Key Points

  • Development of a robust GE signature discriminating localized-stage and advanced-stage FL.

  • The genetic signature may be responsible for the superior outcome of localized-stage FL.

Abstract

The genetic background of follicular lymphomas (FLs) diagnosed in advanced clinical stages III/IV, and which are frequently characterized by t(14;18), has been substantially unraveled. Molecular features, as exemplified in the clinicogenetic risk model m7FLIPI, are important tools in risk stratification. In contrast, little information is available concerning localized-stage FL (clinical stages I/II), which accounts for ∼20% of newly diagnosed FL in which the detection rate of t(14;18) is only ∼50%. To investigate the genetic background of localized-stage FL, patient cohorts with advanced-stage FL or localized-stage FL, uniformly treated within phase 3 trials of the German Low-Grade Lymphoma Study Group, were comparatively analyzed. Targeted gene expression (GE) profiling of 184 genes using nCounter technology was performed in 110 localized-stage and 556 advanced-stage FL patients. By penalized Cox regression, a prognostic GE signature could not be identified in patients with advanced-stage FL, consistent with results from global tests and univariate regression. In contrast, it was possible to define robust GE signatures discriminating localized-stage and advanced-stage FL (area under the curve, 0.98) by penalized logistic regression. Of note, 3% of samples harboring an “advanced-stage signature” in the localized-stage cohort exhibited inferior failure-free survival (hazard ratio [HR], 7.1; P = .0003). Likewise, in the advanced-stage cohort, 7% of samples with a “localized-stage signature” had prolonged failure-free survival (HR, 2.3; P = .017) and overall survival (HR, 3.4; P = .072). These data support the concept of a biological difference between localized-stage and advanced-stage FL that might contribute to the superior outcome of localized FL.

