Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10−15) and HLA-B (rs2922994, P=2.43 × 10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
Marginal zone lymphoma (MZL) is a common subtype of B-cell non-Hodgkin lymphoma. Here the authors carry out a two-stage genome-wide association study in over 8,000 Europeans and identify two new MZL risk loci at chromosome 6p, implicating the major histocompatibility complex in the disease for the first time.
To quantify cancer risk in opioid dependence and the association with infection by the oncogenic blood-borne viruses (BBVs) hepatitis C (HCV), hepatitis B (HBV) and HIV.
New South Wales, Australia.
All 45 412 adults aged 16 years or over registered for opioid substitution therapy (OST) between 1985 and 2007. Notifications of cancer, death and infection with HCV, HBV and HIV were ascertained by record linkage with registries.
Main outcome measures
The ratios of observed to expected number of cancers, standardised incidence ratios (SIRs), and the average annual per cent change (AAPC) in overall age and sex-standardised cancer incidence.
Overall cancer risk was modestly increased compared to the general population (SIR 1.15, 95% CI 1.07 to 1.23). Excess risk was observed for 11 cancers, particularly lung (4.02, 95% CI 3.32 to 4.82), non-Hodgkin's lymphoma (1.51, 95% CI 1.20 to 1.88) and liver (8.04, 95% CI 6.18 to 10.3). Reduced risk was observed for six cancers, including prostate (0.16, 95% CI 0.06 to 0.32) and breast (0.48, 95% CI 0.35 to 0.62). Individuals notified with HCV or HBV had a markedly increased risk of liver cancer; lung cancer risk was also increased in those with HCV. HIV was associated with an elevated risk of liver, anus and kidney cancer, non-Hodgkin lymphoma and Kaposi sarcoma. Cancer risk was not increased in individuals without a BBV notification, apart from pancreatic cancer (3.92, 95% CI 1.07 to 10.0). Cancer incidence increased significantly over time (AAPC 9.4%, 4.2% to 15%, p=0.001).
BBVs play a major role in the cancer risk profile of opioid-dependent individuals registered for OST. To address the dramatic increasing trend in cancer incidence, the OST setting could be utilised for cancer prevention strategies.
Background & Aims
Increasing evidence points towards a role of hepatitis C virus (HCV) infection in causing malignant lymphomas. We pooled case-control study data to provide robust estimates of the risk of non-Hodgkin’s lymphoma (NHL) subtypes after HCV infection.
The analysis included 7 member studies from the International Lymphoma Epidemiology Consortium (InterLymph) based in Europe, North America, and Australia. Adult cases of NHL (n = 4784) were diagnosed between 1988 and 2004 and controls (n = 6269) were matched by age, sex, and study center. All studies used third-generation enzyme-linked immunosorbent assays to test for antibodies against HCV in serum samples. Participants who were human immunodeficiency virus positive or were organ-transplant recipients were excluded.
HCV infection was detected in 172 NHL cases (3.60%) and in 169 (2.70%) controls (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.40–2.25). In subtype-specific analyses, HCV prevalence was associated with marginal zone lymphoma (OR, 2.47; 95% CI, 1.44–4.23), diffuse large B-cell lymphoma (OR, 2.24; 95% CI, 1.68–2.99), and lymphoplasmacytic lymphoma (OR, 2.57; 95% CI, 1.14–5.79). Notably, risk estimates were not increased for follicular lymphoma (OR, 1.02; 95% CI, 0.65–1.60).
These results confirm the association between HCV infection and NHL and specific B-NHL subtypes (diffuse large B-cell lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma).
To conduct a within cohort assessment of risk factors for incident AIDS defining cancers (ADC) and non-ADC (NADC) within the Australian HIV Observational Database (AHOD).
2181 AHOD registrants were linked to the National AIDS Registry/National HIV Database NAR/NHD and the Australian cancer registry to identify those with a notified cancer diagnosis. Included in the current analyses were cancers diagnosed after HIV infection. Risk factors for cancers were also assessed using logistic regression methods.
