Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological
malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A
previous genome-wide association study has established a marker, rs10484561 in
the human leukocyte antigen (HLA) class II region on 6p21.32 associated with
increased FL risk. Here, in a three-stage genome-wide association study,
starting with a genome-wide scan of 379 FL cases and 791 controls followed by
validation in 1,049 cases and 5,790 controls, we identified a second independent
FL–associated locus on 6p21.32, rs2647012
(ORcombined = 0.64,
Pcombined = 2×10−21)
located 962 bp away from rs10484561 (r2<0.1 in controls). After
mutual adjustment, the associations at the two SNPs remained genome-wide
significant (rs2647012:ORadjusted = 0.70,
Padjusted = 4×10−12;
rs10484561:ORadjusted = 1.64,
Padjusted = 5×10−15).
Haplotype and coalescence analyses indicated that rs2647012 arose on an
evolutionarily distinct haplotype from that of rs10484561 and tags a novel
allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up
analysis of the top 6 FL–associated SNPs in 4,449 cases of other NHL
subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma
(ORcombined = 1.36,
Pcombined = 1.4×10−7).
Our results reveal the presence of allelic heterogeneity within the HLA class II
region influencing FL susceptibility and indicate a possible shared genetic
etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA
class II region plays a complex yet important role in NHL.
Earlier studies have established a marker rs10484561, in the HLA class II region
on 6p21.32, associated with increased follicular lymphoma (FL) risk. Here, in a
three-stage genome-wide association study of 1,428 FL cases and 6,581 controls,
we identified a second independent FL–associated marker on 6p21.32,
rs2647012, located 962 bp away from rs10484561. The associations at two SNPs
remained genome-wide significant after mutual adjustment. Haplotype and
coalescence analyses indicated that rs2647012 arose on an evolutionarily
distinct lineage from that of rs10484561 and tags a novel allele with an
opposite, protective effect on FL risk. Moreover, in an analysis of the top 6
FL–associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was
associated with risk of diffuse large B-cell lymphoma. Our results reveal the
presence of allelic heterogeneity at 6p21.32 in FL risk and suggest a shared
genetic etiology with the common diffuse large B-cell lymphoma subtype.
Non-Hodgkin lymphoma (NHL) is a malignancy of lymphocytes, and there is growing evidence for a role of germline genetic variation in immune genes in NHL etiology.
To identify susceptibility immune genes, we conducted a 2-stage analysis of single nucleotide polymorphisms (SNPs) from 1,253 genes using the Immune and Inflammation Panel. In Stage 1, we genotyped 7,670 SNPs in 425 NHL cases and 465 controls, and in Stage 2 we genotyped the top 768 SNPs on an additional 584 cases and 768 controls. The association of individual SNPs with NHL risk from a log-additive model was assessed using the Odds Ratios (ORs) and 95% confidence intervals (CI).
In the pooled analysis, only the TAP2 coding SNP rs241447 (MAF=0.26; Thr655Ala) at 6p21.3 (OR=1.34, 95%CI 1.17-1.53) achieved statistical significance after accounting for multiple testing (p=3.1 × 10−5). The TAP2 SNP was strongly associated with follicular lymphoma (FL, OR=1.82, 95%CI 1.46-2.26; p=6.9 × 10−8), and was independent of other known loci (rs10484561 and rs2647012) from this region. The TAP2 SNP was also associated with diffuse large B-cell lymphoma (DLBCL, OR=1.38, 95% CI 1.08-1.77; p=0.011), but not chronic lymphocytic leukemia (OR=1.08; 95% CI 0.88-1.32). Higher TAP2 expression was associated with the risk allele in both FL and DLBCL tumors.
Genetic variation in TAP2 was associated with NHL risk overall, and FL risk in particular, and this was independent of other established loci from 6p21.3.
Genetic variation in antigen presentation of HLA class I molecules may play a role in lymphomagenesis.
genetics; non-Hodgkin lymphoma; immune function; single nucleotide polymorphisms
B-cell non-Hodgkin lymphoma represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is one of the most common subtypes. Family and epidemiological studies suggest an important genetic role in the etiology of FL. In recent genome-wide association studies (GWAS) of FL, several genetic susceptibility loci have been identified on chromosome 6p21.33 (rs6457327) and 6p21.32 (rs10484561, rs2647012) in the human leukocyte antigen class I and class II regions. To identify new genetic variants and further elucidate the genetic basis of FL, a meta-analysis was performed of the top 1000 SNPs associated with FL risk from two GWAS in the US, Denmark and Sweden (592 cases, 1541 controls), with independent validation in 107 cases and 681 controls.
rs9275517 and rs3117222 in the HLA class II region were validated and inversely associated with FL risk (rs9275517: OR = 0.63, 95% CI = 0.55-0.73, p = 4.03 × 10-11; rs3117222: OR = 0.66, 95% CI = 0.57-0.77, p = 1.45 × 10-7). rs9275517, which is in high linkage disequilibrium with rs2647012 (r2 = 0.9), was no longer associated with FL after conditioning on rs2647012. The rs3117222 association was independent of established FL SNPs, but not of the HLA-DPB1*0301 allele. Using publicly available gene expression profiles with matching genotype information, we found that rs3117222 also was significantly correlated with increased HLA-DPB1 expression.
