Background

A recent genome-wide association study (GWAS) including 253 Chinese individuals from Singapore with B-cell Non-Hodgkin Lymphoma (B-NHL), a new susceptibility locus, rs6773853 was identified between BCL6 (B-cell lymphoma protein 6) and LPP (lipoma preferred partner) on chromosome 3q27. This was significantly associated with an increased risk of B-NHL; Odds ratio (OR) per-copy of the risk allele = 1.44 and diffuse large B-cell lymphoma (DLBCL) OR = 1.47. The aims of this study were to determine the prognostic significance of rs6773853 in a case-only analysis of B-NHL patients and to determine if there were any differences in patients and tumor characteristics in B-NHL patients with rs6773853 locus present and absent.

Methods

Genome-wide genotyping to identify germline mutations from DNA of patients' blood samples have been described. Patient, tumour and treatment data were obtained from clinical and pathology databases as well as electronic and hardcopy of medical records. Fluorescent in-situ hybridization testing for BCL6 translocations using breakapart probes were performed on tumor samples whenever possible. Patients were compared in a two-way (homozygous wild-type [WT] versus presence of 1 or more copies of the risk allele of rs6773853) and three-way (homozygous WT versus heterozygous carrier versus homozygous variant of rs6773853) manner. Prognostic factors were analyzed first by univariate analysis. A multivariate Cox regression model was then fitted including all factors showing statistical significance on univariate analysis to identify the best predictors of overall survival.

Results

Clinical and pathologic data were available for 245 B-NHL patients in whom GWAS was performed. The minor allele of rs6773853 locus was identified in 127 patients: 100 were homozygous and 27 were heterozygous carriers. The WT genotype was present in 118 patients. There were no statistically significant differences in the clinical and tumor characteristics or treatment received in both 2-way (Table 1) and 3-way analyses. On univariate analysis, age >60 years, ECOG 2–4, B symptoms, advanced stage, aggressive B-NHL, 2 or more extra-nodal sites, elevated LDH, high-risk IPI and a personal history of another cancer were associated with a poorer OS. On multivariate analysis the presence of rs6773853 locus was independently associated with a poorer OS. (Table 2) The frequencies of BCL6 translocations were 17.9% (7/39) and 20.8% (10/48) in the B-NHL with rs6773853 locus absent and present respectively.

Table 1

Patient, tumor and treatment of B-cell lymphoma patients with rs6773853 wild-type and carrier genotypes