REFERENCES

REFERENCES
1.
Casulo
C
,
Byrtek
M
,
Dawson
KL
, et al
.
Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study
.
J Clin Oncol
.
2015
;
33
(
23
):
2516
-
2522
.
2.
Jurinovic
V
,
Kridel
R
,
Staiger
AM
, et al
.
Clinicogenetic risk models predict early progression of follicular lymphoma after first-line immunochemotherapy
.
Blood
.
2016
;
128
(
8
):
1112
-
1120
.
3.
Jaffe
ES
,
Harris
NL
,
Swerdlow
SH
, et al
. Follicular lymphoma. In:
Swerdlow
SH
,
Campo
E
,
Harris
NL
, et al, eds.
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues
, 4th ed.
Lyon, France
:
International Agency for Research on Cancer
;
2017
:
266
-
273
.
4.
Dreyling
M
,
Ghielmini
M
,
Rule
S
,
Salles
G
,
Vitolo
U
,
Ladetto
M
;
ESMO Guidelines Committee
.
Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
.
Ann Oncol
.
2016
;
27
(
suppl 5
):
v83
-
v90
.
5.
Dave
SS
,
Wright
G
,
Tan
B
, et al
.
Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells
.
N Engl J Med
.
2004
;
351
(
21
):
2159
-
2169
.
6.
Glas
AM
,
Kersten
MJ
,
Delahaye
LJMJ
, et al
.
Gene expression profiling in follicular lymphoma to assess clinical aggressiveness and to guide the choice of treatment
.
Blood
.
2005
;
105
(
1
):
301
-
307
.
7.
Glas
AM
,
Knoops
L
,
Delahaye
L
, et al
.
Gene-expression and immunohistochemical study of specific T-cell subsets and accessory cell types in the transformation and prognosis of follicular lymphoma
.
J Clin Oncol
.
2007
;
25
(
4
):
390
-
398
.
8.
Alvaro
T
,
Lejeune
M
,
Salvadó
MT
, et al
.
Immunohistochemical patterns of reactive microenvironment are associated with clinicobiologic behavior in follicular lymphoma patients
.
J Clin Oncol
.
2006
;
24
(
34
):
5350
-
5357
.
9.
Carreras
J
,
Lopez-Guillermo
A
,
Fox
BC
, et al
.
High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma
.
Blood
.
2006
;
108
(
9
):
2957
-
2964
.
10.
Pastore
A
,
Jurinovic
V
,
Kridel
R
, et al
.
Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry
.
Lancet Oncol
.
2015
;
16
(
9
):
1111
-
1122
.
11.
Hiddemann
W
,
Cheson
BD
.
How we manage follicular lymphoma
.
Leukemia
.
2014
;
28
(
7
):
1388
-
1395
.
12.
Yahalom
J
.
Radiotherapy of follicular lymphoma: updated role and new rules
.
Curr Treat Options Oncol
.
2014
;
15
(
2
):
262
-
268
.
13.
Leich
E
,
Hoster
E
,
Wartenberg
M
, et al;
German Low Grade Lymphoma Study Group (GLSG)
.
Similar clinical features in follicular lymphomas with and without breaks in the BCL2 locus
.
Leukemia
.
2016
;
30
(
4
):
854
-
860
.
14.
Leich
E
,
Salaverria
I
,
Bea
S
, et al
.
Follicular lymphomas with and without translocation t(14;18) differ in gene expression profiles and genetic alterations
.
Blood
.
2009
;
114
(
4
):
826
-
834
.
15.
Zamò
A
,
Pischimarov
J
,
Schlesner
M
, et al
.
Differences between BCL2-break positive and negative follicular lymphoma unraveled by whole-exome sequencing
.
Leukemia
.
2018
;
32
(
3
):
685
-
693
.
16.
Guilloton
F
,
Caron
G
,
Ménard
C
, et al
.
Mesenchymal stromal cells orchestrate follicular lymphoma cell niche through the CCL2-dependent recruitment and polarization of monocytes
.
Blood
.
2012
;
119
(
11
):
2556
-
2567
.
17.
Staiger
AM
,
Duppel
J
,
Dengler
MA
, et al
.
An analysis of the role of follicular lymphoma-associated fibroblasts to promote tumor cell viability following drug-induced apoptosis
.
Leuk Lymphoma
.
2017
;
58
(
8
):
1922
-
1930
.
18.
Nickenig
C
,
Dreyling
M
,
Hoster
E
, et al;
German Low-Grade Lymphoma Study Group
.
Combined cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) improves response rates but not survival and has lower hematologic toxicity compared with combined mitoxantrone, chlorambucil, and prednisone (MCP) in follicular and mantle cell lymphomas: results of a prospective randomized trial of the German Low-Grade Lymphoma Study Group
.
Cancer
.
2006
;
107
(
5
):
1014
-
1022
.
19.
Hiddemann
W
,
Kneba
M
,
Dreyling
M
, et al
.
Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group
.
Blood
.
2005
;
106
(
12
):
3725
-
3732
.
20.
Engelhard
M
,
Unterhalt
M
,
Hansmann
ML
, et al
.
Follicular lymphoma: curability by radiotherapy in limited stage nodal disease?
Updated results of a randomized trial [abstract]. Ann Oncol.
2011
