Page 131 - 2019_02-Haematologica-web

JUNB, DUSP2, SGK1 and SOCS1 mutations in THRLBCL
ABC
DE
Figure 3. Characteristics of somatic mutations and activation-induced cytidine deaminase expression in nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma. (A) Analysis of distribution of mutations to SHM hotspot motifs. (B) Ratio of mutations at C:G sites to A:T sites. (C) Ratio of transition to transversion mutations. In (A-C) synonymous SNVs were considered in addition to non-synonymous SNVs. Asterisks denote statistical significance. *P<0.05, **P<0.01, ***P<0.001. P-values by χ2 test. (D) Expression of AICDA in the LP cells of NLPHL (400x magnification). (E) Expression of AICDA in the tumor cells of THRLBCL (400x magnification). Tumor cells are highlighted by arrows. AICDA: activation-induced cytidine deaminase; NLPHL: nodular lymphocyte-predomi- nant Hodgkin lymphoma; THRLBCL: T-cell/histiocyte-rich large B-cell lymphoma; SHM: somatic hypermutation; SNVs: single nucleotide variants.
SGK1 and SOCS1 are frequently mutated in germinal center B-cell (GCB)-derived lymphomas such as follicular lymphoma and GCB-type DLBCL.18–21 DUSP2 is less fre- quently mutated in malignant lymphomas; however, DUSP2 mutations have been described in DLBCL,15,22,23 pri- mary mediastinal B-cell lymphoma24 and chronic lympho- cytic leukemia.25 In contrast, to date, JUNB has been reported, to our knowledge, to be relatively specifically mutated in NLPHL.12 The total percentage of samples of hematopoietic and lymphoid neoplasms with mutations in JUNB in the COSMIC database (https://cancer.sanger.ac.uk/cosmic) is 0.09% (3 of 3516 sam- ples tested). Two of these cases had non-synonymous mutations: one DLBCL and one lymphoid neoplasm not otherwise specified (COSMIC ID COSS2121012). The third case, a cutaneous T-cell lymphoma of mycosis fun- goides type,26 presented a synonymous JUNB mutation. In the whole exome sequencing study on classical Hodgkin lymphoma by Tiacci et al.27, only one of 34 cases presented a non-synonymous JUNB mutation. Therefore, the high frequency of non-synonymous JUNB mutations, including a relatively frequent occurrence of JUNB nonsense muta- tions in both NLPHL and THRLBCL, is a hallmark of these lymphoma entities.
Mutations in the four genes JUNB, DUSP2, SGK1 and SOCS1 were more frequent in THRLBCL and the histopathological NLPHL variants than in typical NLPHL. Since we performed ultra-deep targeted resequencing of whole tissue DNA and allowed allele frequencies of muta- tions to range within the expected tumor cell content (0.1-
10%), this approach might more sensitively identify sub- clonal variants in THRLBCL than in NLPHL due to the slightly higher tumor cell content in THRLBCL compared to NLPHL (median 10% versus 3%). However, the tumor cell content did not differ significantly between histopathological NLPHL variants and typical NLPHL (3% versus 2%, respectively) and thus does not explain the higher number of mutations in histopathological NLPHL variants than in typical NLPHL.
SOCS1 is a known target of aberrant SHM,18 and SHM of immunoglobulin genes is known to be ongoing in the tumor cells of NLPHL and THRLBCL.6,7,14 The mutation patterns of JUNB, SGK1, DUSP2 and SOCS1 observed in the tumor cells of NLPHL and THRLBCL suggest that mutations in these four genes are most likely the result of aberrant SHM, which is likely contributing importantly to the development of these lymphomas. The genes DUSP2 and SGK1 were previously identified as potential targets of aberrant SHM in GCB-type DLBCL,15 but are less fre- quently mutated in GCB-type DLBCL than in NLPHL and THRLBCL. SHM activity is reported to start closely down- stream from the transcriptional start site extending up to 2 kb into the gene,28 which is in line with an enrichment of SNVs in SHM hotspot motifs in the three relatively small genes JUNB, DUSP2 and SOCS1 (<2.5 kb). The more fre- quent occurrence of SNVs in SHM hotspot sites in THRL- BCL and histopathological NLPHL variants might be relat- ed to a longer and/or stronger exposure of the tumor cells to the SHM machinery. Aberrant activity of the SHM machinery may be caused by loss of target specificity and
haematologica | 2019; 104(2)
335