139 cancer cases were diagnosed after HIV infection among 129 patients. More than half the diagnoses (n=68, 60%) were ADC, of which 69% were KS and 31% NHL. Among the NADC, the most common cancers were melanoma (n=10), lung cancer (n=6), and 5 cases each of Hodgkin’s lymphoma and anal cancer. Over a total of 21021 person years (PY) of follow-up since HIV diagnosis, the overall crude cancer incidence rate for any cancer was 5.09/1000 PY. The overall rate of cancers decreased from 15.9/1000 PY (95%CI: 9.25-25.40/1000) for CD4 counts below 100 cells/μL to 2.4/1000 PY (95%CI: 1.62-3.39/1000) for CD4 counts above 350 cells/μL. Lower CD4 cell count and prior AIDS diagnoses were significant predictors for both ADC and NADC.
ADC remain the predominant cancers in this population, although NADC rates have increased in the more recent time period. Immune deficiency is a risk factor for both ADC and NADC.
HIV/AIDS; cancer; antiretroviral treatment; cohort
We performed a pooled analysis of data on atopic disease and risk of non-Hodgkin lymphoma (NHL) from 13 case-control studies, including13,535 NHL cases and 16,388 controls. Self-reported atopic diseases diagnosed two or more years before NHL diagnosis (cases) or interview (controls) were analyzed. Pooled odds ratios (OR) and 95% confidence intervals were computed in two-stage random-effects or joint fixed-effects models, adjusted for age, sex, and study center. When modeled individually, lifetime history of asthma, hay fever, a specific allergy (excluding hay fever, asthma and eczema), and food allergy were associated with a significant reduction in NHL risk, and there was no association for eczema. When each atopic condition was included in the same model, reduced NHL risk was only associated with history of allergy (OR 0.80, 95% CI 0.68–0.94), and reduced B-cell NHL risk was associated with history of hay fever (OR 0.85, 95% CI 0.77–0.95) and allergy (OR 0.84, 95% CI 0.76–0.93). Significant reductions in B-cell NHL risk were also observed in individuals who were likely to be truly or highly atopic - those with hay fever, allergy or asthma and at least one other atopic condition over their lifetime. The inverse associations were consistent for the diffuse large B-cell and follicular subtypes. Eczema was positively associated with lymphomas of the skin; misdiagnosis of lymphoma as eczema is likely, but progression of eczema to cutaneous lymphoma cannot be excluded. This pooled study demonstrates evidence of a modest but consistent reduction in the risk of B-cell NHL associated with atopy.
non-Hodgkin lymphoma; atopy; case-control; pooled analysis; risk
Studies of smoking and risk of non-Hodgkin lymphoma (NHL) have yielded inconsistent results, possibly due to subtype heterogeneity and/or genetic variation impacting the metabolism of tobacco-derived carcinogens, including substrates of the N-acetyltransferase enzymes NAT1 and NAT2.
We conducted a pooled analysis of 5,026 NHL cases and 4,630 controls from seven case–control studies in the international lymphoma epidemiology consortium to examine associations between smoking, variation in the N-acetyltransferase genes NAT1 and NAT2, and risk of NHL subtypes. Smoking data were harmonized across studies, and genetic variants in NAT1 and NAT2 were used to infer acetylation phenotype of the NAT1 and NAT2 enzymes, respectively. Pooled odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for risk of NHL and subtypes were calculated using joint fixed effects unconditional logistic regression models.
Current smoking was associated with a significant 30 % increased risk of follicular lymphoma (n = 1,176) but not NHL overall or other NHL subtypes. The association was similar among NAT2 slow (OR 1.36; 95 % CI 1.07–1.75) and intermediate/rapid (OR 1.27; 95 % CI 0.95–1.69) acetylators (pinteraction = 0.82) and also did not differ by NAT1*10 allelotype. Neither NAT2 phenotype nor NAT1*10 allelotype was associated with risk of NHL overall or NHL subtypes.
The current findings provide further evidence for a modest association between current smoking and follicular lymphoma risk and suggest that this association may not be influenced by variation in the N-acetyltransferase enzymes.
Non-Hodgkin lymphoma; Gene environment interaction; Cigarette smoking; N-acetyltransferase; Follicular lymphoma
We performed a pooled analysis of data on self-reported history of infections in relation to the risk of non-Hodgkin lymphoma (NHL) from 17 case-control studies that included 12,585 cases and 15,416 controls aged 16–96 years at recruitment. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were estimated in two-stage random-effect or joint fixed-effect models, adjusting for age, sex and study centre. Data from the two years prior to diagnosis (or date of interview for controls) were excluded. A self-reported history of infectious mononucleosis (IM) was associated with an excess risk of NHL (OR=1.26, 95% CI=1.01–1.57 based on data from 16 studies); study-specific results indicate significant (I2=51%, p=0.01) heterogeneity. A self-reported history of measles or whooping cough was associated with an approximate 15% reduction in risk. History of other infection was not associated with NHL. We find little clear evidence of an association between NHL risk and infection although the limitations of data based on self-reported medical history (particularly of childhood illness reported by older people) are well recognised.