Variablesrs6773853 locusp-value [1]
WT (N = 118)Present (N = 127)
N%N%
Age, Median (Range) 59 (22 - 86) 58 (22 - 94) 0.25 
Gender     0.80 
Female 52 44 58 46  
Male 66 56 69 54  
ECOG     0.35 
0 - 1 103 87 116 91  
2 - 4 10 8 7 6  
B-NHL type based on grade     0.60 
Indolent 42 36 49 39  
Aggressive 74 63 75 59  
Ann-Arbor Stage     0.85 
I/II 65 55 71 56  
III/IV 52 44 54 43  
Number of extra-nodal sites     0.55 
0 - 1 100 85 104 82  
≥ 2 18 15 23 18  
B symptoms     0.75 
Yes 27 23 29 23  
No 66 56 64 50  
LDH     0.20 
Normal 47 40 61 48  
Raised 71 60 66 52  
IPI     0.92 
L 50 42 58 46  
LI 21 18 23 18  
HI 11 9 12 9  
H 14 12 12 9  
Personal history of another cancer     0.67 
Yes 6 5 5 4  
No 112 95 122 96  
Histology     0.43 
DLBCL 61 107 67 118  
Burkitt's 4 7 2 4  
CLL 3 5 5 9  
Follicular 16 28 21 37  
Low grade with transformation 7 12 2 4  
Marginal zone lymphoma 9 16 11 19  
Mantle cell lymphoma 2 4 2 4  
Primary CNS lymphoma 0 0 3 5  
Rituximab     0.15 
Yes 83 70 85 67  
No 35 30 36 28  
Anthracycline     0.43 
Yes 72 61 70 55  
No 46 39 55 43  
Variablesrs6773853 locusp-value [1]
WT (N = 118)Present (N = 127)
N%N%
Age, Median (Range) 59 (22 - 86) 58 (22 - 94) 0.25 
Gender     0.80 
Female 52 44 58 46  
Male 66 56 69 54  
ECOG     0.35 
0 - 1 103 87 116 91  
2 - 4 10 8 7 6  
B-NHL type based on grade     0.60 
Indolent 42 36 49 39  
Aggressive 74 63 75 59  
Ann-Arbor Stage     0.85 
I/II 65 55 71 56  
III/IV 52 44 54 43  
Number of extra-nodal sites     0.55 
0 - 1 100 85 104 82  
≥ 2 18 15 23 18  
B symptoms     0.75 
Yes 27 23 29 23  
No 66 56 64 50  
LDH     0.20 
Normal 47 40 61 48  
Raised 71 60 66 52  
IPI     0.92 
L 50 42 58 46  
LI 21 18 23 18  
HI 11 9 12 9  
H 14 12 12 9  
Personal history of another cancer     0.67 
Yes 6 5 5 4  
No 112 95 122 96  
Histology     0.43 
DLBCL 61 107 67 118  
Burkitt's 4 7 2 4  
CLL 3 5 5 9  
Follicular 16 28 21 37  
Low grade with transformation 7 12 2 4  
Marginal zone lymphoma 9 16 11 19  
Mantle cell lymphoma 2 4 2 4  
Primary CNS lymphoma 0 0 3 5  
Rituximab     0.15 
Yes 83 70 85 67  
No 35 30 36 28  
Anthracycline     0.43 
Yes 72 61 70 55  
No 46 39 55 43  
1]

Two-sided p-values based on Fisher's Exact Test/ Chi-Square Test, excluding unknowns

View Large
Table 2

Multivariate analysis showing factors independently prognostic for OS amongst the cohort of patients with B-NHL

CharacteristicsHR (95% C.I.)p-value
Age   
2 60 1 - 
> 60 3.20 (1.74 - 5.90) <0.001 
ECOG   
0 - 1 1 - 
2 - 4 3.69 (1.59 - 8.55) 0.0020 
Stage   
I/II 1 - 
III/IV 2.53 (1.35 - 4.75) 0.0040 
B symptoms   
Yes 1 - 
No 0.39 (0.21 - 0.73) 0.0030 
rs6773853 
WT 1 - 
Present 1.81 (1.01 - 3.25) 0.046 
CharacteristicsHR (95% C.I.)p-value
Age   
2 60 1 - 
> 60 3.20 (1.74 - 5.90) <0.001 
ECOG   
0 - 1 1 - 
2 - 4 3.69 (1.59 - 8.55) 0.0020 
Stage   
I/II 1 - 
III/IV 2.53 (1.35 - 4.75) 0.0040 
B symptoms   
Yes 1 - 
No 0.39 (0.21 - 0.73) 0.0030 
rs6773853 
WT 1 - 
Present 1.81 (1.01 - 3.25) 0.046 
View Large
Conclusions

The rs6773853 susceptibility locus to B-NHL is independently prognostic of a poorer OS. This may be related to its close proximity to BCL6, the transcriptional repressor that tightly regulates the germinal centre reaction, although exploratory analysis showed that rs6773853 did not confer a greater risk of BCL6 translocations. Further functional studies and fine mapping will investigate the role of BCL in the tumorigenesis of these B-NHL patients with rs6773853.

Disclosures:

No relevant conflicts of interest to declare.

Topics:
b-cell lymphomas, neoplasms, diffuse large b-cell lymphoma, electrocorticogram, cancer, extranodal disease, lymphoma, medical history, social history, anthracycline antibiotics

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2013 by The American Society of Hematology
2013
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