specificities, comparison with a cohort of DLBCL and Primary central nervous System lymphoma (PCNSL) analyzed by the same targeted panel was performed. Results: Our study clearly identifies an original mutational landscape of PCLBCL‐LT with a very restricted set of highly recurrent mutations (>40%) involving MYD88 (p.L265P variant), PIM1 and CD79B. Other genes involved in B‐cell signaling, NFKB activation or DNA modeling were found altered notably TBL1XR1 (33%), MYC (26%) CREBBP (26%) and IRF4 (21%) or HIST1H1E(41%). MYD88L265P variant was associated with copy number variations or copy neutral loss of heterozygosity in 60% of cases. The most frequent genetic losses involved CDKN2A/2B, TNFAIP3/A20, PRDM1, TCF3 and CIITA. The high recurrence of specific gene mutations such as MYD88 and the absence of mutations of KMT2D or FOXO1 are distinct features from nodal DLBCLs of either GC or ABC subtypes. Interestingly PCLBCL‐LT exhibits a mutational pattern that is closer to PCNSL than to ABC‐type nodal DLBCL but also has distinctive features, such as a very high mutational rate for PIM1, a higher rate of CD79B mutations and other original mutations such as CREBBP, MYC and IRF4 mutations (figure 1). Conclusion: This study describes for the first time the genomic landscape of a series of untreated PCLBCL‐LT. Our results obtained by WES and targeted sequencing underscore several similarities with ABC‐DBCL and more specifically with PCNSL subtypes. On the other hand, we pinpoint specificities that may sustain distinctive clinical features and guide therapeutic strategies according to an individual genetic analysis.
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https://hal-normandie-univ.archives-ouvertes.fr/hal-02484228
Contributor : Elodie Bohers <>
Submitted on : Wednesday, February 19, 2020 - 10:31:43 AM
Last modification on : Thursday, February 20, 2020 - 1:36:26 AM

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F. Jardin, S. Mareschal, A. Pham-Ledard, P. Viailly, M. Carlotti, et al.. THE LANDSCAPE OF SOMATIC MUTATIONS OF PRIMARY CUTANEOUS DIFFUSE LARGE B-CELL LYMPHOMA, LEG-TYPE. 14th International Conference on Malignant Lymphoma, Jun 2017, Lugano, Switzerland. pp.107-109, ⟨10.1002/hon.2437_97⟩. ⟨hal-02484228⟩

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