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INTRODUCTIONIGH and MYC translocation is one of the representative genetic abnormalities in Burkitt lymphoma/leukemia (BL). Generally, BL shows a mature B‐cell phenotype. However, in the WHO Classification, a more immature phenotype of BL (preBLL) is listed as a phenotype of precursor B‐cells, with expression of terminal deoxynucleotidyl transferase (TdT), and sometimes CD34, and absence of CD20 and surface immunoglobulin expression.1 Recently, Wagener et al. reported that preBLL and classical BL could be distinguished from each other by differences in the translocation architecture of IGH‐MYC.2–4 They reported that aberrant V (variable), D (diversity), and J (joining) gene segments recombination resulting in IG‐MYC characterized by N‐sequences and loss of some bases at the breakpoint are features of preBLL. They also revealed a difference in mutation profile between preBLL and BL. PreBLL was associated with NRAS and/or KRAS mutations whereas BL was associated with MYC, ID3, and CCND3. Subsequently, Yoon et al. showed that IGH‐MYC translocations due to the aberrant VDJ recombination were also detected in the TdT‐negative cases, which indicated that these cases were at a more advanced maturation stage than those of Wagener et al.5 Their cases were associated with mutations in MYC and/or TP53, which are often mutated genes in BL.Therefore, preBLL and BL have been found to have different genetic features, including IGH‐MYC translocation architecture. Meanwhile, it is still unclear at which maturation stage preBLL and BL can be distinguished, due to the limited number of reported cases. We here present an infant preBLL case with IGH‐MYC translocations due to the aberrant VDJ recombination despite revealing BL‐specific genetic abnormalities, suggesting a more advanced maturation stage than previous reports.RESULTSClinical course of the caseA 10‐month old boy was admitted with a 2‐week history of ill complexion and fever. Physical examination showed head masses and bilateral renal swelling. A laboratory examination revealed thrombocytopenia (5.5 × 104 platelets/μl) and total leukocyte count of 11 400/μl with blast cells with basophilic cytoplasm containing vacuoles. Flow cytometric immunophenotyping of blast cells was positive for cyCD22 (98.6%), cCD79a (99.7%), CD19 (99.0%), CD10 (97.9%), CD24 (99.1%), cyμ (91.5%), CD22 (98.8%), HLA‐DR (99.5%), and CD38 (99.8%), and negative for CD20, μ, κ, λ, CD34, and TdT (Table S1). The expression of CD45 was bright. Karyotyping analysis showed 46, XY, dup(1)(q21q32)x2,t(8;14)(q24;q32) /46, XY . Fluorescence in situ hybridization analysis on blast cells identified the fusion signal of IGH‐MYC, leading to a diagnosis of Burkitt leukemia with B‐cell phenotype (detailed in Figure S1). Morphological findings, negativity for CD34 and TdT, and positivity for cyμ and CD45 were suggestive of mature B‐cell phenotype, whereas negative for CD20 and surface globulins were immature B‐cell features (preBLL). Cerebrospinal fluid examination showed an increase in the number of dysmorphic cells (40/μl) with a high N/C ratio, nucleus with irregular shapes, and distinct nucleoli, and was cytologically determined as class V. Computed tomography revealed bilateral renal swelling, hepatomegaly, and splenomegaly. As the present case had both B‐cell precursor and mature B‐cell features of ALL, we considered that both lymphoma‐oriented intensive block‐type chemotherapy and ALL‐oriented chemotherapy, including maintenance therapy, should be adopted. Although the present case was infant ALL, we did not adopt infant‐specific chemotherapy such as in MLL‐10,6 which did not include block‐type treatment. Therefore, the present case was treated according to AIEOP‐BFM ALL 2000 high‐risk chemotherapy.7 Despite suspending prednisolone for 2 days due to tumor lysis syndrome, the patient showed a good prednisolone response. The patient achieved a complete remission (CR) after induction therapy. Considering that the patient was an infant, intensification of intrathecal chemotherapy was adopted to avoid the late complications of cranial radiotherapy. As of 38 months from diagnosis, the patient