First described in 1967, hyperdiploidy (HD) is the most frequent genetic abnormality in B-cell-precursor leukemia (BCP-ALL) in children, comprising about 25% of all cases. ...most notably, forced ...expression of hLZTR1p.Arg283Trp and hLZTR1p.Tyr535Ter induced mitotic recombination by 4-fold and 3.4-fold, respectively (Figure , Supporting Information S1: Figure ). Both patients developed HD BCP-ALL and the girl with hLZTR1p.Tyr535Ter variant was in vivo diagnosed at a rather atypical age (17 years old) for the occurrence of an HD karyotype, as the HD genetic subtype while predominant in childhood, is observed less frequently in adults and young adolescents. ...sequencing of the respective HD BCP-ALL of both children harboring the two functional significant germline variants, hLZTR1p.Tyr535Ter and hLZTR1p.Arg283Trp, unveiled secondary somatic mutations in RAS pathway genes: a stop gain LZTR1:p.Glu339Ter mutation and a NRAS:c.38G>A mutation, respectively, which could be interpreted as an oncogenic second hit. After obtaining the above encouraging in vivo functional results, we mined germline WES data from other 178 children BCP-ALL who had been treated in several additional German pediatric oncology centers. ...overall our study comprised 283 children with BCP-ALL, of whom we collected comprehensive clinical and germline data after obtaining informed consent.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Burkitt lymphoma (BL) represents the most aggressive B‐cell‐lymphoma. Beside the hallmark of IG‐MYC‐translocation, surface B‐cell receptor (BCR) is expressed, and mutations in the BCR pathway are ...frequent. Coincidental infections in endemic BL, and specific extra‐nodal sites suggest antigenic triggers. To explore this hypothesis, BCRs of BL cell lines and cases were screened for reactivities against a panel of bacterial lysates, lysates of Plasmodium falciparum, a custom‐made virome array and against self‐antigens, including post‐translationally modified antigens.
An atypically modified, SUMOylated isoform of Bystin, that is, SUMO1‐BYSL was identified as the antigen of the BCR of cell line CA46. SUMO1‐BYSL was exclusively expressed in CA46 cells with K139 as site of the SUMOylation. Secondly, an atypically acetylated isoform of HSP40 was identified as the antigen of the BCR of cell line BL41. K104 and K179 were the sites of immunogenic acetylation, and the acetylated HSP40 isoform was solely present in BL41 cells. Functionally, addition of SUMO1‐BYSL and acetylated HSP40 induced BCR pathway activation in CA46 and BL41 cells, respectively. Accordingly, SUMO1‐BYSL‐ETA’ immunotoxin, produced by a two‐step intein‐based conjugation, led to the specific killing of CA46 cells. Autoantibodies directed against SUMO1‐BYSL were found in 3 of 14 (21.4%), and autoantibodies against acetylated HSP40 in 1/14(7.1%) patients with sporadic Burkitt‐lymphoma. No reactivities against antigens of the infectious agent spectrum could be observed.
These results indicate a pathogenic role of autoreactivity evoked by immunogenic post‐translational modifications in a subgroup of sporadic BL including two EBV‐negative BL cell lines.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Keywords: MALT lymphoma; marginal zone lymphoma; extra-nodal lymphoma; DNA methylation; lymphoma progression Summary Extra-nodal marginal zone B-cell lymphoma (MZBL) of mucosa-associated lymphoid ...tissue is an indolent lymphoma mostly affecting the gastrointestinal tract. The lymphoma initially has small-cell morphology (SC-MZBL) and often arises in the background of Helicobacter pylori-induced gastritis. In some cases, a clonal malignant progression to large-cell morphology (LC-MZBL) is observed. Here, we studied the DNA methylation profile of 30 gastric MZBLs along their progression. Genome-wide DNA methylation profiling, identified 7698 significantly differentially methylated loci during gastric MZBL progression (I/I.sub.max ayen0*4, q less than or equal to 0*001). LC-MZBL showed hypermethylation in comparison to SC-MZBL with an enrichment of regions involved in transcriptional regulation. In conclusion, our present data show that the morphological distinction between SC- and LC-MZBL is reflected by characteristic DNA methylation profiles. Article Note: R.D. and R.W. contributed equally to the work. CAPTION(S): Fig S1. Histology and Ki-67 immunohistochemical staining of MZBL. Fig S2. Scatterplot displaying the DNA methylation level of 822908 loci for the three paired samples. Fig S3. Phylogenetic tree based on the DNA methylation pattern of 1302 CpGs loci described to become differentially methylated during B-cell development. Fig S4. Comparison of the DNA methylation profile during MZBL progression. Fig S5. DNA methylation profile of germinal centre B cell (gcBC), naive B cell (naiBC) and benign T cell at loci identified to be significantly differentially methylated between the SC- and the LC-MZBL. Fig S6. DNA methylation profile of gastric mucosa samples infected with Helicobacter pylori at loci identified to be significantly differentially methylated between the SC- and the LC-MZBL. Fig S7. Supervised analysis between the SC-MZBL and benign samples. Fig S8. Haematoxylin and eosin and immunohistochemistry staining for Ki-67 for Com(SC+LC) lymphoma. Fig S9. Haematoxylin and eosin and immunohistochemical staining for Ki-67 of Com(SC+LC)-3 lymphoma. Fig S10. Relative distribution of the loci differentially methylated during MALT lymphoma progression between SC- and LC-MZBL. Fig S11. Relative distribution of the loci differentially methylated during MALT lymphoma progression between the SC- and LC-MZBL. Fig S12. Integrated analysis of differentially methylated and differentially expressed genes in LC- in comparison to SC-MZBL. Data S1. Supplemental methods. Table SI. Case identifiers for the study cohort. Table SII. Overview on the features of the analysed gastric MZBL cases, benign T cells and benign gastric mucosa infected with Helicobacter pylori. Table SIII. Overview of the analysed B-cell populations of various differentiation stages. Table SIV. Enrichment analysis of differentially methylated loci between SC- and LC-MZBL for Polycomb repressive complex target regions and Kulis Modules.1 Table SV. Pathway enrichment analysis of differentially methylated loci between the SC- and the LC-MZB using PANTHER (i) and g:Profiler (ii). Table SVI. Integrated analysis of DNA methylation and gene expression data: 53 genes are differentially expressed and differentially methylated between SC- and LC-MZBL. Table SVII. Expression of CDCA8 protein detected by immunohistochemistry. Byline: Rucha Dugge, Rabea Wagener, Peter MOs.ller, Thomas F. E. Barth