H2AFX encodes a histone variant involved in signaling sites of DNA damage and recruiting repair factors. Genetic variants in H2AFX may influence risk of non-Hodgkin lymphoma (NHL), a heterogeneous group of lymphoid tumors that are characterized by chromosomal translocations. We previously reported that rs2509049, a common variant in the promoter of H2AFX, was associated with risk for NHL in the British Columbia population. Here we report results for 13 single nucleotide polymorphisms (SNPs) in 100 Kb surrounding H2AFX in an expanded collection of 568 NHL cases and 547 controls. After correction for multiple testing, significant associations were present for mantle cell lymphoma (p=0.007 for rs604714) and all B-cell lymphomas (p=0.046 for rs2509049). Strong linkage disequilibrium in the 5 Kb upstream of H2AFX limited the ability to determine which specific SNP (rs2509049, rs7759, rs8551, rs643788, rs604714, or rs603826), if any, was responsible. There was a significant interaction between sex and rs2509049 in the all B-cell lymphomas group (p=0.002); a sex-stratified analysis revealed that the association was confined to females (p=0.001). Neither the overall nor the female-specific association with rs2509049 was replicated in any of four independent NHL sample sets. Meta-analysis of all five study populations (3,882 B-cell NHL cases and 3,718 controls) supported a weak association with B-cell lymphoma (OR=0.92, 95% CI=0.86-0.99, p=0.034), although this association was not significant after exclusion of the British Columbia data. Further research into the potential sex-specificity of the H2AFX-NHL association may identify a subset of NHL cases that are influenced by genotype at this locus.
The balance between Th1 and Th2 activity is critical in lymphoid cell development and differentiation. Immune dysfunction underlies lymphomagenesis, so an alteration in the regulation of key Th1/Th2 cytokines may lead to the development of non-Hodgkin lymphoma (NHL). To study the impact of polymorphism in Th1/Th2 cytokines on NHL risk, we analyzed 145 tag single nucleotide polymorphisms (SNPs) in 17 Th1/Th2 cytokine and related genes in three population-based case-control studies (1,946 cases and 1,808 controls). Logistic regression was used to compute odds ratios (OR) for NHL and four major NHL subtypes in relation to tag SNP genotypes and haplotypes. A gene-based analysis adjusting for the number of tag SNPs genotyped in each gene showed significant associations with risk of NHL combined and one or more NHL subtypes for Th1 (IL12A and IL12RB1) and Th2 (IL4, IL10RB, and IL18) genes. The strongest association was for IL12A rs485497, which plays a central role in bridging the cellular and humoral pathways of innate resistance and antigen-specific adaptive immune responses (allele risk OR=1.17; P(trend)=0.00099). This SNP was also associated specifically with risk of follicular lymphoma (allele risk OR=1.26; P(trend)=0.0012). These findings suggest that genetic variation in Th1/Th2 cytokine genes may contribute to lymphomagenesis.
Non-Hodgkin lymphoma; single nucleotide polymorphisms; immunogenetics; case-control study
Genetic variation in immune-related genes may play a role in the development of non-Hodgkin lymphoma (NHL). To test the hypothesis that innate immunity polymorphisms may be associated with NHL risk, we genotyped 144 tag single nucleotide polymorphisms (tagSNPs) capturing common genetic variation within 12 innate immunity gene regions in three independent population-based case-control studies (1946 cases and 1808 controls). Gene-based analyses found IL1RN to be associated with NHL risk (minP = 0.03); specifically, IL1RN rs2637988 was associated with an increased risk of NHL (per-allele odds ratio = 1.15, 95% confidence interval = 1.05 – 1.27; ptrend = 0.003), which was consistent across study, subtype, and gender. FCGR2A was also associated with a decreased risk of the follicular lymphoma NHL subtype (minP = 0.03). Our findings suggest that genetic variation in IL1RN and FCGR2A may play a role in lymphomagenesis. Given that conflicting results have been reported regarding the association between IL1RN SNPs and NHL risk, a larger number of innate immunity genes with sufficient genomic coverage should be evaluated systematically across many studies.
