chapuyMolecularSubtypesDiffuse2018

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title: '' bibliography: 'morinlab.bib'

@chapuyMolecularSubtypesDiffuse2018

Study Overview

In their 2018 study published in Nature Medicine, Chapuy et al. conducted a comprehensive genetic analysis of 304 primary diffuse large B-cell lymphoma (DLBCL) samples. Through integrative analysis of somatic mutations, copy number alterations, and structural variants, they identified five distinct molecular subtypes of DLBCL, labeled C1 through C5, each characterized by unique genetic alterations and associated clinical outcomes.

Key Findings

Molecular Subtypes Identified

1. C1 Subtype:

   • Characterized by mutations in NOTCH2 and BCL6.
   • Suggests an extrafollicular/marginal zone origin.

2. C2 Subtype:

   • Defined by biallelic inactivation of TP53 and CDKN2A loss.
   • Associated with genomic instability.

3. C3 Subtype:

   • Enriched for BCL2 translocations and mutations in chromatin modifiers such as EZH2.
   • Indicates a germinal center B-cell origin.

4. C4 Subtype:

   • Marked by mutations in SGK1, BRAF, and STAT3.
   • Associated with a favorable prognosis.

5. C5 Subtype:

   • Characterized by co-mutations in MYD88 and CD79B.
   • Associated with chronic active B-cell receptor signaling.

Clinical Implications

• The study demonstrated that these molecular subtypes correlate with distinct survival outcomes, independent of the traditional International Prognostic Index (IPI).
• Findings suggest potential for subtype-specific therapeutic strategies, emphasizing the need for personalized treatment approaches in DLBCL.

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Post-Publication Discussion

Subsequent analyses have validated the existence of these molecular subtypes and their clinical relevance. However, some studies have noted challenges in replicating the exact classification due to differences in sequencing techniques and cohort compositions. Additionally, the dynamic nature of DLBCL genetics necessitates continuous refinement of these subtypes to incorporate emerging genetic data.

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Conclusion

Chapuy et al.'s study significantly advanced the understanding of DLBCL heterogeneity by identifying molecular subtypes with distinct genetic and clinical features. These insights have paved the way for more targeted therapeutic interventions, although ongoing research is essential to refine these classifications and translate them into clinical practice effectively.

Summary of novel genes

Entity	Tier 1 genes	Tier 2 genes	Tier 3 genes
DLBCL	10	13	6

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This study, New Tier 1, 10
New Tier 1, DLBCL Tier 1, 10
This study, New Tier 2, 13
New Tier 2, DLBCL Tier 2, 13
This study, New Tier 3, 6
New Tier 3, DLBCL Tier 3, 6
All other DLBCL studies, DLBCL Tier 1, 115
All other DLBCL studies, DLBCL Tier 2, 197
All other DLBCL studies, DLBCL Tier 3, 381

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Novel genes reported in this study

Tier 1

New gene	DLBCL tier	Average variant quality	QC outcome
EEF1A1	1
HIST1H1B	1
HIST1H2AM	1
HIST2H2BE	1
HLA-C	1
HVCN1	1
LTB	1
POU2AF1	1
SIN3A	1
ZC3H12A	1

Tier 2

New gene	DLBCL tier	Average variant quality	QC outcome
BCL11A	2
COQ7	2	★ ★ ★ ☆ ☆	PASS
CRIP1	2	★ ★ ★ ☆ ☆	PASS
DOCK1	2	★ ★ ★ ☆ ☆	PASS
GABRA2	2
HLA-DMA	2
IGLL5	2
IL6	2	★ ★ ★ ☆ ☆	PASS
LYN	2	★ ★ ★ ★ ☆	PASS
NAV1	2
PRPS1	2	★ ★ ★ ★ ☆	PASS
TLR2	2	★ ★ ★ ★ ☆	PASS
ZNF423	2	★ ★ ★ ☆ ☆	PASS

Tier 3

New gene	DLBCL tier	Average variant quality	QC outcome
CCL4	3	☆ ☆ ☆ ☆ ☆	FAIL
FUT5	3	★ ☆ ☆ ☆ ☆	FAIL
NANOG	3	☆ ☆ ☆ ☆ ☆	FAIL
NLRP8	3	★ ★ ☆ ☆ ☆	FAIL
PDE4DIP	3	★ ★ ☆ ☆ ☆	FAIL
RAD9A	3	☆ ☆ ☆ ☆ ☆	FAIL

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