Le Lymphome et les Nouvelles Technologies Génomiques

Pierre Laneuville, MD

Centre universitaire de santé McGill

Progression-free survival in aggressive NHL:

National High-Priority Lymphoma Study

Adapted from Fisher et al. N Engl J Med 1993;328:1002–6

CHOP

m-BACOD

ProMACE-CytaBOM

MACOP-B

100

80

60

40

20

0

Pati

en

ts (

%)

0 1 2 3 4 5 6

Years after randomisation

DNA Sequencing Laboratory

ED Green et al. Nature 470, 204-213 (2011) doi:10.1038/nature09764

Genomic achievements since the Human Genome Project.

Exon 1 Exon 2 Exon 3 Exon 4 Exon 5 Exon 6

Exon 1 Exon 2

Exon 4 Exon 5

Alternative splicing

Translation

Exon 6

Exon 1

(a) Alternative splicing

Exon 3 Exon 4

or

or

Exon 5 Exon 6

pre-mRNA

Exon 1 Exon 2

Exon 4 Exon 6

Why is the proteome so large? Alternative splicing

Proteolytic

processing

Attachment of

prosthetic

groups, sugars,

or lipids

Sugar

Heme

group

Phospholipid

Disulfide bond

formation

S S SH SH

Irreversible modifications

(b) Posttranslational covalent modification

Phosphorylation

Methylation

Phosphate

group

Acetyl

group

Methyl

group

PO42-

C

CH3

CH3

O

Reversible modifications

Acetylation

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Why is the proteome so

large? Post translational

modification

Beyond the Sequence: The ENCODE Project

Joseph RE et al. Nature 489:52 (2012).

Maher B. Nature 489:46 (2012).

Goal of Genomic Investigations

Chan WC et al. JNCCN 8:353 (2010).

Basics of microarrays

• DNA attached to solid support

– Glass, plastic, or nylon

• RNA is labeled

– Usually indirectly

• Bound DNA is the probe

– Labeled RNA is the “target”

Benfey and Protopapas, "Genomics" © 2005 Prentice Hall Inc. / A Pearson Education Company / Upper

Saddle River, New Jersey 07458

Two Immune Patterns in Follicular Lymphoma

Lejeune M et al. 94:16 (2009).

Gene-Expression Profiles in Diffuse Large B-Cell Lymphoma

Rosenwald A et al. NEJM 346:1937 (2002).

Overall Survival According to Subgroup of Diffuse Large B-Cell Lymphoma

Rosenwald A et al. NEJM 346:1937 (2002).

Three Types of DLCL by Molecular Profiling

GCB ABC PMBL

Germinal Center

B-Cell Like

Activated B-Cell

Like

Primary

Mediastinal B-Cell

Lymphoma

t(14;18)

Amp c-rel

5 yr OS

59%

Activation

NF-kappa B

bcl-2 +ve

5 yr OS

30%

PDL2

Overlap HL

5 yr OS

64%

Rosenwald A et al. NEJM 346:1937 (2002).

B Cell Receptor Signalling

Preclinical Testing of Inhibitors of B Cell Receptor Signalling Diffuse Large Cell Lymphoma

Davis RE et al. Nature 463:88 (2010).

Chan WC et al. JNCCN 8:353 (2010).

Personal Genomics

Sickle Cell Anemia

Mechanism of Action of Imatinib Mesylate

Goldman JM, Melo JV. N Engl J Med. 344:1084-1086.

Summary

• Advances

– Recognition of new clinically relevant subtypes

– Recognition of new “drugable” targets

• Disappointments

– Genome more complicated than imagined

– Less therapeutic insights than hoped for

• Personal Genomics

– Not ready for prime time…but likely in the future