non-Hodgkin lymphoma; immune; innate immunity; genetic variation; single nucleotide polymorphisms
There is inconsistent evidence that increasing birth order may be associated with risk of non-Hodgkin lymphoma (NHL). The authors examined the association between birth order and related variables and NHL risk in a pooled analysis (1983–2005) of 13,535 cases and 16,427 controls from 18 case-control studies within the International Lymphoma Epidemiology Consortium (InterLymph). Overall, the authors found no significant association between increasing birth order and risk of NHL (P-trend = 0.082) and significant heterogeneity. However, a significant association was present for a number of B- and T-cell NHL subtypes. There was considerable variation in the study-specific risks which was partly explained by study design and participant characteristics. In particular, a significant positive association was present in population-based studies, which had lower response rates in cases and controls, but not in hospital-based studies. A significant positive association was present in higher-socioeconomic-status (SES) participants only. Results were very similar for the related variable of sibship size. The known correlation of high birth order with low SES suggests that selection bias related to SES may be responsible for the association between birth order and NHL.
birth order; case-control studies; lymphoma, non-Hodgkin; selection bias; social class
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.
To identify susceptibility loci for non-Hodgkin lymphoma (NHL) subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma (FL) in 1,465 FL cases/6,958 controls at 6p21.32 (rs10484561, rs7755224, r2=1.0; combined p-values=1.12×10-29, 2.00×10-19), providing further support that MHC genetic variation influences FL susceptibility. Confirmatory evidence of a previously reported association was also found between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined p-value=4.24×10-9).
Elevated incidence of lymphoma has been observed among carriers of rare high-penetrance mutations in DNA repair genes (e.g., Nijmegen breakage syndrome, Ataxia-telangectasia syndrome, etc.). Common gene variants in DNA repair genes may also influence lymphomagenesis.
Study subjects were pooled from three population-based case-control studies of non-Hodgkin lymphoma (NHL) in the US and Australia. A total of 1,946 cases and 1,808 controls were analyzed. A total of 319 tag single nucleotide polymorphisms (SNPs) in 27 DNA repair gene regions were genotyped. Unconditional logistic regression models were used to estimate the relative risk of NHL and NHL subtypes in relation to SNPs. Tail-strength statistics were used to test for the association between DNA repair pathways and NHL or NHL subtypes. The statistical significance of the smallest P-trend within each gene region was estimated by permutation-based resampling methods.
Overall, DNA repair genetic polymorphisms were associated with NHL (P = 0.005). Tests for the double strand break repair (P = 0.02) and nucleotide excision repair (P = 0.04) pathways were also significant. Four gene regions were significantly associated with NHL or NHL subtypes at the 0.05 level: RAD50, BLM, RAD51/FAM82C, and ERCC3/MAP3K2. Specifically, BLM rs441399 (P trend = 0.004) and FAM82C rs2304583 (P trend = 0.001) were associated with follicular lymphoma, and XRCC4 rs13178127 was associated with NHL overall (P trend = 0.006) significantly. In addition, the ERCC3 rs4150506 was associated with reduced risk for marginal zone lymphoma (P trend = 0.002).
These results support the hypothesis that common genetic polymorphisms in human DNA repair genes may modify the risk of NHL.
non-Hodgkin lymphoma; DNA repair; single nucleotide polymorphism; pooled analysis
To describe changes in cancer incidence in people with HIV in Australia since the introduction of highly active antiretroviral therapy (HAART).
Population-based, retrospective cohort study of people with HIV (n = 20 232) using data linkage between national registers of HIV/AIDS and cancer in 1982–2004.
Age-adjusted and sex-adjusted incidence rate ratios with 95% confidence intervals were calculated to compare site-specific cancer incidence during the early (1996–1999) and late (2000–2004) HAART periods with that prior to HAART (1982–1995). Five-year age-specific, sex-specific, calendar year-specific, and state-specific standardized incidence ratios with 95% confidence interval were also calculated for each period.