is alive without disease relapse.Identification of additional somatic mutations and IGH‐MYC translocation architectureTo reveal the present case's genetic characteristics, we further performed whole‐exome sequencing of tumor‐normal pairs (detailed in Data S1). We filtered out the variants that were present in normal sample, and identified two somatic mutations in FBXO11 and one in TNIK (Table 1). Visual screening using the integrative genomics viewer (IGV) viewer (IGV 2.3.97) revealed that the two mutations in FBXO11 were located on different alleles (Figure S2). Next, we focused on the breakpoint junction of the IGH‐MYC translocation using the IGV. The breakpoint mapped to the 5′ end of IGHJ4, with loss of some bases from the 5′ end, and 1.7 kbp upstream of MYC (Figure 1A). As the breakpoint was close to recombination signal sequences and nucleotides resembling N‐sequences were added at the breakpoint, the translocation most likely occurred through an aberrant VDJ recombination.1TABLESomatic mutations detected by whole‐exome sequencingGeneRegionAA changeSIFTPP2_HDIVCADDFBXO11SplicingNM_001190274:exon14:c.1797+1G>A28.5FBXO11ExonicNM_001190274:exon14:c.A1713C:p.L571FTaPb24.7TNIKExonicNM_001161566:exon24:c.G2978A:p.R993QDcDd35Abbreviation: PP2, PolyPhen 2.aTolerated.bPossibly damaging.cDeleterious.dProbably damaging.1FIGUREGenetic characterization of the case. (A) Translocation architecture of IGH‐MYC breakpoint junctions. The breakpoint mapped to the 5′ end of IGHJ4, with loss of three bases from the 5′ end, and 1.7 kbp upstream of MYC. Nucleotides resembling N‐sequences were added at the breakpoint. (B) The summary of the present case's characteristics along with a comparison with typical preBLL and BL characteristics with the reference to previous report of Wagener et al.3 The findings of typical preBLL and classical BL that are consistent with the present case are marked in bordeaux color. The recurrent mutated genes were listed with reference to previous genetic analysis of preBLL and classical BL.3,4 BL, Burkitt lymphoma/leukemia; CSR, class switch recombination; preBLL, B‐cell phenotype Burkitt leukemia; SHM, somatic hypermutationIdentification of germline variants of cancer‐predisposing genesAs the present case developed atypical leukemia in infancy, we further searched for germline pathogenic variants of cancer‐associated genes (detailed in Data S1). As a result, a pathogenic variant of KRAS (c.G34C, p.G12R), which has been registered as a somatic mutation in NCBI ClinVar and Catalog of Somatic Mutations in Cancer (COSMIC), was identified with a suspected mosaic mutation frequency (variant allele frequency = 19%) in a peripheral blood sample during CR. This KRAS variant was also identified in tumor samples. To obtain the precise frequency of mutation alleles, droplet digital PCR procedures were performed using QX‐200 and ddPCR™ Mutation Assay: KRAS p.G12R (Bio‐Rad, Hercules, CA). The mutation allele frequency was 9.5% in the CR sample and 46% in the tumor sample, respectively. The mosaicism could not be validated in any other organ due to the lack of available samples. The summary of the present case's characteristics is shown in Figure 1B, along with a comparison with typical preBLL and BL characteristics.DISCUSSIONWagener et al. and López et al. recently reported the features of IG‐MYC translocation architecture in preBLL and BL, respectively.3,4 They showed that preBLL and BLL were well distinguished from each other by IG‐MYC translocation architecture and mutated genes. However, more recently, Yoon et al. reported TdT‐negative preBLL cases carrying IG‐MYC due to aberrant VDJ and additional mutations in BL‐specific genes.In addition to being negative for TdT and CD34, the present case was positive for cyμ, and expression of CD45 was bright. These immunophenotypic profiles indicated a more advanced maturation stage of preBLL than in those of Yoon et al.5 The translocation architecture of IGH‐MYC in the present case showed the characteristics of preBLL, whereas additional mutations were identified in FBXO11. FBXO11 is considered as a tumor suppressor gene in the pathogenesis of B‐cell lymphomas.8,9 Mutation in FBXO11 was identified