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TIRAP, a novel familial lymphoma risk gene
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Figure 2. Overall load of numerical and structural genomic alterations in the lymphomas of both siblings. (A) Number (N.) of all validated (by IonProton sequencing) non-silent somatic clonal mutations identified through whole exome sequencing in the two tumors. (B) Chromosomal gains and losses detected in the two lymphomas by array comparative genomic hybridization (aCGH). In the aCGH profiles, the normalized log2 ratios are plotted based on their chromosome position, with vertical bars separating the chromosomes. Regions with losses and gains are represented by decreased and increased log2 ratios, respectively. Genomic changes are marked in red (gain) and green (loss). Copy number (CN) alterations that are present in both tumors are underlined. (C) Combined load of somatic non-silent muta- tions as well as CN gains and losses identified in the two investigated lymphomas.
ing from the 9p24 gain (Figure 4A) is a common feature of both lymphomas, PDL1 was only expressed on the malig- nant B-cells of sister 1 (Figure 4B).
The co-occurrence of genetic alterations involving genes related to immune-cell crosstalk in the lymphoma of sister 1 involving PDL1 expression, B2M p.M1R mutation and genomic alterations of CIITA are an interesting finding that suggests a combined role in escape from immune-sur- veillance.24,25 In summary, we identified genetic lesions that may collectively contribute to the distinct clinical out- come. Of note, TP53 mutations, MYC gains, CIITA translocation and expression of PDL1 on malignant B cells, all solely present in the lymphoma of sister 1, have been associated with an inferior overall and progression-free survival in DLBCL.26-29 BCL2 expression, as observed in the lymphoma of sister 1, in the absence of a translocation (Online Supplementary Table S2) has a controversial prog- nostic role.30
Whole exome sequencing identified lymphoma risk genes
The low age- and gender-adjusted incidence rate for sporadic DLBCL (0.1/100,000 cases in Switzerland31), and the occurrence of 2 siblings affected by mediastinal B-cell lymphomas suggested a genetic predisposition for lym- phomagenesis in this family. Therefore, we performed
WES on DNA from PBMCs of both sisters and all the other members of the core family (Figure 1). A total of 547 rare protein altering variants in 444 genes were identified out of 86,000 screened variants in the germline DNA of each sister. After excluding variants that were present as homozygote in unaffected family members, 274 variants in 234 genes remained. To find a potential link between those 234 candidate genes and deregulated proliferation, we performed a comprehensive gene ontology and path- way enrichment analysis. The result indicated a signifi- cant link between 45 of these candidate genes with cancer and/or malignant lymphoma. To identify potential delete- rious alterations, the pathogenicity of variants in those 45 cancer related genes was examined by five different in sil- ico algorithms. At the end, 15 variants in 15 candidate genes were predicted as deleterious by all algorithms and were considered for further analyses (Online Supplementary Figure S1A). Mutated genes were significantly enriched in processes like proliferation, lymphocyte activation and response to DNA damage, all pathways crucial for tumori- genesis (Online Supplementary Figure S1B). Of note, MLL the only PMBL/DLBCL susceptibility gene reported so far was not found to harbor variants in this family.19
Interestingly, we identified TIRAP among those candi- dates. TIRAP is an adapter protein that engages signals from TLR2 and 4 and thereby activates the NF-kB path-
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