What causes B cell lymphoma?

Causes of B-Cell Lymphoma

B-cell lymphomas are primarily caused by genetic alterations including chromosomal translocations involving immunoglobulin loci, mutations in tumor suppressor genes, and chronic antigenic stimulation from infectious agents or environmental factors. 1

Genetic Mechanisms

Chromosomal Translocations

• Reciprocal chromosomal translocations involving immunoglobulin loci are hallmarks of most mature B-cell lymphomas 1
• These translocations lead to dysregulated expression of key genes:
  • Proto-oncogenes important for cell proliferation (c-myc)
  • Genes involved in cell cycle progression (cyclin D1)
  • Genes causing differentiation blocks (bcl-6, PAX5)
  • Genes promoting cell survival (bcl-2, NF-κB)

Specific Genetic Alterations by Lymphoma Subtype

• Mantle cell lymphoma: t(11;14) translocation involving CCND1-IGH 1
• Follicular lymphoma: t(14;18) translocation involving BCL2-IGH 1
• Diffuse large B-cell lymphoma (DLBCL): Rearrangements of IGH (50%), BCL6 (30%), BCL2 (20-30%), and MYC (10%) 1
• Burkitt lymphoma: t(8;14) translocation involving MYC-IGH 1

Tumor Suppressor Gene Inactivation

• Inactivation of tumor suppressor genes (p53, p16) is frequently detected in lymphoma tissues 2
• These genes are normally regulated by signals from the B-cell antigen receptor

Infectious and Environmental Factors

Viral and Bacterial Infections

• High prevalence of bacterial and viral infections in lymphoma patients supports their contributory role 1, 2
• Infectious agents can promote lymphomagenesis through:
  • Direct induction of polyclonal B-cell hyperactivation (EBV, HCV)
  • Providing chronic antigenic stimulation (EBV, HCV, HBV, H. pylori)
  • Mimicking B-cell antigen receptor signaling (EBV, HCV, HHV8)

Environmental Factors

• Increased pesticide use has been linked to rising lymphoma incidence 1
• Worldwide increase in lymphoma incidence (approximately 30% in 5 years) may be partially attributed to environmental factors 1

B-Cell Development Abnormalities

Disruption of Normal B-Cell Processes

• Abnormalities in V(D)J rearrangements, immunoglobulin-gene somatic hypermutation, and class-switch recombination 3
• These disruptions can lead to chromosomal translocations and genomic mutations affecting genes involved in:
  • B-cell survival
  • B-cell proliferation

B-Cell Receptor (BCR) Signaling

• Most B-cell lymphomas depend on BCR expression for survival 4
• Antigen activation through BCR signaling appears to be an important factor in lymphoma pathogenesis 4
• Modulation of BCR signaling emerges as a potentially powerful therapeutic strategy 2

Microenvironment Factors

• Stimulatory signals from reactive T cells, local cytokines, and growth factors contribute to transformation progression 2
• The lymphoma microenvironment provides factors essential for lymphoma cell survival 4
• Recent insights into the microenvironment's role offer new therapeutic strategies 4

Clinical Implications

Diagnostic Approaches

• Diagnosis requires adequate tumor biopsy following WHO classification 1
• Immunohistochemistry is essential for differential diagnosis, including at least CD20, CD10, CD5, CD23, cyclin D1, IgD, and SOX-11 1
• Next-generation sequencing technologies allow for identification of somatic mutations and gene expression signatures 5

Emerging Biomarkers

• Lymphoma-specific somatic mutations can be detected in cell-free circulating DNA from peripheral blood 5
• This opens possibilities for minimally invasive diagnosis, monitoring, and predicting treatment response 5

B-cell lymphomagenesis is clearly a multistep transformation process involving complex interplay between genetic alterations, infectious agents, and microenvironmental factors, with chromosomal translocations involving immunoglobulin loci being the most characteristic feature.