;22(suppl 4). Abstract 027.
21.
Hummel
M
,
Bentink
S
,
Berger
H
, et al;
Molecular Mechanisms in Malignant Lymphomas Network Project of the Deutsche Krebshilfe
.
A biologic definition of Burkitt’s lymphoma from transcriptional and genomic profiling
.
N Engl J Med
.
2006
;
354
(
23
):
2419
-
2430
.
22.
Rosenwald
A
,
Wright
G
,
Chan
WC
, et al;
Lymphoma/Leukemia Molecular Profiling Project
.
The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma
.
N Engl J Med
.
2002
;
346
(
25
):
1937
-
1947
.
23.
Scott
DW
,
Chan
FC
,
Hong
F
, et al
.
Gene expression-based model using formalin-fixed paraffin-embedded biopsies predicts overall survival in advanced-stage classical Hodgkin lymphoma
.
J Clin Oncol
.
2013
;
31
(
6
):
692
-
700
.
24.
Staiger
AM
,
Ziepert
M
,
Horn
H
, et al;
German High-Grade Lymphoma Study Group
.
Clinical impact of the cell-of-origin classification and the MYC/ BCL2 dual expresser status in diffuse large B-cell lymphoma treated within prospective clinical trials of the German High-Grade Non-Hodgkin’s Lymphoma Study Group
.
J Clin Oncol
.
2017
;
35
(
22
):
2515
-
2526
.
25.
Geiss
GK
,
Bumgarner
RE
,
Birditt
B
, et al
.
Direct multiplexed measurement of gene expression with color-coded probe pairs [published correction appears in Nat Biotechnol. 2008;26:709]
.
Nat Biotechnol
.
2008
;
26
(
3
):
317
-
325
.
26.
Kridel
R
,
Xerri
L
,
Gelas-Dore
B
, et al
.
The prognostic impact of CD163-positive macrophages in follicular lymphoma: a study from the BC Cancer Agency and the Lymphoma Study Association
.
Clin Cancer Res
.
2015
;
21
(
15
):
3428
-
3435
.
27.
Byers
RJ
,
Sakhinia
E
,
Joseph
P
, et al
.
Clinical quantitation of immune signature in follicular lymphoma by RT-PCR-based gene expression profiling
.
Blood
.
2008
;
111
(
9
):
4764
-
4770
.
28.
de Jong
D
,
Koster
A
,
Hagenbeek
A
, et al
.
Impact of the tumor microenvironment on prognosis in follicular lymphoma is dependent on specific treatment protocols
.
Haematologica
.
2009
;
94
(
1
):
70
-
77
.
29.
Amé-Thomas
P
,
Maby-El Hajjami
H
,
Monvoisin
C
, et al
.
Human mesenchymal stem cells isolated from bone marrow and lymphoid organs support tumor B-cell growth: role of stromal cells in follicular lymphoma pathogenesis
.
Blood
.
2007
;
109
(
2
):
693
-
702
.
30.
Huet
S
,
Tesson
B
,
Jais
J-P
, et al
.
A gene-expression profiling score for prediction of outcome in patients with follicular lymphoma: a retrospective training and validation analysis in three international cohorts
.
Lancet Oncol
.
2018
;
19
(
4
):
549
-
561
.
31.
Carter
SL
,
Eklund
AC
,
Mecham
BH
,
Kohane
IS
,
Szallasi
Z
.
Redefinition of Affymetrix probe sets by sequence overlap with cDNA microarray probes reduces cross-platform inconsistencies in cancer-associated gene expression measurements
.
BMC Bioinformatics
.
2005
;
6
(
1
):
107
.
32.
Dai
M
,
Wang
P
,
Boyd
AD
, et al
.
Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data
.
Nucleic Acids Res
.
2005
;
33
(
20
):
e175
.
33.
Gautier
L
,
Møller
M
,
Friis-Hansen
L
,
Knudsen
S
.
Alternative mapping of probes to genes for Affymetrix chips
.
BMC Bioinformatics
.
2004
;
5
(
1
):
111
.
34.
Kong
SW
,
Hwang
KB
,
Kim
RD
, et al
.
CrossChip: a system supporting comparative analysis of different generations of Affymetrix arrays
.
Bioinformatics
.
2005
;
21
(
9
):
2116
-
2117
.
35.
Liu
H
,
Zeeberg
BR
,
Qu
G
, et al
.
AffyProbeMiner: a web resource for computing or retrieving accurately redefined Affymetrix probe sets
.
Bioinformatics
.
2007
;
23
(
18
):
2385
-
2390
.
36.
Jaffe
ES
,
Harris
NL
,
Siebert
R
, et al
. Paediatric-type follicular lymphoma. In:
Swerdlow
SH
,
Campo
E
,
Jaffe
ES
, et al, eds
.
WHO Classification of Tumours of Haematopoetic and Lymphoid Tissues
, 4th ed.
Lyon, France
:
IARC Press Lyon
;
2017
:
278
-
279
.
37.
Koch
K
,
Hoster
E
,
Unterhalt
M
, et al
.
The composition of the microenvironment in follicular lymphoma is associated with the stage of the disease
.
Hum Pathol
.
2012
;
43
(
12
):
2274
-
2281
.
38.
Huet
S
,
Sujobert
P
,
Salles
G
.
From genetics to the clinic: a translational perspective on follicular lymphoma
.
Nat Rev Cancer
.
2018
;
18
(
4
):
224
-
239
.
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