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Genetic landscape of plasmablastic lymphoma
The copy number profile of 49 cases of ABC-DLBCL was compared with that of PBL (Online Supplementary Figure S10).21 PBL displayed lower levels of genetic complexity (12.2 vs. 22.1 alterations/case; Wilcoxon test, P<0.01), more frequently carried gains of 1q32.2-qter but lacked gains of 3q, 18q and 19q13.43 compared to ABC-DLBCL. PBL also lacked recurrent 9p21.3 alterations typically seen in ABC- DLBCL. In comparison with ABC-DLBCL,25 PBL had more frequent STAT3 and NRAS mutations, a lower incidence of KMT2D mutations and virtual absence of mutations affect- ing the NFκB pathway (Figure 4B).
Compared to 41 cases of PCM,22,23 PBL had similar levels of genetic complexity in terms of the copy number profile (12.6 vs. 13 alterations/case; Wilcoxon test, P=0.5) (Online Supplementary Figure S11). PBL resembled PCM for the pres- ence of 1q gains and trisomy 7 but carried significantly more gains of 12p. Otherwise, PBL lacked trisomies typical- ly seen in hyperdiploid PCM (chromosomes 3, 5, 9, 11, 15, 19 and 21). Regarding the mutational landscape, PBL resem- bled PCM26 as both harbor recurrent mutations targeting MAPK pathway genes (NRAS, KRAS and BRAF) (Figure 4C). Nonetheless, PBL had more TP53, STAT3, and MYC mutations, among others (Fisher test, P<0.05).
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Discussion
In this study we performed a large-scale, high-resolution analysis of genomic alterations in 34 cases of PBL. MYC rearrangement was present in 87% of the cases, a higher incidence than previously reported (50%).2,6 These MYC rearrangements may intensify MYC activity in cell prolifer- ation, cell growth, DNA replication, cell metabolism, and cell survival, as described in other lymphomas, such as BL.32 Multiple MYC mutations were identified in six cases with concomitant MYC rearrangement (5 cases including exonic mutations and 1 case with only intronic mutations). These mutations were observed 2.5 kb after a transcript start site (including exon1-intron1-exon2) involving AID-motifs, sug- gestive of an aberrant somatic hypermutation pattern.31,33
The copy number landscape of our PBL series was char- acterized by high genetic complexity (12.2 alterations/case) and recurrent 1q21.1-q44, trisomy 7, 8q23.2-q24.21, 11p13- p11.2, 11q14.2-q25, 12p and 19p13.3-p13.13 gains and 1p33, 1p31.1-p22.3, 13q and 17p13.3-p11.2 losses. Some of these alterations had been previously identified in PBL.8,10 However, our analysis identified novel regions of alteration such as losses of 13q and 17p13.3-p11.2 or 16q11.2-q24.3
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