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Genetic landscape of plasmablastic lymphoma
CNN-LOH. Our cases showed recurrent regions of amplifi- cation with some of them in the context of chromothripsis- like patterns. Amplifications of 1q21 had already been described as an important prognostic marker in PCM.34 We also identified IL6R, ADAR and CKS1B genes included in the 1q21.3-q23.2 amplified region.27,28 These genes have been identified to drive disease aggressiveness in 1q21- amplified PCM cases, and consequently, could be consid- ered possible targets of the 1q21 amplification.27,28 In detail, 1q21 amplification and overexpression of CKS1B have been described to confer poor prognosis in PCM, as a result of enhanced degradation of p27/Kip1.28 Besides, IL6R and ADAR genes cooperate, inducing hyperactivation of the JAK-STAT pathway, leading to the transcription of pro-sur- vival and anti-apoptotic genes in PCM.27 Of note, the copy number profile identified in PBL differed from that in other lymphoma entities such as BL, ABC-DLBCL and PCM. PBL were genetically more complex than BL, and lacked com- mon aberrations of ABC-DLBCL such as 9p21.3 losses and 18q gains or typical trisomies of the hyperdiploid profile found in PCM. On the other hand, PBL had specific alter- ations including gains of 12p (including KRAS) and 16q11.2- q24.3 CNN-LOH.
Regarding the mutational profile of PBL, the most fre- quently mutated genes were STAT3, NRAS and TP53, fol- lowed by MYC, EP300, CARD11, SOCS1 and TET2. These mutations mainly affect the MAPK pathway, epigenome/chromatin modifier genes, the JAK-STAT path- way and cell cycle genes. Altough some of these results have already been described (Online Supplementary Figure
S12),9,10 we also demonstrated a previously undetected asso- ciation between clonal TP53 alterations and EBV negativity. Interestingly, several of those genes could be targets for novel therapies (Online Supplementary Table S8). The identi- fication of recurrent STAT3 and NRAS mutations is in line with recent results in HIV-positive PBL in South Africa.10 Moreover, Garcia-Reyero et al. also found recurrent mis- sense PRDM1 mutations,9 which we were not able to iden- tify in our cases. Several of those described PRDM1 muta- tions were predicted in the study as neutral, in contrast to the truncating PRDM1 mutations associated with ABC- DLBCL.35
In our study we identifed recurrently mutated pathways that have an important role in the pathogenesis of PBL. In this sense, the MAPK pathway was the most frequently mutated pathway, with mutations in NRAS, KRAS, BRAF and MAP2K1 being found in 49% of the cases. This finding is similar to the recent observation in South-African patients and highlights its relevance in PBL.10 KRAS and NRAS mutations were mainly located in the hotspot amino acid positions 13 and 61, previously described to impair intrinsic GTPase activity, leading to constitutive activation of the MAPK pathway.36 Two BRAF mutations affecting the G469V/A position and located on the p-loop of the kinase domain were also recognized. These mutations have been demonstrated in lung cancer to induce a higher kinase activ- ity compared to non-mutated BRAF.37 These MAPK path- way mutations were also frequently found in PCM (46- 59% of cases), leading to MEK/ERK activation and resulting in increased proliferation, growth and survival.26,38
Figure 3. Overview of recurrent alterations in plasmablastic lymphomas. Different rows represent recurrent mutations (>10%) and copy number alterations (>25%). The upper bar plot indicates the number of driver mutations per case whereas the lower bar plot indicates the number of copy number alterations per case. EBV: Epstein-Barr virus; LOH: loss of heterozygosity, CNN-LOH: copy number neutral loss of heterozygosity; CNA: copy number alteration.
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