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Genetic landscape of plasmablastic lymphoma
Table 1. Pathological and genetic features of 34 cases of plasmablastic lymphoma.
Case Location Age/ HIV CD79a CD20 PAX5 CD56 CD138 MUM1/ HHV-8 EBER MYC BCL2 BCL6
gender
PBL1 Sinus 38/M PBL2 CervicalLN 43/M PBL3 MesentericLN 49/M PBL4 Abdominalmass 58/F
IRF4
- NA NA + + NA
- NA - - + -
- - - - + - - R N N - - NA - + - - N N NA
- + + + + + NA +
NA - -* +** NA -
- N N NA + R N NA
BAP BAP BAP
PBL5 Nasalmucosa PBL6 Sigma
PBL7 Submandibularmass PBL8 Skin
PBL9 NA
PBL10 NA
PBL12 Oralmucosa 56/F PBL13 Gastrostomy 11/F PBL14 Oralmucosa 49/M PBL15 Oralmucosa 48/M PBL16 Perirectal 47/M PBL17 Small-large bowel 80/F PBL18 Oralmucosa 49/M PBL19 Ethmoidmass 56/M PBL20 Smallbowel 42/M PBL21 Tongue 67/M PBL22 Abdominal mass 63/M PBL23 Stomachmass 68/F PBL24 Mediastinal mass 51/M PBL25 Testis 49/M PBL26 CervicalLN 59/F PBL27Suprapubicarea 87/F PBL28 Thyroidmass 57/F
82/M 72/F 37/M 42/M
- - + + NA - +** - + + - NA - - + - + - - +
NA + NA + - +
A A NA RN NA
+ + F NA NA M NA NA
NA NA NA NA NA NA - - -
NA + NA + NA +
NA - - R NANAN NANAR
NA NA N NA NN NN N N N N NA NA N N N N NA NA NA NA
NA A
N N
NN
NA NA
NA NA
NA NA
NA NA
NA NA
NA NA
NA NA
NA NA
NA NA
NA NA
NA NA
NA NA
NA NA
NA NA
+ - + + + NA + + + NA NA + NA +
NA - + + NA +
NA - NA - + + NA + NA - NA - NA - NA -
- - - + + - NA - NA + - - NA NA + - - - + +
- - - - - - - - -
- R + R + R + R + R - R + R - R + R -R + R
- NA + - NA - - - NA - - NA - -- - - - - NA - - - + - - - - - - - - + - - NA
NA NA + NA + + + + + NA - + + NA + + + + + + + + - +
-
NA NA R
PBL29 Colon PBL30 Testis PBL31 Maxilla PBL32 Palate PBL33SubmaxillaryLN PBL34 RetroperitonealLN
PBL35 Anal
74/M
M NA +
- - - - - NA
NA
- - +
+ + +
- + +
NA + +
--R NA+R NA - R NA + R NA - R
- - R - NA R - + NA - + NA
NA + R
- + R
NA + NA
27/M
36/M
30/M
40/M
39/M
+ -
+ - NA
NA +
+ +
+ +
- - - - +
- - NA + +
- NA - + +
*This patient had a post-transplant associated immunodeficiency. ** Weak and focal positivity. LN: lymph node; M: male; F: female; HIV: human immunodeficiency virus; NA: not available N: negative; R: rearranged; A: amplified.
cytidine deaminase (AID)-motifs (corresponding to sequences WA/TW/WRCY/RGYW/WGCW)31 (65% vs. 39% expected; P<0.05) suggesting that those mutations ful- fill a somatic hypermutation pattern (Online Supplementary Table S7).
We additionally evaluated the occurrence of mutations in genes within predefined pathogenic pathways (Figure 2E; Online Supplementary Table S2). The MAPK pathway was the most frequently mutated pathway (49%) in our cohort, with there being recurrent mutations in NRAS (33%) and additional mutations in KRAS, BRAF and MAP2K1 (2 cases each) and MAPK1 (1 case). In addition MAP2K5 was locat- ed in the minimal amplified region of 15q23 (2 cases). Other recurrently mutated pathways comprised epigenome/chro- matin modifier genes (including EP300 and TET2 muta- tions, among others) (45%), JAK-STAT and cell cycle (40% each), and the NFκB pathway (22%). In detail, JAK-STAT pathway mutations included the activating STAT3 variants
located in the SH2 domain and inactivating mutations of the negative regulator SOCS1. NFκB pathway alterations included CARD11 mutations (3 cases), TNFAIP3, NFKB1, NFKBIE, TRAF3, MYD88 (1 case each) and TRAF5 and TRAF6 amplifications in the minimal amplified region of 1q32.1-q41 and 11p13-p11.2 (2 cases each).
Epstein-Barr virus-positive plasmablastic lymphomas are genetically different from negative cases
Differences in copy numbers and mutational profiling between EBV-positive and -negative PBL were investigated (Figure 3). Of note, EBV-negative PBL had higher mutational load (8.3 vs. 2.9; Wilcoxon test, P=0.006) and more frequent TP53, CARD11 and MYC mutations (P<0.05) whereas EBV- positive PBL tended to harbor frequent mutations affecting the JAK-STAT pathway (STAT3 and SOCS1 mutations) (57% vs. 22%; Fisher test, P<0.2). EBV-negative PBL also had more mutations affecting epigenome/chromatin modi-
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