Incidence of Kaposi sarcoma and non-Hodgkin lymphoma declined significantly (Ptrend < 0.001). Incidence of Hodgkin lymphoma was significantly higher during the early-HAART period (incidence rate ratio 2.34, 95% confidence interval 1.19–4.63) but declined thereafter (Pdiff = 0.014). Incidence of anal cancer was unchanged (Ptrend = 0.451) and remained raised more than 30-fold. Incidence declined significantly for melanoma (Ptrend = 0.041) and prostate cancer (Ptrend = 0.026), and, during the late-HAART period, was lower than in the general population for both cancers. Incidence of colorectal cancer was consistently lower than in the general population.
Incidence of Kaposi sarcoma and non-Hodgkin lymphoma has continued to decline among people with HIV in Australia, though it remains very substantially elevated. Incidence of Hodgkin lymphoma may now also be declining. Incidence of anal cancer has remained stable, and it is now the third most common cancer in HIV-infected Australians. Reasons for the reduced incidence of colorectal and prostate cancer, and more recently of melanoma, are unclear.
cancer; cohort studies; HAART; HIV; infection
Chromosomal translocations are the hallmark genetic aberration in non-Hodgkin lymphoma (NHL), with specific translocations often selectively associated with specific NHL subtypes. Because many NHL-associated translocations involve cell cycle, apoptosis, and lymphocyte development regulatory genes, we evaluated NHL risk associated with common genetic variation in 20 candidate genes in these pathways. Genotyping of 203 tag single nucleotide polymorphisms (SNPs) was conducted in 1946 NHL cases and 1808 controls pooled from three independent population-based case-control studies. We used logistic regression to compute odds ratios (OR) and 95% confidence intervals (CI) for NHL and four major NHL subtypes in relation to tag SNP genotypes and haplotypes. We observed the most striking associations for tag SNPs in the pro-apoptotic gene BCL2L11 (BIM) and BCL7A, which is involved in a rare NHL-associated translocation. Variants in BCL2L11 were strongly related to follicular lymphoma only, particularly rs3789068 (ORAG=1.41, 95%CI 1.10–1.81; ORGG=1.65, 95%CI 1.25–2.19; p-trend=0.0004). Variants in BCL7A were strongly related to diffuse large B-cell lymphoma only, particularly rs1880030 (ORAG=1.34, 95%CI 1.08–1.68; ORAA=1.60, 95%CI 1.22–2.08; p-trend=0.0004). The associations for both variants were similar in all three studies and supported by haplotype analyses. We also observed notable associations for variants in BCL6, CCND1, and MYC. Our results support the role of common genetic variation in cell cycle, apoptosis, and lymphocyte development regulatory genes in lymphomagenesis, and suggest that effects may vary by NHL subtype. Replication of our findings and further study to identify functional SNPs are warranted.
lymphoma; non-Hodgkin; polymorphism; single nucleotide; apoptosis; cell cycle
Objective To compare cancer incidence in kidney transplant recipients during periods of transplant function (and immunosuppression) and after transplant failure (when immunosuppression is ceased or reduced).
Design, setting, and participants Nationwide, population based retrospective cohort study of 8173 Australian kidney transplant recipients registered on the Australia and New Zealand Dialysis and Transplant Registry who first received a transplant during 1982-2003. Incident cancers were ascertained using linkage with national cancer registry records.
Main outcome measures Cancer-specific standardised incidence ratios for periods of transplant function and for dialysis after transplant failure. Incidence was compared between periods using multivariate incidence rate ratios adjusted for current age, sex, and duration of transplantation.
Results All cases of Kaposi’s sarcoma occurred during transplant function. Standardised incidence ratios were significantly elevated during transplant function, but not during dialysis after transplant failure, for non-Hodgkin’s lymphoma, lip cancer, and melanoma. For each of these cancers, incidence was significantly lower during dialysis after transplant failure in multivariate analysis (incidence rate ratios 0.20 (95% CI 0.06 to 0.65) for non-Hodgkin’s lymphoma, 0.04 (0.01 to 0.31) for lip cancer, and 0.16 (0.04 to 0.64) for melanoma). In contrast, standardised incidence ratios during dialysis after transplant failure remained significantly elevated for leukaemia and lung cancer, and cancers related to end stage kidney disease (kidney, urinary tract, and thyroid cancers), with thyroid cancer incidence significantly higher during dialysis after transplant failure (incidence rate ratio 6.77 (2.64 to 17.39)). There was no significant difference in incidence by transplant function for other cancers.
Conclusions The effect of immunosuppression on cancer risk is rapidly reversible for some, but not all, cancer types. Risk reversal was mainly observed for cancers with a confirmed infectious cause. Risk of other cancers, especially those related to end stage kidney disease, remained significantly increased after reduction of immunosuppression.
