High Throughput Sequencing Analysis of the Immunoglobulin Heavy Chain Gene from Flow-Sorted B Cell Sub-Populations Define the Dynamics of Follicular Lymphoma Clonal Evolution.
Understanding the dynamics of evolution of Follicular Lymphoma (FL) clones during disease progression is important for monitoring and targeting this tumor effectively. Genetic profiling of serial FL biopsies and examples of FL transmission following bone marrow transplant suggest that this disease may evolve by divergent evolution from a common ancestor cell. However where this ancestor cell resides and how it evolves is still unclear. The analysis of the pattern of somatic hypermutation of the immunoglobulin gene (Ig) is traditionally used for tracking the physiological clonal evolution of B cells within the germinal center and allows to discriminate those cells that have just entered the germinal center and display features of ancestor cells from those B cells that keep re-circulating across different lymphoid organs. Here we investigated the pattern of somatic hypermutation of the heavy chain of the immunoglobulin gene (IgH-VH) in 4 flow-sorted B cells subpopulations belonging to different stages of differentiation, from sequential lymph node biopsies of cases displaying diverse patterns of evolution, using the GS-FLX Titanium sequencing platform. We observed an unexpectedly high level of clonality, with hundreds of distinct tumor subclones in the different subpopulations from the same sample, the majority detected at a frequency <10-2. By using a lineage trees analysis we observed in all our FL and t-FL cases that the oligoclonal FL population was trapped in a narrow intermediate stage of maturation that maintains the capacity to undergo SHM, but was unable to further differentiate. The presence of such a complex architecture highlights challenges currently encountered in finding a cure for this disease.
Centre for Haemato-Oncology, Barts Cancer Institute - a CR-UK Centre Of Excellence, Queen Mary University of London, London, United Kingdom.
Emanuela
E
Carlotti
Centre for Haemato-Oncology, Barts Cancer Institute - a CR-UK Centre Of Excellence, Queen Mary University of London, London, United Kingdom.
David
D
Wrench
Flow Cytometry Core Facility, Barts Cancer Institute - a CR-UK Centre Of Excellence, Queen Mary University of London, London, United Kingdom.
Guglielmo
G
Rosignoli
Centre for Molecular Oncology, Barts Cancer Institute - a CR-UK Centre Of Excellence, Queen Mary University of London, London, United Kingdom.
Jacek
J
Marzec
Centre for Molecular Oncology, Barts Cancer Institute - a CR-UK Centre Of Excellence, Queen Mary University of London, London, United Kingdom.
Ajanthah
A
Sangaralingam
The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
Lena
L
Hazanov
The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
Miri
M
Michaeli
Centre for Haemato-Oncology, Barts Cancer Institute - a CR-UK Centre Of Excellence, Queen Mary University of London, London, United Kingdom.
Simon
S
Hallam
Centre for Haemato-Oncology, Barts Cancer Institute - a CR-UK Centre Of Excellence, Queen Mary University of London, London, United Kingdom.
Tracy
T
Chaplin
Centre for Haemato-Oncology, Barts Cancer Institute - a CR-UK Centre Of Excellence, Queen Mary University of London, London, United Kingdom.
Sameena
S
Iqbal
Centre for Haemato-Oncology, Barts Cancer Institute - a CR-UK Centre Of Excellence, Queen Mary University of London, London, United Kingdom.
Maria
M
Calaminici
Centre for Haemato-Oncology, Barts Cancer Institute - a CR-UK Centre Of Excellence, Queen Mary University of London, London, United Kingdom.
Bryan
B
Young
The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
Ramit
R
Mehr
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
Peter
P
Campbell
Centre for Haemato-Oncology, Barts Cancer Institute - a CR-UK Centre Of Excellence, Queen Mary University of London, London, United Kingdom.
Jude
J
Fitzgibbon
Centre for Haemato-Oncology, Barts Cancer Institute - a CR-UK Centre Of Excellence, Queen Mary University of London, London, United Kingdom.
John G
JG
Gribben
D016175:B-Lymphocyte Subsets / Q000502:physiology*; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic; D060965:Clonal Evolution / Q000502:physiology*; D005434:Flow Cytometry; D055106:Genome-Wide Association Study; D015698:Genomic Library; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics* / Q000502:physiology; D008224:Lymphoma, Follicular / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide
D007143:Immunoglobulin Heavy Chains