By performing a meta-analysis of two GWAS of FL, we further validated the relevance of HLA-DPB1*0301 as a protective allele in the pathogenesis of FL. Moreover, the protective rs3117222 A allele correlated with increased levels of HLA-DPB1, suggesting a possible disease mechanism involving HLA-DPB1 expression regulation. Our results add further support to the major role of HLA genetic variation in the pathogenesis of FL.
Follicular lymphoma (FL); Genome-wide association studies (GWAS); Human leukocyte antigen (HLA); Meta-analysis
Risk of non-Hodgkin lymphoma (NHL) is higher among individuals with a family history or a prior diagnosis of other cancers. Genome-wide association studies (GWAS) have suggested that some genetic susceptibility variants are associated with multiple complex traits (pleiotropy).
We investigated whether common risk variants identified in cancer GWAS may also increase the risk of developing NHL as the first primary cancer.
As part of the Population Architecture using Genomics and Epidemiology (PAGE) consortium, 113 cancer risk variants were analyzed in 1,441 NHL cases and 24,183 controls from three studies (BioVU, Multiethnic Cohort Study, Women's Health Initiative) for their association with the risk of overall NHL and common subtypes [diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL)] using an additive genetic model adjusted for age, sex and ethnicity. Study-specific results for each variant were meta-analyzed across studies.
The analysis of NHL subtype-specific GWAS SNPs and overall NHL suggested a shared genetic susceptibility between FL and DLBCL, particularly involving variants in the major histocompatibility complex region (rs6457327 in 6p21.33: FL OR = 1.29, p = 0.013; DLBCL OR = 1.23, p = 0.013; NHL OR = 1.22, p = 5.9×E-05). In the pleiotropy analysis, six risk variants for other cancers were associated with NHL risk, including variants for lung (rs401681 in TERT: OR per C allele = 0.89, p = 3.7×E-03; rs4975616 in TERT: OR per A allele = 0.90, p = 0.01; rs3131379 in MSH5: OR per T allele = 1.16, p = 0.03), prostate (rs7679673 in TET2: OR per C allele = 0.89, p = 5.7×E-03; rs10993994 in MSMB: OR per T allele = 1.09, p = 0.04), and breast (rs3817198 in LSP1: OR per C allele = 1.12, p = 0.01) cancers, but none of these associations remained significant after multiple test correction.
This study does not support strong pleiotropic effects of non-NHL cancer risk variants in NHL etiology; however, larger studies are warranted.
The genetics of lymphoma susceptibility reflect the marked heterogeneity of diseases that comprise this broad phenotype. However, multiple subtypes of lymphoma are observed in some families, suggesting shared pathways of genetic predisposition to these pathologically distinct entities. Using a two-stage GWAS, we tested 530,583 SNPs in 944 cases of lymphoma, including 282 familial cases, and 4,044 public shared controls, followed by genotyping of 50 SNPs in 1,245 cases and 2,596 controls. A novel region on 11q12.1 showed association with combined lymphoma (LYM) subtypes. SNPs in this region included rs12289961 near LPXN, (PLYM = 3.89×10−8, OR = 1.29) and rs948562 (PLYM = 5.85×10−7, OR = 1.29). A SNP in a novel non-HLA region on 6p23 (rs707824, PNHL = 5.72×10−7) was suggestive of an association conferring susceptibility to lymphoma. Four SNPs, all in a previously reported HLA region, 6p21.32, showed genome-wide significant associations with follicular lymphoma. The most significant association with follicular lymphoma was for rs4530903 (PFL = 2.69×10−12, OR = 1.93). Three novel SNPs near the HLA locus, rs9268853, rs2647046, and rs2621416, demonstrated additional variation contributing toward genetic susceptibility to FL associated with this region. Genes implicated by GWAS were also found to be cis-eQTLs in lymphoblastoid cell lines; candidate genes in these regions have been implicated in hematopoiesis and immune function. These results, showing novel susceptibility regions and allelic heterogeneity, point to the existence of pathways of susceptibility to both shared as well as specific subtypes of lymphoid malignancy.
B-cell lymphomas comprise several diseases representing aberrant proliferations of immune cells at various stages of maturation. It might be expected that dissimilar subtypes of lymphoma will have different etiologic and pathogenic mechanisms, reflecting the distinct histologic and clinical characteristics of these diseases. This study aims to define both shared as well as specific genetic risk factors for lymphoma. Utilizing a genome-wide approach, we discovered novel locations in the genome associated with risk for lymphoid malignancies. Common variants in these regions, on chromosome 11q12.1 and 6p23, were each associated with a modest modification of risk for lymphoma. These regions harbor several genes of biological importance in lymphoid maturation and function. We also further characterized the HLA region at 6p21.32, previously associated with lymphoma risk and thought to be important in immune function. Some of the associated SNP markers were specific for one common subtype of lymphoma, e.g. follicular lymphoma. However, others were associated with combined subsets of disease, suggesting that there are both shared and subtype-specific associations between common genetic variants and human lymphoid cancer. Secondary analyses showed that the two novel regions harbor candidates that are biologically relevant and that regulate cell development and hematopoiesis.
Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV–related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV–positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 (OR = 1.30, P = 1.13×10−19) and rs455804 (GRIK1) on 21q21.3 (OR = 0.84, P = 1.86×10−8), which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR = 1.25, P = 1.71×10−4; rs455804: OR = 0.84, P = 6.92×10−3). We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC.
Previous studies strongly suggest the importance of genetic susceptibility for hepatocellular carcinoma (HCC). However, the studies about genetic etiology on HBV–related HCC were limited. Our genome-wide association study included 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers for the discovery analysis. 2,112 HBV–positive HCC cases and 2,208 HBV carriers (the initial validation), and 1,021 cases and 1,491 HBV carriers (the second validation), were then analyzed for validation. The fourth independent samples of 1,298 cases and 1,026 controls were analyzed as replication. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 and rs455804 (GRIK1) on 21q21.3. HLA-DRB1 molecules play an important role in chronic HBV infection and progression to HCC. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC.
Non-Hodgkin lymphoma (NHL) is a malignancy etiologically linked to immunomodulatory exposures and disorders. Endogenous female sex hormones may modify immune function and influence NHL risk. Few studies have examined associations between reproductive factors, which can serve as surrogates for such hormonal exposures, and NHL risk by subtype.
Women in the California Teachers Study cohort provided detailed data in 1995–1996 on reproductive history. Follow-up through 2007 identified 574 women with incident B-cell NHL. Hazard rate ratios (RR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models to assess associations between reproductive factors and all B-cell NHL combined, diffuse large B-cell lymphomas, follicular lymphomas, and B-cell chronic lymphocytic leukemias/small lymphocytic lymphomas. Pregnancy was marginally associated with lower risk of B-cell NHL (RR = 0.84, 95% CI = 0.68–1.04). Much of the reduction in risk was observed after one full-term pregnancy relative to nulligravid women (RR = 0.75, 95% CI = 0.54–1.06; P for trend <0.01), particularly for diffuse large B-cell lymphomas (P for trend = 0.13), but not among women who had only incomplete pregnancies. Age at first full-term pregnancy was marginally inversely associated with B-cell NHL risk overall (P for trend = 0.08) and for diffuse large B-cell lymphomas (P for trend = 0.056). Breast feeding was not associated with B-cell NHL risk overall or by subtype.
Full-term pregnancy and early age at first full-term pregnancy account for most of the observed reduction in B-cell NHL risk associated with gravidity. Pregnancy-related hormonal exposures, including prolonged and high-level exposure to progesterone during a full-term pregnancy may inhibit development of B-cell NHL.
We conducted genome-wide association studies of non-Hodgkin lymphoma using Illumina HumanHap550 BeadChips to identify subtype-specific associations in follicular, diffuse large B-cell and chronic lymphocytic leukemia/small lymphocytic lymphomas. We found that rs6457327 on 6p21.33 was associated with susceptibility to follicular lymphoma (FL, N=189 cases/592 controls) with validation in an additional 456 FL cases and 2,785 controls (combined allelic p-value=4.7×10−11). The region of strongest association overlaps C6orf15(STG), located near psoriasis susceptibility region 1(PSORS1).
Molecular and genetic evidence suggests that DNA repair pathways may contribute to lymphoma susceptibility. Several studies have examined the association of DNA repair genes with lymphoma risk, but the findings from these reports have been inconsistent. Here we provide the results of a focused analysis of genetic variation in DNA repair genes and their association with the risk of non-Hodgkin's lymphoma (NHL). With a population of 1,297 NHL cases and 1,946 controls, we have performed a two-stage case/control association analysis of 446 single nucleotide polymorphisms (SNPs) tagging the genetic variation in 81 DNA repair genes. We found the most significant association with NHL risk in the ATM locus for rs227060 (OR = 1.27, 95% CI: 1.13–1.43, p = 6.77×10−5), which remained significant after adjustment for multiple testing. In a subtype-specific analysis, associations were also observed for the ATM locus among both diffuse large B-cell lymphomas (DLBCL) and small lymphocytic lymphomas (SLL), however there was no association observed among follicular lymphomas (FL). In addition, our study provides suggestive evidence of an interaction between SNPs in MRE11A and NBS1 associated with NHL risk (OR = 0.51, 95% CI: 0.34–0.77, p = 0.0002). Finally, an imputation analysis using the 1,000 Genomes Project data combined with a functional prediction analysis revealed the presence of biologically relevant variants that correlate with the observed association signals. While the findings generated here warrant independent validation, the results of our large study suggest that ATM may be a novel locus associated with the risk of multiple subtypes of NHL.
