Page 123 - 2020_09-Haematologica-web

Somatic mutations in DLBCL
translocation partner was the immunoglobulin heavy chain locus, found in 92 of 92 (100%), 29 of 32 (90.6%), and 57 of 100 (57.0%) cases where the rearrangement partner could be determined, respectively (Online Supplementary Table S2).
Frequencies of genomic alterations among cell-of-origin subsets
Of the patients for whom both COO and NGS were available (n=482), 272 (56%), 78 (16%), and 132 (27%) were classified as GCB, unclassified, and ABC DLBCL, respectively (Online Supplementary Table S1). This was sim- ilar to findings for the overall COO population [n=933; GCB, n=540 (58%); unclassified, n=150 (16%); ABC, n=243 (26%)]. Within the GCB subtype, the most preva- lent mutated genes were BCL2 [88 of 272 (32%)], MLL2 (KMT2D) [82 of 272 (30%)] and CREBBP [60/272 (22%)]; loss of CDKN2A [64 of 132 (49%)] and CDKN2B [40 of 132 (30%)] and mutations of MYD88 [45 of 132 (34%)] were most frequently observed in the ABC subtype (Table 1 and Online Supplementary Table S3). Fifteen genes were found to be significantly differentially mutated between the GCB and ABC subtypes at FDR <0.05 (Figure 1B). Alterations of BCL2, CREBBP, TNFRSF14, EZH2, REL, BCL7A and SGK1 were more frequently observed in GCB DLBCL whereas BCOR, ETV6, PRDM1, PIM1, CD79b, CDKN2B, MYD88 and CDKN2A were more frequently mutated in ABC DLBCL (Figure 1B). In the case of BCL2
Table 1. Prevalence of most frequent* gene mutations according to diffuse large B-cell lymphoma cell-of-origin (COO) subtype.
GCB, Unclassified, ABC, n=272 (%) n=78 (%) n=132 (%)
BCL2 32.4 5.1 4.5
and CDKN2A, specific types of alterations displayed dif- ferent frequencies between the GCB and ABC subtypes (Figure 1C). While BCL2 translocations and SNV were more frequently found in the GCB subtype, high-level BCL2 amplifications (≥6 copies) were enriched within the ABC subtype [ABC, 9 of 132 (6.8%); GCB, 4 of 272 (1.5%); Fisher’s exact test P=0.012]. An analysis of low- level BCL2 amplifications (≥1 copy above median ploidy and ≥3 copies) confirmed the enrichment in ABC DLBCL samples [ABC, 83 of 132 (62.9%); GCB, 45 of 272 (16.5%); Fisher’s exact test P<0.001]. The enrichment of CDKN2A alterations within the ABC subtype was pronounced only
Figure 2. Association between BCL2 gene alterations and progression-free sur- vival (PFS) in diffuse large B-cell lymphoma (DLBCL). (A) All BCL2 alterations. (B) BCL2 single nucleotide variant. (C) BCL2 translocations. CI: confidence inter- val; FDR: false discovery rate; HR: hazard ratio; MUT: mutant; WT: wild-type.
A
B
C
KMT2D 30.1
CREBBP 22.1
TP53 19.5
BCL6 18.8
B2M 17.6
TNFRSF14 17.3
EZH2 16.2
TNFAIP3 15.4
REL 13.2
BCL7A 10.7
CDKN2A 10.3
MYD88 8.8
CD58 8.5
TMEM30A 8.1
CD70 7.7
PIM1 7.0
CDKN2B 5.1
NOTCH2 4.0
CD79B 2.2
PRDM1 1.5
ETV6 0.7
21.8 28.8
7.7 3.8
17.9 15.2
35.9 22.0
12.8 12.9
1.3 0.0
6.4 0.8
11.5 9.1
5.1 0.8
2.6 2.3
21.8 48.5
15.4 34.1
10.3 6.8
11.5 8.3
17.9 6.1
5.1 24.2
11.5 30.3
10.3 6.8
9.0 25.0
3.8 19.7
5.1 10.6
Listed in order of frequency in the germinal center B-cell-like (GCB) subgroup.*Gene mutations occurring in ≥10% of patients in any COO subgroup. n=number; ABC: acti- vated B-cell-like.
haematologica | 2020; 105(9)
2301