Winter Meeting 2011 - The Pathological Society of Great Britain ...

15.15–15.45 [S10] Diffuse Large B-cell Lymphomas: Molecular Biology and Sub-classification
Prof A Rosenwald
Institute of Pathology, University of Würzburg, Germany, Josef-Schneider-Str. 2, Würzburg, Germany
The clinical heterogeneity of diffuse large B-cell lymphoma (DLBCL) is mirrored by a large variation of its
underlying genetic and molecular features. The gene expression based distinction into the germinal centre B-like
(GCB) and activated B-like (ABC) subtypes was shown to have significant prognostic impact in the CHOP
treatment era and appears to remain prognostically relevant when patients are treated with R-CHOP. Moreover,
GCB and ABC DLBCL tumours have different genetic alterations. The translocation t(14;18) and PTEN deletions
are predominantly detected in GCB DLBCL, whereas ABC DLBCL are characterized by deletions of p16 and
amplification of the BCL2 locus. A major pathogenetic feature of ABC DLBCL is the constitutive activation of
the oncogenic NFkB signaling pathway that may be targeted therapeutically in the future. Recent work identified
mutations in several genes associated with NFkB leading to deregulation and aberrant activation of this pathway.
For example, activating mutations of CARD 11, a protein that physiologically assembles with BCL10 and MALT1
in B-cells upon antigen engagement, are present in approximately 10% of ABC DLBCL tumours. Likewise,
inactivation of A20, a negative regulator of NFkB, is also frequently detected in DLBCL. The B-cell receptor
associated signaling subunits CD79A and CD79B carry mutations in approximately 20% of ABC DLBCL which
result in increased expression of the B-cell receptor leading to chronic active B-cell receptor signaling. It is likely
that additional molecular alterations of the NFkB pathway in DLBCL will be identified in the near future.
15.45–16.15 TEA / POSTER VIEWING / Trade Exhibition [Cloisters]
16.15–16.45 Intermediate Lymphoma between Burkitt Lymphoma and DLBCL
Prof H Stein, Institute for PathDiagnostic, Berlin, Germany
16.45–17.15 [S11] Selection of Therapy According to Molecular Phenotype in Diffuse Large B-Cell Lymphoma
P Prof P Johnson 1 ; AJ Davies 1 ; P Fields 2 ; M-Q Du 3 ; A Jack 4
CR UK Centre, Southampton, Southampton, United Kingdom; 2 Guy’s Hospital, London, United
Kingdom; 3 University Department of Pathology, Cambridge, United Kingdom; 4 HMDS, Leeds, United
Kingdom
Several oncogenic mechanisms distinguish the two sub-groups of DLBL. In particular, constitutive activation
of the nuclear factor-kB (NF-kB) signalling pathway appears central to cell survival in ABC-like lymphomas.
These rely upon the CARD11/MALT1/BCL10 signalling complex to activate IkB kinase. More than half of ABC-
DLBL carry somatic mutations in multiple genes, including negative (A20) and positive (CARD11, TRAF2,
TRAF5, MAP3K7 and TNFRSF11A) regulators of NF-kB. Mutations in B-cell receptor components such as
CD79B may be responsible for abnormal retention of the BCR on the cell membrane following stimulation.
Induction of the NF-kB pathway appears to suppress the apoptotic effect of cytotoxic chemotherapy and this
may contribute to the observed differences in outcome. These findings provide the rationale for exploration of
small molecule therapeutics to target elements of the dysregulated pathways. This can be done downstream, for
example by proteosome inhibitors to reduce degradation of inhibitory IkB, or closer to the start of the pathway,
for example with inhibitors of Bruton’s tyrosine kinase. The challenge is to design clinical trials based upon realtime
determination of molecular phenotype, since immunohistochemistry remains imprecise in distinguishing
biologically distinct sub-groups. The NCRI Lymphoma Group is conducting a study based upon gene expression
profiling on formalin fixed paraffin embedded tumour material, in which patients will be randomised to receive
Bortezomib in addition to standard R-CHOP chemotherapy. Randomisation is stratified according to the
molecular phenotype, with stopping rules to exclude sub-groups according to the interaction of the gene expression
profile and the targeted therapy.
17.15 Close of Meeting
Detailed Programme – Friday 7 January 2011
Presenter = P · Abstract numbers are shown in bold and square brackets eg [S123]
Scientific Programme | Winter Meeting (199 th ) 6 – 7 January 2011 | Visit our website: www.pathsoc.org
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