Non-Hodgkin lymphoma (NHL) is a hematological malignancy of the immune system, and, as with autoimmune and inflammatory diseases (ADs), is influenced by genetic variation in the major histocompatibility complex (MHC). Persons with a history of specific ADs also have increased risk of NHL. As the coexistence of ADs and NHL could be caused by factors common to both diseases, here we examined whether some of the associated genetic signals are shared. Overlapping risk loci for NHL subytpes and several ADs were explored using data from genome-wide association studies. Several common genomic regions and susceptibility loci were identified suggesting a potential shared genetic background. Two independent MHC regions showed the main overlap, with several alleles in the human leukocyte antigen (HLA) Class II region exhibiting an opposite risk effect for follicular lymphoma and type I diabetes. These results support continued investigation to further elucidate the relationship between lymphoma and autoimmune diseases.
Non-Hodgkin lymphoma; Autoimmune diseases; Genome-wide Association Studies; Human Leukocyte Antigen
Non-Hodgkin lymphoma (NHL), the most common hematologic malignancy, consists of numerous subtypes. The etiology of NHL is incompletely understood, and increasing evidence suggests that risk factors may vary by NHL subtype. However, small numbers of cases have made investigation of subtype-specific risks challenging. The International Lymphoma Epidemiology Consortium therefore undertook the NHL Subtypes Project, an international collaborative effort to investigate the etiologies of NHL subtypes. This article describes in detail the project rationale and design.
We pooled individual-level data from 20 case-control studies (17471 NHL cases, 23096 controls) from North America, Europe, and Australia. Centralized data harmonization and analysis ensured standardized definitions and approaches, with rigorous quality control.
The pooled study population included 11 specified NHL subtypes with more than 100 cases: diffuse large B-cell lymphoma (N = 4667), follicular lymphoma (N = 3530), chronic lymphocytic leukemia/small lymphocytic lymphoma (N = 2440), marginal zone lymphoma (N = 1052), peripheral T-cell lymphoma (N = 584), mantle cell lymphoma (N = 557), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (N = 374), mycosis fungoides/Sézary syndrome (N = 324), Burkitt/Burkitt-like lymphoma/leukemia (N = 295), hairy cell leukemia (N = 154), and acute lymphoblastic leukemia/lymphoma (N = 152). Associations with medical history, family history, lifestyle factors, and occupation for each of these 11 subtypes are presented in separate articles in this issue, with a final article quantitatively comparing risk factor patterns among subtypes.
The International Lymphoma Epidemiology Consortium NHL Subtypes Project provides the largest and most comprehensive investigation of potential risk factors for a broad range of common and rare NHL subtypes to date. The analyses contribute to our understanding of the multifactorial nature of NHL subtype etiologies, motivate hypothesis-driven prospective investigations, provide clues for prevention, and exemplify the benefits of international consortial collaboration in cancer epidemiology.
Interleukin-10 (IL-10) single nucleotide polymorphisms (SNPs) have been indicated to be correlated with Non-Hodgkin’s lymphoma (NHL) susceptibility. However, the results of these studies on the association remain inconsistent. This meta-analysis was conducted to derive a more accuracy estimation of the association between the common SNPs (rs1800890, rs1800896, rs1800871 and rs1800872) in IL-10 and NHL risk. Meta-analyses were performed on 21 studies with 7,749 cases and 8584 controls. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the NHL risk. Meta-analyses showed that rs1800890, rs1800871 and rs1800872 polymorphisms had no association with NHL risk. However, rs1800896 polymorphism has association with NHL risk based on the following comparison models (G vs. A: OR = 1.14, 95% CI = 1.00-1.29; AG vs. AA: OR = 1.20, 95% CI = 1.05-1.37; GG+AG vs. AA: OR = 1.22, 95% CI = 1.08-1.39). In the ethnic subgroup analysis, rs1800896 had an increased NHL risk in Caucasians based on the heterozygote model (OR = 1.21, 95% CI = 1.04-1.41) and dominant model (OR = 1.22, 95% CI = 1.00-1.48). When stratified by subtypes, rs1800890, rs1800896 and rs1800872 polymorphisms were found significant association with an increased risk of diffuse large B-cell Lymphoma (DLBCL) in different comparison models, whereas negative results were obtained for Follicular Lymphoma (FL) and chronic lymphocytic Leukemia/small lymphocytic Lymphoma (CLL/SLL) in all genetic models. Our meta-analysis suggested that the rs1800896 polymorphism had an increased risk with NHL susceptibility, where as the rs1800890, rs1800871 and rs1800872 had no association with NHL risk. Among the common subtypes of NHL, three polymorphisms (rs1800890, rs1800896 and rs1800872) had significant association with DLBCL risk.