Toll-like receptors (TLRs) may influence the development of non-Hodgkin lymphoma (NHL) given their important roles in recognizing microbial pathogens and stimulating multiple immune pathways. We conducted an investigation of TLR gene variants in a pooled analysis including three population-based case–control studies of NHL (1946 cases and 1808 controls). Thirty-six tag single-nucleotide polymorphisms (SNPs) in TLR2, TLR4 and the TLR10–TLR1–TLR6 gene cluster were genotyped. Two TLR10–TLR1–TLR6 variants in moderate linkage disequilibrium were significantly associated with NHL: rs10008492 [odds ratio for CT genotype (ORCT) 1.12, 95% confidence interval (CI) 0.97–1.30; ORTT 1.40, 95% CI 1.15–1.71; Ptrend = 0.001] and rs4833103 (ORAC 0.75, 95% CI 0.64–0.88; ORAA 0.74, 95% CI 0.62–0.90; Ptrend = 0.002; Pdominant = 0.0002). Associations with these SNPs were consistent across all the three studies and did not appreciably differ by histologic subtype. We found little evidence of association between TLR2 variation and all NHL, although the rare variant rs3804100 was significantly associated with marginal zone lymphoma (MZL), both overall (ORCT/CC 1.89, 95% CI 1.27–2.81; Pdominant = 0.002) and in two of the three studies. No associations with TLR4 variants were observed. This pooled analysis provides strong evidence that variation in the TLR10–TLR1–TLR6 region is associated with NHL risk and suggests that TLR2 variants may influence susceptibility to MZL.
Specimen-to-specimen carryover during ThinPrep slide preparation was evaluated by comparing human papillomavirus genotypes detected prior and subsequent to the ThinPrep processing of 121 PreservCyt samples. Overall, 52 samples generated concordant genotypes and 38 had additional and 21 had fewer genotypes postprocessing. PreservCyt samples should be aliquoted for PCR testing prior to ThinPrep processing.
A promoter polymorphism in the pro-inflammatory cytokine tumor necrosis factor (TNF) (TNF G-308A) is associated with increased non-Hodgkin lymphoma (NHL) risk. The protein product, TNF-α, activates the nuclear factor kappa beta (NF-κB) transcription factor, and is critical for inflammatory and apoptotic responses in cancer progression. We hypothesized that the TNF and NF-κB pathways are important for NHL and that gene variations across the pathways may alter NHL risk.
We genotyped 500 tag single nucleotide polymorphisms (SNPs) from 48 candidate gene regions (defined as 20 kb 5′, 10 kb 3′) in the TNF and TNF receptor superfamilies and the NF-κB and related transcription factors, in 1946 NHL cases and 1808 controls pooled from three independent population-based case-control studies. We obtaineded a gene region-level summary of association by computing the minimum p-value (“minP test”). We used logistic regression to compute odds ratios and 95% confidence intervals for NHL and four major NHL subtypes in relation to SNP genotypes and haplotypes. For NHL, the tail strength statistic supported an overall relationship between the TNF/NF-κB pathway and NHL (p = 0.02). We confirmed the association between TNF/LTA on chromosome 6p21.3 with NHL and found the LTA rs2844484 SNP most significantly and specifically associated with the major subtype, diffuse large B-cell lymphoma (DLBCL) (p-trend = 0.001). We also implicated for the first time, variants in NFKBIL1 on chromosome 6p21.3, associated with NHL. Other gene regions identified as statistically significantly associated with NHL included FAS, IRF4, TNFSF13B, TANK, TNFSF7 and TNFRSF13C. Accordingly, the single most significant SNPs associated with NHL were FAS rs4934436 (p-trend = 0.0024), IRF4 rs12211228 (p-trend = 0.0026), TNFSF13B rs2582869 (p-trend = 0.0055), TANK rs1921310 (p-trend = 0.0025), TNFSF7 rs16994592 (p-trend = 0.0024), and TNFRSF13C rs6002551 (p-trend = 0.0074). All associations were consistent in each study with no apparent specificity for NHL subtype.
Our results provide consistent evidence that variation in the TNF superfamily of genes and specifically within chromosome 6p21.3 impacts lymphomagenesis. Further characterization of these susceptibility loci and identification of functional variants are warranted.