Follicular Lymphoma, Susceptibility To, 1
Description
Follicular non-Hodgkin lymphoma is an indolent B-cell malignancy with an annual incidence exceeding 10,000 cases in the United States (Bohen et al., 2003). One form of susceptibility to follicular lymphoma (FL1) is associated with a region on chromosome 6p21.33.
MappingIn a subtype-specific genomewide association study of non-Hodgkin lymphoma susceptibility, Skibola et al. (2009) found that the single-nucleotide polymorphism (SNP) rs6457327 on chromosome 6p21.33 was associated with susceptibility to follicular lymphoma in 189 cases and 592 controls, with validation in another 456 follicular lymphoma cases and 2,785 controls (combined allelic P = 4.7 x 10(-11)). The SNP rs6457327 is 5 kb downstream of the 3-prime untranslated region of the C6ORF15 gene (STG; 611401) and telomeric to HLA-C (see 142840) in the major histocompatibility complex, an allele of which influences susceptibility to psoriasis (see PSORS1, 177900).
In a 3-stage genomewide association study to identify susceptibility loci for non-Hodgkin lymphoma (NHL) subtypes, Conde et al. (2010) identified 2 variants associated with follicular lymphoma at 6p21.32, rs10484561 (combined p = 1.12 x 10(-29)) and rs7755224 (combined p = 2.00 x 10(-19)), supporting the idea that major histocompatibility complex (MHC) genetic variation influences follicular lymphoma susceptibility. The authors noted that the association appeared to be independent of the follicular lymphoma susceptibility locus at PSORS1. In addition, Conde et al. (2010) did not observe markedly significant associations between the MHC region and the risk of chronic lymphocytic leukemia/small cell leukemia or diffuse large B-cell lymphoma, suggesting that the influence of MHC genetic variation differs by NHL subtype.
Biochemical FeaturesNgan et al. (1988) found immunoreactive BCL2 (151430) protein in the neoplastic cells of almost all follicular lymphomas, whereas no BCL2 protein was detected in follicles affected by nonneoplastic processes or in normal lymphoid tissue. Every tumor with molecular genetic evidence of t(14;18) translocation expressed detectable levels of BCL2 protein, regardless of whether the breakpoint was located in or at a distance from the BCL2 gene. Demonstration of the protein with anti-BCL2 antibodies should be useful in the diagnosis of many non-Hodgkin lymphomas.
CytogeneticsYunis et al. (1982) found a translocation between chromosomes 18 and 14 in 16 of 19 patients with follicular lymphomas, one of the most common forms of B-cell neoplasia. They found 8;14 translocation in 5 of 6 patients with small noncleaved-cell (non-Burkitt) lymphoma or large-cell immunoblastic lymphoma and trisomy 12 in 4 of 11 patients with small-cell lymphocytic lymphoma. They stated: 'It is conceivable that when DNA at the breakpoint site of the donor chromosome 8 or 18 becomes contiguous with genes involved in immunoglobulin synthesis, lymphomatous transformation is initiated.' The assignment of an oncogene to chromosome 18 (ERV1; 131150) suggested to O'Brien et al. (1983) that it may serve the same role in neoplastic transformation in follicular lymphoma as the MYC gene (190080) appears to fill in the case of Burkitt lymphoma.
By studying cloned recombinant DNA probes from the area flanking the breakpoints in chromosome 18 in cells from patients with acute lymphocytic leukemia of the B-cell type carrying t(14;18), Tsujimoto et al. (1985) found 2 that detected DNA rearrangements in about 60% of cases of follicular lymphoma screened. Most of the breakpoints in 18q21 in follicular lymphoma were clustered in a stretch of DNA about 2.1 kb long. The BCL2 gene seemed to be interrupted in most cases of follicular lymphoma carrying the t(14;18) translocation. This study involved chromosome walking to identify the putative BCL2 gene.
In a study of 71 patients with follicular lymphoma, Yunis et al. (1987) observed 14;18 translocation in 85% of the patients and concluded that this is the main determinant of a follicular pattern. Different changes were found in other patients; the changes seemed to correlate with the evolution of the patients' malignant disease.
