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C.R. Bolen et al.
Figure 3. BCL2 alterations according to cell-of-origin (COO) subtype. *Germinal center B-cell-like (GCB), 31%; unclassi- fied, 5.1%; activated B-cell-like (ABC), 0.8%. †GCB, 11%; unclassified, 0%; ABC, 4.5%. ‡GCB, 1.5%; unclassified, 2.6%; ABC, 6.8%. amp: amplification; NA: not available; SNV: single nucleotide variant; trans: translocation.
for CDKN2A deletions; SNV occurred to the same degree in all COO subtypes.
Correlation of individual alterations with clinical outcomes
Alterations of 23 genes (fulfilling the predefined criteria based on their prevalence in the analyzed cohort) were evaluated for association with PFS on univariate and mul- tivariate analyses. Prognostic trends were observed among a number of previously studied biomarkers, including BCL2, CREBBP, REL, TP53 and CDKN2A (all P<0.05, unadjusted). However, alterations of BCL2 (including translocations, SNV and high-level amplifications) were the most strongly associated with PFS [hazard ratio (HR): 2.6; 95% confidence interval (CI): 1.6-4.2; FDR, 0.0037] independent of COO, IPI, treatment arm, number of planned chemotherapy cycles, and geographic region (Table 2). None of the 23 biomarkers showed significant differences in prognostic impact between treatment arms. The BCL2 prognostic effect was observed for both BCL2 SNV (HR: 2.6; 95%CI: 1.5-4.7; FDR, 0.022) and transloca- tions (HR: 2.5; 95%CI: 1.4-4.2; FDR, 0.0028) (Table 2 and Figure 2) individually. The prognostic role of high-level BCL2 amplification was not tested separately due to the low prevalence of this alteration in the current study. No association was found between survival and low-level BCL2 amplifications (HR: 1.2; 95%CI: 0.8-1.9; FDR, 0.58). BCL2 alterations were detected in 20% (102 of 499) of patients, with 92 of 102 patients having a BCL2 transloca- tion, 90% (83 of 92) of whom were GCB patients, with only one translocated ABC patient. Of 39 patients with BCL2 SNV, 80% (31 of 39) and 15% (6 of 39) were in the GCB and ABC subgroups, respectively. The majority of patients with BCL2 SNV harbored BCL2 translocations (74%, 29 of 39) (Figure 3), but BCL2 SNV were still asso- ciated with worse prognosis among patients without a BCL2 translocation (HR: 2.8; 95%CI: 1.0-7.9; P=0.047). BCL2 mutations were also significantly correlated with
BCL2 gene and protein expression levels (Online Supplementary Figure S1).
Alterations of CREBBP (HR: 2.1; 95%CI: 1.3-3.4; FDR, 0.054) and TP53 (HR: 1.6; 95%CI: 1.1-2.5; FDR, 0.22) were also associated with PFS on multivariate analysis, but did not fulfill the predefined criteria for significance (FDR <0.05). Alterations of CREBBP were detected in 15% (73 of 499) of patients; 82% (60 of 73), 8% (6 of 73), and 7% (5 of 73) of whom belonged to the GCB, unclassified and ABC subtypes, respectively. Four of the 73 patients har- bored two different CREBBP mutations. In the majority of cases, CREBBP alterations were SNV (97%, 71 of 73), with only two cases of CREBBP deletion. Alterations of TP53 were found in 18% (92 of 499) of patients, of whom 58% (53 of 92), 15% (14 of 92), and 22% (20 of 92) had the GCB, unclassified, and ABC DLBCL subtype, respectively. Overall, 105 TP53 alterations were observed in 92 patients, with 13 of 92 patients harboring two simultane- ous TP53 mutations. SNV were the most frequently observed TP53 alterations (98%, 103 of 105), while TP53 deletions and rearrangements were observed in two cases, and one case, respectively.
CDKN2A alterations were associated with shorter PFS on univariate analysis (HR: 1.7; 95%CI: 1.2-2.5; FDR, 0.13). This effect was driven by CDKN2A deletions (HR: 1.6; 95%CI: 1.1-2.4; FDR, 0.058). No significant associa- tion with PFS was observed on multivariate analysis for all CDKN2A alterations or for CDKN2A deletions only (Table 2). CDKN2A alterations were observed in 23% (113 of 499) of DLBCL patients. Of all cases with any CDKN2A alteration, 25% (28 of 113), 15% (17 of 113), and 57% (64 of 113) belonged to the GCB, unclassified, and ABC sub- types, respectively. The majority of the CDKN2A alter- ations were homozygous gene deletions, which were enriched within the ABC subtype. Patients with CDKN2A deletions had adverse clinical disease characteristics (IPI, extranodal sites, age, and serum lactate dehydrogenase) compared with patients without a CDKN2A deletion,
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