Format

Send to

Choose Destination
See comment in PubMed Commons below
Nat Genet. 2014 Feb;46(2):176-81. doi: 10.1038/ng.2856. Epub 2013 Dec 22.

Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma.

Author information

1
1] Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK. [2].
2
1] Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK. [2] 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary. [3].
3
1] Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK. [2].
4
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
5
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
6
1] School of Biology, Georgia Institute of Technology, Atlanta, Georgia, USA. [2] Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia, USA.
7
Centre for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy.
8
Genome Centre, Barts and the London School of Medicine and Dentistry, London, UK.
9
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
10
Cancer Sciences Division, University of Southampton, Southampton, UK.
11
Oncology Department, Biodonostia Research Institute, San Sebastian, Spain.
12
1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
13
Department of Histopathology, Christie National Health Service (NHS) Foundation Trust, Manchester, UK.
14
Department of Histopathology, Manchester Royal Infirmary, Manchester, UK.
15
Department of Hematology, Oncology and Tumor Immunology, Charité Universitätsmedizin, Berlin, Germany.

Abstract

Follicular lymphoma is an incurable malignancy, with transformation to an aggressive subtype representing a critical event during disease progression. Here we performed whole-genome or whole-exome sequencing on 10 follicular lymphoma-transformed follicular lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and we report the key events and evolutionary processes governing tumor initiation and transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histone, JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses identified early driver mutations in chromatin regulator genes (CREBBP, EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation. Collectively, this study provides new insights into the genetic basis of follicular lymphoma and the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations in the CPC represents an attractive therapeutic strategy.

PMID:
24362818
PMCID:
PMC3907271
DOI:
10.1038/ng.2856
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Secondary source ID, Grant support

Publication types

MeSH terms

Substances

Secondary source ID

Grant support

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Nature Publishing Group Icon for PubMed Central
    Loading ...
    Support Center