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Recent genome-wide studies have demonstrated that a significant proportion of children with cancer carry predisposing germline variants, with varying incidence according to cancer type. In general, ...there is a lower incidence of underlying germline predisposing variants among patients with B-cell acute lymphoblastic leukemia (B-ALL) compared to other types of cancer, but higher rates may be found in patients with specific leukemia subtypes. Two categories of ALL-predisposing variants have been described: common polymorphisms, conferring low-penetrance ALL susceptibility, and rare variants, conferring high-penetrance ALL susceptibility. Variants in genes encoding hematopoietic transcription factors are an example of the latter, and include ETV6, IKZF1, PAX5 and RUNX1. Here, we present an overview of the germline variants detected in patients with B-ALL in these four genes and a summary of functional studies analyzing the impacts of these variants upon protein function, and hence their effects with regard to leukemia predisposition. Furthermore, we review specific clinical characteristics of patients with B-ALL, including specific features of the patient or family history and associated somatic genetic characteristics, which are suggestive of underlying germline alterations in one of these genes. This review may be of assistance in the interpretation of patient genetic germline findings, made even more challenging by the absence of a suggestive family history or by an unknown familial cancer history. Despite a low incidence of underlying germline alterations in ETV6, IKZF1, PAX5 and RUNX1 in patients with B-ALL, identification of an underlying ALL predisposition syndrome is relevant to the clinical management of patients and their relatives, as the latter are also at risk of developing cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive ...analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.
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KISLJ, NUK, SBMB, UL, UM, UPUK
Predisposing CHEK2 germline variants are associated with various adult‐type malignancies, whereas their impact on cancer susceptibility in childhood cancer is unclear. To understand the frequency of ...germline variants in the CHEK2 gene and their impact on pediatric malignancies, we used whole‐exome sequencing to search for CHEK2 variants in the germlines of 418 children diagnosed with cancer in our clinics. Moreover, we performed functional analysis of the pathogenic CHEK2 variants to analyze the effect of the alterations on CHK2 protein function. We detected a CHEK2 germline variant in 32/418 (7.7%) pediatric cancer patients and 46.8% of them had leukemia. Functional analysis of the pathogenic variants revealed that 5 pathogenic variants impaired CHK2 protein function. 6/32 patients carried one of these clearly damaging CHEK2 variants and two of them harbored a matching family history of cancer. In conclusion, we detected germline CHEK2 variants in 7.7% of all pediatric cancer patients, of which a minority but still relevant fraction of approximately 20% had a profound impact on protein expression or its phosphorylation after irradiation‐induced DNA damage. Accordingly, we conclude that CHEK2 variants increase the risk for not only adult‐onset but also pediatric cancer.
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Germline mutations in the tumor suppressor gene CHEK2 increase susceptibility to adult‐onset cancer. Whether such variants also contribute to pediatric cancers remains unclear. In this study, the authors investigated the frequency of CHEK2 variants in an unselected cohort of children diagnosed with cancer and in the children's parents. Pathogenic CHEK2 germline variants were detected in 7.7% of children with cancer, about 47% of which were diagnosed with leukemia. Among pediatric cancer patients with germline CHEK2 mutations, nearly one‐fifth suffered impaired CHK2 protein function. The findings suggest that CHEK2 germline variants are predisposing factors to childhood cancer.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The new recently described provisional lymphoma category Burkitt-like lymphoma with 11q aberration comprises cases similar to Burkitt lymphoma (BL) on morphological, immunophenotypic and ...gene-expression levels but lacking the IG-MYC translocation. They are characterized by a peculiar imbalance pattern on chromosome 11, but the landscape of mutations is not yet described. Thus, we investigated 15 MYC-negative Burkitt-like lymphoma with 11q aberration (mnBLL,11q,) cases by copy-number analysis and whole-exome sequencing. We refined the regions of 11q imbalance and identified the INO80 complex-associated gene NFRKB as a positional candidate in 11q24.3. Next to recurrent gains in 12q13.11-q24.32 and 7q34-qter as well as losses in 13q32.3-q34, we identified 47 genes recurrently affected by protein-changing mutations (each ≥3 of 15 cases). Strikingly, we did not detect recurrent mutations in genes of the ID3-TCF3 axis or the SWI/SNF complex that are frequently altered in BL, or in genes frequently mutated in germinal center–derived B-cell lymphomas like KMT2D or CREBBP. An exception is GNA13, which was mutated in 7 of 15 cases. We conclude that the genomic landscape of mnBLL,11q, differs from that of BL both at the chromosomal and mutational levels. Our findings implicate that mnBLL,11q, is a lymphoma category distinct from BL at the molecular level.
•Burkitt-like lymphoma with 11q aberration harbors a mutational landscape distinct from sporadic BL.•Biallelic inactivation indicates a pathogenic role of the INO80 complex-associated NFRKB gene in mnBLL,11q.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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