in diffuse large B‐cell lymphoma and BL.4,10 Additionally, a point mutation in TNIK was also identified. TNIK is one of the enzymes associated with Wnt signaling and is associated with its activation.11 As the TNIK mutation identified in the present case was not previously reported, the pathogenicity is unknown. It might have contributed to the oncogenesis. Meanwhile, mutations in other BL‐specified genes, such as MYC and ID3, were not detected in the present case. These atypical patterns of additional mutated genes might be responsible for the differences in the maturation stages of preBLL.As another genetic abnormality, KRAS mutation, p.G12R, was detected in a CR sample with a suspected mosaic mutation frequency. p.G12R is one of the hot spot somatic mutations in KRAS registered in COSMIC. Germline and/or somatic mosaicisms of KRAS are shown to be associated with developmental disorders, such as Noonan syndrome.12 In the process of B‐cell development, KRAS contributes to early B‐cell development at the pre‐B‐cell stage and late B‐cell maturation.13 As KRAS p.G12R is a gain‐of‐function missense mutation, the oncogenic KRAS may have been responsible for the abnormalities in preBLL development and maturation in the present case. In support of that, the percentage of KRAS mutations was greater in tumor samples than in CR samples. As the KRAS mutation was mosaic, the patient would have not showed the symptoms characterizing Noonan syndrome. This finding indicates the importance of germline specimen analysis to evaluate the effect of genetic background on the development of childhood cancer.Although our case fortunately achieved sustained remission, optimal therapeutic strategy of preBLL has not yet been established. In recent studies comparing treatment outcomes of preBLL, mature B‐cell NHL type chemotherapy is encouraging because of the favorable outcome.14,15 Further genetic studies for this unique subset might provide us a clue to the best strategy against preBLL.ACKNOWLEDGMENTSWe would like to thank Ms. Etsuko Mochizuki for her technical assistance. The authors also thank the medical editor from the Division of Education for Clinical Research at NCCHD for professionally editing this manuscript. This work was supported in part by the Japan Society for the Promotion of Science (JSPS) through a Grant‐in‐Aid for Scientific Research (grant number 19K22608), by the Japan Agency for Medical Research and Development (AMED) (grant numbers JP20ck0106467 and 20kk0305014).CONFLICT OF INTERESTThe authors have stated explicitly that there are no conflicts of interest in connection with this article.AUTHOR CONTRIBUTIONSAll authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conceptualization, data curation, formal analysis, investigation, validation, visualization, writing—original draft, M.Y.; Conceptualization, resources, supervision, writing—review and editing, D.T.; Data curation, formal analysis, investigation, validation, S.Y.; Conceptualization, resources, T.O.; Data curation, investigation, methodology, software, K.N.; Data curation, investigation, methodology, software, H.O.‐K.; Data curation, investigation, methodology, software, K.I.; Investigation, methodology, visualization, A.S.‐O.; Resources, Y.K.; Supervision, S.I.; Resources, supervision, K.M.; Data curation, investigation, methodology, T.D.; Data curation, investigation, methodology, supervision, N.K.; Investigation, methodology, resources, visualization, T.Y.; Methodology, software, supervision, K.H.; Conceptualization, funding acquisition, methodology, project administration, resources, supervision, writing—review and editing, M.K.ETHICAL STATEMENTGenomic analysis was approved by the Institutional Review Board of the National Center for Child Health and Development (#1035), and the required informed consent was obtained from the guardians of the patient.DATA AVAILABILITY STATEMENTThe data that support the findings of this study are available on request from the corresponding author. 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Cancer Reports – Wiley
Published: Jul 1, 2022
Keywords: FBXO11; IGH‐ MYC; KRAS; preBLL
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