CLINICAL SIGNIFICANCE OF c-MYC REARRANGEMENT IN DIFFUSE LARGE B-CELL LYMPHOMA

GC Caponetti, B Dave, L Smith, P Meyer, M Bast, P Bierman, G Bociek, J Vose, J Armitage,

P Aoun, K Fu, TC Greiner, WC Chan and DD Weisenburger.

University of Nebraska Medical Center, Omaha, NE

Sex
Age
LDH
Number of
extranodal sites
Stage
Performance score
IPI category
B symptoms

Materials & Methods

We conducted a search of the Nebraska Lymphoma Study Group registry
database for all cases of de novo DLBCL with available clinical data,
patient consent, no pretreatment, available conventional cytogenetics
results and/or fluorescence in situ hybridization (FISH) results.
Patients with a history of HIV infection or organ transplantation were
excluded.
Conventional cytogenetic and/or FISH studies were analyzed for
rearrangements of c-MYC and BCL2.
Based on the rearrangement of these two genes, cases of DLBCL were
classified into three groups: c-MYC+/BCL2+, c-MYC+/BCL2- and c-MYC(with or without BCL2 rearrangement).
The 5-year overall survival (OS) and event free survival (EFS) of the three
groups was compared.
The histological features of the tumors and the cytogenetic status were
correlated.

Size of largest mass

at diagnosis
Response to therapy

36%
64%
36%
64%
27%
73%
64%
36%
45%
55%
64%
36%
45%
55%
64%
36%
36%
64%

8
6
8
6
6
6
9
5
7
7
12
2
8
4
4
10
3
9

57%
43%
57%
43%
50%
50%
64%
36%
50%
50%
86%
14%
67%
33%
29%
71%
25%
75%

96
95
65
126
85
90
140
49
93
98
162
27
113
61
136
53
59
116

50%
50%
34%
66%
49%
51%
74%
26%
49%
51%
86%
14%
65%
35%
72%
28%
34%
66%

Complete
remission

36%

50%

122

64%

28%

64%

48%

5-year event-free survival

18%

43%

41%

0.57
0.23
0.38
0.54
0.97
0.16
0.45
0.003
0.88
0.034

Figure 1 . Overall survival (A and C) and event-free survival (B and D) of patients with
DLBCL according to the presence or absence of rearrangement of the c-MYC and BCL2
genes.
100

100
|
|

Overall Survival (%)

80

c-MYC+/BCL2+

70
|

60

||

c-MYC-/BCL2-/+
|||

50

c-MYC+/BCL2-

| | || |
||

||

| |

| |||| |

|| |

||

40

| |
|

| || |

30

| || | |

|
|

|| |
|

20

||
|

| |

||
|
|
|
|

90

|
||
|

10

p=0.15

Figure 2: Histological features of a case of DLBCL with rearrangement of c-MYC and

BLC2. This case displayed frequent mitoses, apoptosis and conspicuous small
nucleoli, but these features were also seen in cases without these cytogenetic
abnormalities.

Table 2. Multivariate analysis of prognostic factors for overall survival in DLBCL.

Hazard Ratio

95% Confidence Interval

P-value

c-MYC/BCL2

C-MYCC-MYC+/BCL2-/+
C-MYC+/BCL2+

1
0.8
2

0.35 1.64
0.99 3.89

0.11

International
Prognostic Index
(IPI)

Low (0-2)
High (3-5)

1
3

2.04 4.17

80
||
|
|
|

70
60

c-MYC+/BCL2+
c-MYC+/BCL2c-MYC-/BCL2-/+

|
||

50

40

||
||| | ||

| | | | ||
|
| ||
| | ||

30

| |

||

| || |

<0.0001

|
|

20

|| |

|| ||

10

p=0.21

0
0

10

15

20

10

Years

15

20

Years

Conclusion

100

100
|
|
90

|
|
||
|

80

Overall Survival (%)

We identified 216 cases of DLBCL that met the study criteria, with a
male:female ratio of 1:1 and a median age at diagnosis of 66.1 years
(range, 20.4 to 90.3 years).
Based on rearrangement of the c-MYC and BCL2 genes, the cases were
classified into three groups: 11 cases (5%) were c-MYC+/BCL2+, 14 cases
(6.5%) were c-MYC+/BCL2- and 191 cases (88.5%) were c-MYC- with or
without BCL2 rearrangement.
No distinguishing histological features were identified among the cases
with c-MYC, or c-MYC and BCL2 rearrangements when compared with
cases lacking these cytogenetic abnormalities.
No significant differences in clinical characteristics were identified among
the three groups except for B-symptoms in the c-MYC+/BCL2- group
(Table 1).
A decreased complete remission rate and a trend towards worse survival
were identified in the c-MYC+/BCL2+ group.

4
7
4
7
3
8
7
4
5
6
7
4
5
6
7
4
4
7

5-year overall survival

90

Results

Male
Female
< 60
>= 60
Normal
High
<2
>= 2
I/II
III/IV
> 70
<= 70
Low (0-2)
High (3-5)
No
Yes
< 5cm
>=5cm

Event-free Survival(%)

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of

aggressive B-cell lymphomas with a wide variation in prognosis due, in
part, to various genetic abnormalities.
Rearrangements of the c-MYC oncogene are seen in up to 10% of patients
with DLBCL, but the prognostic importance of this abnormality is unclear.
Another oncogene often rearranged in DLBCL is BCL2. Since both c-MYC
and BCL2 are dominant oncogenes which play an important pathogenetic
role in DLBCL, expression of both may have a synergistic effect leading to
poor survival.
To study this issue, we performed a retrospective analysis of DLBCL cases
tested for translocations involving c-MYC and BCL2, and treated with CHOP
or R-CHOP-like therapy.

c-MYC+/BCL2+ c-MYC+/BCL2- c-MYC-/BCL2-/+

P-value
(n=11)
(n=14)
(n=191)

Clinical features

80

c-MYC+/BCL2+
c-MYC-, c-MYC+/BCL2-

|
70
|
60

||
||
|
|
|

90

Event-free Survival(%)

Introduction

Table 1. Patient characteristics by c-MYC/BCL2 status in DLBCL (n=216).

||
|||
|

50

| || | | ||
| |

| ||||||

40

|| | | |

| ||

| | || |
|
|| |
|| |

30
20

||
|

|| |

||
|

10

||

p=0.057

70
60

10

Years

15

20

Patients with DLBCL having both the c-MYC and BCL2 rearrangements have
a poor complete remission rate and survival.

c-MYC+/BCL2+
c-MYC-, c-MYC+/BCL2-

||
|
|
|
|
||
|

50

40

||||
| | || |

| |
| ||
| ||
||| ||

30

No histological features in DLBCL predict the rearrangement of c-MYC with

or without BCL2 rearrangement.
|

| ||
| ||
|
|

20

|| ||

10

||

||

|
|

p=0.08

10

Years

15

20