Non-Hodgkin’s lymphoma; interleukin-10; polymorphism; meta-analysis
Infection with Epstein-Barr virus (EBV) is highly prevalent worldwide, and it has been associated with infectious mononucleosis and severe diseases including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal lymphoma, and lymphoproliferative disorders. Although EBV has been the focus of extensive research, much still remains unknown concerning what makes some individuals more sensitive to infection and to adverse outcomes as a result of infection. Here we use an integrative genomics approach in order to localize genetic factors influencing levels of Epstein Barr virus (EBV) nuclear antigen-1 (EBNA-1) IgG antibodies, as a measure of history of infection with this pathogen, in large Mexican American families. Genome-wide evidence of both significant linkage and association was obtained on chromosome 6 in the human leukocyte antigen (HLA) region and replicated in an independent Mexican American sample of large families (minimum p-value in combined analysis of both datasets is 1.4×10−15 for SNPs rs477515 and rs2516049). Conditional association analyses indicate the presence of at least two separate loci within MHC class II, and along with lymphocyte expression data suggest genes HLA-DRB1 and HLA-DQB1 as the best candidates. The association signals are specific to EBV and are not found with IgG antibodies to 12 other pathogens examined, and therefore do not simply reveal a general HLA effect. We investigated whether SNPs significantly associated with diseases in which EBV is known or suspected to play a role (namely nasopharyngeal lymphoma, Hodgkin lymphoma, systemic lupus erythematosus, and multiple sclerosis) also show evidence of associated with EBNA-1 antibody levels, finding an overlap only for the HLA locus, but none elsewhere in the genome. The significance of this work is that a major locus related to EBV infection has been identified, which may ultimately reveal the underlying mechanisms by which the immune system regulates infection with this pathogen.
Many factors influence individual differences in susceptibility to infectious disease, including genetic factors of the host. Here we use several genome-wide investigative tools (linkage, association, joint linkage and association, and the analysis of gene expression data) to search for host genetic factors influencing Epstein-Barr virus (EBV) infection. EBV is a human herpes virus that infects up to 90% of adults worldwide, infection with which has been associated with severe complications including malignancies and autoimmune disorders. In a sample of >1,300 Mexican American family members, we found significant evidence of association of anti–EBV antibody levels with loci on chromosome 6 in the human leukocyte antigen region, which contains genes related to immune function. The top two independent loci in this region were HLA-DRB1 and HLA-DQB1, both of which are involved in the presentation of foreign antigens to T cells. This finding was specific to EBV and not to 12 other pathogens we examined. We also report an overlap of genetic factors influencing both EBV antibody level and EBV–related cancers and autoimmune disorders. This work demonstrates the presence of EBV susceptibility loci and provides impetus for further investigation to better understand the underlying mechanisms related to differences in disease progression among individuals infected with this pathogen.
Hodgkin lymphoma (HL) and Anaplastic Large Cell Lymphoma (ALCL), are forms of malignant lymphoma defined by unique morphologic, immunophenotypic, genotypic, and clinical characteristics, but both overexpress CD30. We used sub-megabase resolution tiling (SMRT) array-based comparative genomic hybridization to screen HL-derived cell lines (KMH2 and L428) and ALCL cell lines (DEL and SR-786) in order to identify disease-associated gene copy number gains and losses.
Significant copy number gains and losses were observed on several chromosomes in all four cell lines. Assessment of copy number alterations with 26,819 DNA segments identified an average of 20 genetic alterations. Of the recurrent minimally altered regions identified, 11 (55%) were within previously published regions of chromosomal alterations in HL and ALCL cell lines while 9 (45%) were novel alterations not previously reported. HL cell lines L428 and KMH2 shared gains in chromosome cytobands 2q23.1-q24.2, 7q32.2-q36.3, 9p21.3-p13.3, 12q13.13-q14.1, and losses in 13q12.13-q12.3, and 18q21.32-q23. ALCL cell lines SR-786 and DEL, showed gains in cytobands 5p15.32-p14.3, 20p12.3-q13.11, and 20q13.2-q13.32. Both pairs of HL and ALCL cell lines showed losses in 18q21.32-18q23.
This study is considered to be the first one describing HL and ALCL cell line genomes at sub-megabase resolution. This high-resolution analysis allowed us to propose novel candidate target genes that could potentially contribute to the pathogenesis of HL and ALCL. FISH was used to confirm the amplification of all three isoforms of the trypsin gene (PRSS1/PRSS2/PRSS3) in KMH2 and L428 (HL) and DEL (ALCL) cell lines. These are novel findings that have not been previously reported in the lymphoma literature, and opens up an entirely new area of research that has not been previously associated with lymphoma biology. The findings raise interesting possibilities about the role of signaling pathways triggered by membrane associated serine proteases in HL and aggressive NHL, similar to those described in epithelial tumors.
To determine the spectrum of renal lesions in patients with kidney involvement in non-Hodgkin's lymphoma (NHL) by renal biopsy.
The clinical features and histological findings at the time of the renal biopsy were assessed for each patient.
We identified 20 patients with NHL and renal involvement, and the diagnosis of NHL was established following the kidney biopsy in 18 (90%) patients. The types of NHL include the following: chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 8), diffuse large B-cell lymphoma (n = 4), T/NK cell lymphoma (n = 3), lymphoplasmacytic lymphoma (n = 2), cutaneous T-cell lymphoma (n = 1), mucosa-associated lymphoid tissue lymphoma (n = 1) and mantle cell lymphoma (n = 1). All presented with proteinuria, and 15 patients had impaired renal function. The pathological findings included (1) membranoproliferative glomerulonephritis-like pattern in seven patients; (2) crescent glomerulonephritis in four; (3) minimal-change disease in three, and glomeruli without specific pathological abnormalities in three; (4) intraglomerular large B-cell lymphoma in one; (5) intracapillary monoclonal IgM deposits in one; (6) primary diffuse large B-cell lymphoma of the kidneys in one; and (7) lymphoma infiltration of the kidney in eight patients.