Pegoraro et al. (1984) postulated 2 steps in the malignant process. First, the 14;18 translocation, occurring in an activated B cell and involving the IgH heavy chain allele on 14q32 (IGHG1; 147100) and the BCL2 gene on chromosome 18, brought a heavy chain enhancer close to the BCL2 gene. Constitutive expression of BCL2 led to clonal expansion of t(14;18) cells and a relatively low-grade malignancy. Second, within the malignant clone of B cells, the t(8;14) translocation occurred, leading to high-grade malignancy through activation of MYC. Mufti et al. (1983) reported a double translocation of the same type in a case of acute leukemia.
Lee et al. (1987) used a method of DNA amplification to detect t(14;18) hybrid DNA sequences in a patient with follicular lymphoma in whom remission marrow and blood samples showed no abnormality by morphologic examination and conventional Southern blot analysis. By Southern blot analysis in cases of non-Hodgkin lymphoma, Aisenberg et al. (1988) found frequent rearrangement of the BCL2 gene.
Using a nested PCR assay for quantitation of rare t(14;18) translocations, Liu et al. (1994) demonstrated that this oncogenic mutation occurs in persons without lymphoid neoplasia and in an age-dependent fashion. The translocations copurified with B lymphocytes. The frequency of the translocations increased with age in both peripheral blood lymphocytes and spleens, as does human risk for lymphoma. Average translocation frequency was more than 40 times greater in the spleen and 13 times greater in the peripheral blood in the oldest individuals (61 years and older) compared with the youngest individuals (20 years or younger). Particular t(14;18)-bearing clones persisted over a period of 5 months in 2 persons. On the basis of these findings, Liu et al. (1994) proposed a multihit model of lymphomagenesis involving t(14;18) translocation followed by antigen stimulation. They suggested that the t(14;18)-bearing B-cell clones accumulate other mutations in growth-dysregulatory or lymphomagenic loci.
Clinical ManagementYunis et al. (1989) found that response to therapy was poorer in those patients with B-cell nonimmunoblastic lymphoma or follicular lymphoma who had a BCL2 oncogene rearrangement than it was in patients without BCL2 rearrangement.
Bohen et al. (2003) analyzed the patterns of gene expression in follicular lymphomas from 24 patients and concluded that 2 groups of tumors could be distinguished. All patients, whose biopsies were obtained before any treatment, were treated with rituximab, a monoclonal antibody directed against the B cell antigen, CD20 (112210). Gene expression patterns in the tumors that subsequently failed to respond to rituximab appeared more similar to those of normal lymphoid tissues than to gene expression patterns of tumors from rituximab responders. These findings suggested the possibility that the response of follicular lymphoma to rituximab treatment may be predicted from the gene expression pattern of tumors.
Molecular GeneticsConde et al. (2013) presented a method that integrates RNA sequencing (RNA-seq) and allele-specific expression data with genomewide association study (GWAS) data to further characterize SNPs associated with follicular lymphoma. Conde et al. (2013) investigated the influence on gene expression of 3 established FL-associated loci--rs10484561, rs2647012, and rs6457327--by measuring their correlation with human leukocyte antigen (HLA) expression levels obtained from publicly available RNA-seq expression datasets from lymphoblastoid cell lines. Conde et al. (2013) concluded that their results suggest that SNPs linked to the protective variant rs2647012 exert their effect by a cis-regulatory mechanism involving modulation of HLA-DQB1 expression. In contrast, no effect on HLA expression was observed for the colocalized risk variant rs10484561.
Foo et al. (2013) conducted imputation, HLA typing, and sequencing in 3 independent populations for a total of 689 cases of follicular lymphoma and 2,446 controls. Foo et al. (2013) identified a hexa-allelic amino acid polymorphism at position 13 in exon 2 of the HLA-DR beta chain that showed the strongest association with follicular lymphoma within the major histocompatibility complex (MHC) region (multiallelic p = 2.3 x 10(-15)). Out of 6 possible amino acids that occurred at that position within the population, Foo et al. (2013) classified 2 as high risk (tyr and phe), 2 as low risk (ser and arg), and 2 as moderate risk (his and gly). There was a 4.2-fold difference in risk (95% CI, 2.9-6.1) between subjects carrying 2 alleles encoding high-risk amino acids and those carrying 2 alleles encoding low-risk amino acids (p = 1.01 x 10(-14)). Foo et al. (2013) concluded that this coding variant might explain the complex SNP associations identified by GWAS studies and suggests a common HLA-DR antigen-driven mechanism for the pathogenesis of follicular lymphoma and rheumatoid arthritis (180300).