To define the B-cell differentiation stage of PIOL tumor cells a molecular study of immunoglobulin (Ig) gene rearrangements in association with sequence analysis of rearranged variable (V) region genes is a suitable tool. The generation of functional antigen receptors by somatic recombination of the immunoglobulin variable (V), diversity (D), and joining (J) gene segments is a unique feature of B-lymphocytes.
12 In a normal immune response, B lymphocytes stimulated by antigen can undergo somatic hypermutation in their immunoglobulin (Ig) variable region genes in the germinal centers.
13 Somatic hypermutation includes point mutations in the nucleic acids coding for the rearranged IgH chain V regions and results in an adapted antigen affinity of antigen-specific antibodies.
14 15 16 B-cells with high affinity for antigen are selectively rescued from apoptosis, which occurs at a very high rate in the germinal centers, to differentiate into either circulating memory cells or antibody-producing plasma cells.
13 14 B-cell lymphomas arise from cells that represent a certain differentiation stage when neoplastic transformation took place. Analysis of the IgVH region genes has provided invaluable information on the status of tumors in B-cell differentiation and has added another dimension to classification of B-cell tumors at the molecular level. For example, naive pre–germinal-center B cells carry nonmutated VH genes, whereas germinal-center B cells and germinal-center–derived memory cells harbor mutated VH region genes.
14 15 17 18 Correspondingly, B-cell malignancies descended from pregerminal B cells (e.g., mantle cell lymphoma
19 ), and those from post–germinal-center B cells (e.g., marginal zone B-cell lymphomas
20 21 ), usually demonstrate few or several somatic mutations (up to 5%), respectively.
22 Because they arise from germinal center cells, follicular lymphomas usually demonstrate a high rate of somatic mutations (average, 10.5%).
22 Typical also for follicular lymphomas are so-called “ongoing mutations” or the continued accumulation of mutations, resulting in intraclonal heterogeneity, indicating that the mutation mechanism is still active within the tumor cell population.
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