A wide spectrum of renal lesions can be observed in patients with NHL, and NHL may be first proven by renal biopsies for evaluation of kidney injury or proteinuria. Renal biopsy is necessary to establish the underlying cause of renal involvement in NHL.
Nutritional status and physical activity are known to alter immune function, which may be relevant to lymphomagenesis. The authors examined body size measurements and recreational physical activity in relation to risk of B-cell non-Hodgkin lymphoma (NHL) in the prospective California Teachers Study. Between 1995 and 2007, 574 women were diagnosed with incident B-cell NHL among 121,216 eligible women aged 22–84 years at cohort entry. Multivariable-adjusted relative risks and 95% confidence intervals were estimated by fitting Cox proportional hazards models for all B-cell NHL combined and for the 3 most common subtypes: diffuse large B-cell lymphoma, follicular lymphoma, and B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma. Height was positively associated with risk of all B-cell NHLs (for >1.70 vs. 1.61–1.65 m, relative risk = 1.50, 95% confidence interval: 1.16, 1.96) and chronic lymphocytic leukemia/small lymphocytic lymphoma (relative risk = 1.93, 95% confidence interval: 1.09, 3.41). Weight and body mass index at age 18 years were positive predictors of B-cell NHL risk overall. These findings indicate that greater height, which may reflect genetics, early life immune function, infectious exposures, nutrition, or growth hormone levels, may play a role in NHL etiology. Adiposity at age 18 years may be more relevant to NHL etiology than that in later life.
body mass index; body size; cohort studies; exercise; hip; lymphoma, non-Hodgkin; waist-hip ratio
Although no definite risk factors have emerged for the different hematological malignancies, a viral cause has been postulated. Several studies have detected SV40 DNA sequences in tumor tissues obtained from non-Hodgkin’s lymphoma patients. A link between SV40 and NHL is biologically plausible because SV40 causes hematological malignancies in laboratory rodents.
We investigated 266 Egyptian cases of different hematological malignancies, for the presence of SV40 DNA using multiplex nested PCR technique. These cases consisted of 158 non-Hodgkin’s lymphoma (NHL), 54 Hodgkin’s disease(HD), 26 acute lymphocytic leukemia (ALL), 13 acute myeloid leukemia (AML), 8 chronic lymphoblastic leukemia (CLL), 7 chronic myeloid leukemia (CML), in addition to 34 subjects of control group.
Our results have shown that SV40 DNA sequences were found in 53.8% of non-Hodgkin lymphoma patients, 29.6% of Hodgkin’s disease patients, and 40.7% of different types of leukemia cases. Frequency of SV40 DNA sequences was higher in NHL patients compared to the other tumor cases. Also, frequency of SV40 DNA sequences was significantly higher (p<0.05) in NHL patients than in the control group. Regarding the different histological types of non-Hodgkin’s lymphoma, SV40 DNA sequences were detected frequently in diffuse large B-cell lymphoma and in follicular lymphoma.
The present study suggests that SV40 DNA virus is significantly associated with non-Hodgkin’s lymphoma and might have a role in the development of these hematological malignancies. Polyomavirus SV40 may act as a cofactor in the pathogenesis of these tumors and this could lead to new diagnostic, therapeutic, and preventive approaches.
Greater consumption of red meat, processed meat and dairy products has been associated with an increased risk of non-Hodgkin lymphoma (NHL) in several previous reports. Phytanic acid, a saturated fatty acid obtained primarily through the consumption of ruminant meat and dairy products, may offer a potential underlying mechanism for these associations. In a population-based case–control study of 336 cases and 460 controls conducted in Nebraska during 1999–2002, we examined whether phytanic acid-containing foods or total phytanic acid intake, estimated from a food frequency questionnaire and the published phytanic acid values of 151 food items, were associated with increased NHL risk. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals for overall NHL and the common NHL histologic subtypes. In multivariable models, higher intakes of density-adjusted beef [ORT3 vs. T1 = 1.5 (1.1–2.2); Ptrend = 0.02], total dairy products [OR = 1.5 (1.1–2.2); Ptrend = 0.02) and milk [OR = 1.6 (1.1–2.3); Ptrend = 0.01] were associated with an increased risk of NHL. Intake of total phytanic acid was positively associated with NHL risk [OR = 1.5 (1.0–2.1); Ptrend = 0.04]. In analyses stratified by NHL subtype, greater consumption of beef was associated with an increased risk of diffuse large B-cell lymphoma, and greater consumption of milk was associated with an increased risk of follicular lymphoma (FL). Total phytanic acid intake was associated with an increased risk of FL and small lymphocytic lymphoma/chronic lymphocytic leukemia. Our results provide support that total phytanic acid and phytanic acid-containing foods may increase NHL risk.
Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes.
We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case–control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P
Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P
NODE < 1.0×10−4), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P
NODE < 1.0×10−4). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.
Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.
Non-Hodgkin’s lymphomas (NHL) are etiologically heterogeneous malignancies. In Egypt, we previously reported an association of increased NHL risk with chronic hepatitis C virus (HCV) infection. Our present aim is to assess the association between HCV infection and histological subtypes of NHL.
We conducted a case–control study at the National Cancer Institute of Cairo University. Cases with NHL (n = 486) were matched to controls (n = 786) who were orthopedic patients from the same referral regions. Participants provided a blood sample for HCV markers (anti-HCV, HCV RNA) and answered a questionnaire on possible risk factors. Case–control differences were assessed by odds ratios and 95% confidence intervals from logistic regression analysis.
Cases with diffuse large B cell lymphoma (n = 146), chronic lymphocytic leukemia (n = 58), marginal zone lymphoma (n = 24), follicular lymphoma (n = 23), and mantle cell lymphoma (n = 16) were recruited. HCV RNA prevalence was 27% in controls and 26%–48% in the NHL subgroups: it was associated (p <0.001) with diffuse large B cell, marginal zone, and follicular lymphomas with odds ratios of 3.2, 4.4, and 3.3, respectively.
HCV is a risk factor for diffuse large B cell, marginal zone, and follicular lymphomas in Egypt.
Non-Hodgkin’s lymphoma; Hepatitis C virus; Egypt; Epidemiology; Risk factors
Farming and pesticide use have previously been linked to non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). We evaluated agricultural use of specific insecticides, fungicides, and fumigants and risk of NHL and NHL-subtypes (including CLL and MM) in a U.S.-based prospective cohort of farmers and commercial pesticide applicators. A total of 523 cases occurred among 54,306 pesticide applicators from enrollment (1993–97) through December 31, 2011 in Iowa, and December 31, 2010 in North Carolina. Information on pesticide use, other agricultural exposures and other factors was obtained from questionnaires at enrollment and at follow-up approximately five years later (1999–2005). Information from questionnaires, monitoring, and the literature were used to create lifetime-days and intensity-weighted lifetime days of pesticide use, taking into account exposure-modifying factors. Poisson and polytomous models were used to calculate relative risks (RR) and 95% confidence intervals (CI) to evaluate associations between 26 pesticides and NHL and five NHL-subtypes, while adjusting for potential confounding factors. For total NHL, statistically significant positive exposure-response trends were seen with lindane and DDT. Terbufos was associated with total NHL in ever/never comparisons only. In subtype analyses, terbufos and DDT were associated with small cell lymphoma/chronic lymphocytic leukemia/marginal cell lymphoma, lindane and diazinon with follicular lymphoma, and permethrin with MM. However, tests of homogeneity did not show significant differences in exposure-response among NHL-subtypes for any pesticide. Because 26 pesticides were evaluated for their association with NHL and its subtypes, some chance finding could have occurred. Our results showed pesticides from different chemical and functional classes were associated with an excess risk of NHL and NHL subtypes, but not all members of any single class of pesticides were associated with an elevated risk of NHL or NHL subtypes. These findings are among the first to suggest links between DDT, lindane, permethrin, diazinon and terbufos with NHL subtypes.
BACKGROUND: Classical Hodgkin's disease (HD) and B-cell non-Hodgkin lymphoma (NHL) occasionally occur in the same patient. Such composite lymphomas represent interesting models to study the pathogenesis of B-cell lymphomas and the relationship between HD and B-cell NHL. MATERIALS AND METHODS: We analyzed two composite lymphomas (a combination of classical HD with follicular lymphoma [FL] and a combination of classical HD with B-cell chronic lymphocytic leukemia [B-CLL]) by micromanipulation of single cells from tissue sections and amplification of immunoglobulin V region genes for the clonal relationship of the tumor cells. RESULTS: In both cases, clonally related variable (V) genes with both shared as well as distinct somatic mutations were obtained from the two lymphomas, showing that in each of the cases the distinct tumor cells were members of a common germinal center (GC) B-cell clone. FL cells from two different lymph nodes of patient 1 showed a similar mutation pattern, suggesting that infiltration of these lymph nodes by tumor cells was not restricted to a particular FL cell or subclone. In the FL, a single cell was identified with a mutation signature indicating that premalignant cells can persist in the tissue. CONCLUSIONS: The cases presented here further underline the close relationship between HD and B-cell NHL and the role of the GC in lymphomagenesis. Whereas the latter was already suggested for FL and HD, the present study indicates that also in the B-CLL subset characterized by mutated Ig genes, important steps in malignant transformation happen in the GC, and that HRS cells can derive from CD5-positive B cells.
Introduction: The distribution of the major subtypes of non-Hodgkin’s lymphoma (NHL) differs across geographic regions. This study, from the north Indian state of Punjab, has incorporated immunophenotypic findings while investigating the distribution of NHL subtypes based on World Health Organization (WHO)/ Revised European-American Classification of Lymphoid Neoplasms (REAL) system of classification.
Patients and methods: Over all seventy seven cases of lymphoma over a period of one year (between April 2012 and April 2013) were diagnosed in the Department of Pathology, Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar (Punjab). Of these 30 cases (39%) were of Hodgkin’s Lymphoma (HL) and 47 cases (61%) were of Non Hodgkins lymphoma NHL.
Of the total of cases of lympho-proliferative disorders, the diagnosis of NHL was done by light microscopy alone. All the cases diagnosed provisionally as NHL were taken up for immunophenotyping with Immunohistochemical (IHC) studies. There was 100 % concordance between the light microscopy and IHC studies.
The individual NHL cases were classified according to the WHO/REAL classification according to the positive or relevant negative immonophenotypic expression and tabulated to ascertain the morphological spectrum of NHL in this part of the country.
Results: B-cell lymphomas formed 89.3%, whereas T-cell lymphomas formed 10.7% of the NHLs. Diffuse Large B-Cell Lymphoma (DLBCL) was the most common subtype (46.8% of all NHLs). B-cell small lymphocytic lymphoma, Mantle-Cell Lymphoma (MCL), marginal zone B-cell lymphomas (including MALT lymphomas), Diffuse, mixed small cleaved cell and large-cell type and Follicular centre-cell lymphomas amounted to 17%, 12.8%, 2.1%, 2.1% and 4.3%, respectively. Among the T-cell lymphomas, T-cell lymphoblastic lymphoma, anaplastic large-cell lymphomas of T/null-cell type, and Angioimmunoblastic T-cell lymphoma (AITL) accounted for 6.4%, 2.1%, and 2.1% of all NHL cases, respectively.
Conclusions: The distribution of NHL subtypes in India shows disparity with those from the rest of the world. Follicular Lymphoma (FL) and MCL are less common in India compared to Europe and the USA. Peripheral T-cell lymphomas and T/NK-cell lymphomas of nasal and nasal types, which are common in many other Asian countries, are also less prevalent. T-cell lymphoblastic lymphoma and anaplastic large T/null cell lymphoma are more prevalent in India.
Non Hodgkins lymphoma; WHO/REAL classification; Immunophenotyping; B-cell lymphomas; T-cell lymphomas
Genetic factors are important in the etiology and pathogenesis of chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma (HL), and non-Hodgkin's lymphoma (NHL). Only a few small studies have assessed clinical characteristics and prognosis for familial patients, with inconsistent findings.
Using population-based registries from Sweden and Denmark, 7,749 patients with CLL, 7,476 patients with HL, and 25,801 patients with NHL with linkable first-degree relatives were identified. Kaplan-Meier curves were constructed to compare survival in patients with lymphoma with and without a family history of lymphoma. The risk of dying was assessed using adjusted Cox proportional hazard models.
We found 85 patients with CLL (1.10%), 95 patients with HL (1.28%), and 206 patients with NHL (0.80%) with a family history of any lymphoma. Five-year mortality was similar for patients with CLL (hazard ratio [HR], 1.28; 95% CI, 0.95 to 1.72), HL (HR, 0.78; 95% CI, 0.49 to 1.25), and NHL (HR, 0.91; 95% CI, 0.74 to 1.12) versus without a family history of any lymphoma. Mortality was also similar for patients with versus without a family history of the same lymphoma. T-cell/anaplastic lymphoma patients with a family history of NHL had poorer outcome 5-years after diagnosis (HR, 5.38; 95% CI, 1.65 to 17.52). Results were similar for 10 years of follow-up.
With the exception of T-cell/anaplastic lymphoma, survival patterns for patients with CLL, HL, and NHL with a family history of lymphoma were similar to those for sporadic patients, suggesting that most familial lymphomas do not have an altered clinical course. Our findings provide no evidence to modify therapeutic strategies for patients with CLL, HL, or NHL based solely on family history.
Circadian genes have the potential to influence a variety of cancer-related biological pathways, including immune regulation, which may influence susceptibility to non-Hodgkin’s lymphoma (NHL). However, few studies have examined the role of circadian genes in lymphomagenesis. The current study examined Cryptochrome 2 (CRY2), a core circadian gene and transcriptional repressor, as a potential circadian biomarker for NHL. We first performed genetic association analyses of tagging SNPs in CRY2 and NHL risk using DNA samples from a population-based case-control study (N= 455 cases and 527 controls). Three SNPs were found to be significantly associated with risk of NHL when combining all subtypes (dbSNP IDs, odds ratios (ORs), and 95% confidence intervals: rs11038689, OR=2.34 (1.28-4.27), P=0.006; rs7123390, OR=2.40 (1.39-4.13), P=0.002; and rs1401417, OR=2.97 (1.57-5.63), P=0.001). Each of these associations remained significant when restricting the analysis to B-Cell cases and when further restricting to follicular lymphomas. An analysis of CRY2 diplotypes confirmed these significant findings. To further determine the functional impact of CRY2, we silenced the gene in vitro and performed a whole genome expression microarray. A pathway-based analysis showed that genes significantly altered by CRY2 knockdown formed networks associated with immune response and hematological system development. In addition, these genes were predicted to have significant impacts on several disease processes, including cancer (B-H P-value=3.75E-9) and hematological disease (B-H P=8.01E-8). In conclusion, both genetic association and functional analyses suggest that the circadian gene CRY2 may play an important role in NHL development.
CRY2; NHL; Circadian Genetics