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
The optimal management of stage I follicular lymphoma, according to consensus guidelines, is based on uncontrolled experiences of select institutions. Diverse treatment approaches are used despite guidelines that recommend radiation therapy (XRT).
Patients and Methods
We analyzed outcomes of patients with stage I follicular lymphoma enrolled onto the National LymphoCare database.
Of 471 patients with stage I follicular lymphoma, 206 patients underwent rigorous staging as defined by both a bone marrow aspirate and biopsy and an imaging study (a computed tomography [CT] scan of the whole body, a positron emission tomography [PET]/CT scan, or both). Rigorously staged patients had superior progression-free survival (PFS) compared with nonrigorously staged patients (hazard ratio [HR], 0.63). Treatments given to rigorously staged patients were rituximab/chemotherapy (R-chemo; 28%), XRT (27%), observation (17%), systemic therapy + XRT (13%), rituximab monotherapy (12%), and other (3%). With a median follow-up of 57 months for PFS, there were 44 progression events (in 21% of patients) for rigorously staged patients. For these patients, PFS was significantly improved with either R-chemo or systemic therapy + XRT compared with patients receiving XRT alone after adjustment for histology, LDH, and the presence of B symptoms. There were no differences in overall survival.
In this largest, prospectively enrolled group of patients with stage I follicular lymphoma, variable treatment approaches resulted in similar excellent outcomes, which challenges the paradigm that XRT should be standard for this presentation.
Antioxidants, primarily from fruits and vegetables, have been hypothesized to protect against non-Hodgkin lymphoma (NHL). The Oxygen Radical Absorbance Capacity (ORAC) assay, which measures total antioxidant capacity of individual foods and accounts for synergism, can be estimated using a food-frequency questionnaire (FFQ). We tested the hypothesis that higher intake of antioxidant nutrients from foods, supplements, and FFQ-based ORAC values are associated with a lower risk of NHL in a clinic-based study of 603 incident cases and 1007 frequency-matched controls. Diet was assessed with a 128-item FFQ. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals adjusted for age, sex, residence and total energy. Dietary intake of α-tocopherol (OR=0.50; p-trend=0.0002), β-carotene (OR=0.58; p-trend=0.0005), lutein/zeaxanthin (OR=0.62; p-trend=0.005), zinc (OR=0.54; p-trend=0.003) and chromium (OR=0.68; p-trend=0.032) were inversely associated with NHL risk. Inclusion of supplement use had little impact on these associations. Total vegetables (OR=0.52; p-trend<0.0001), particularly green leafy (OR=0.52; p-trend<0.0001) and cruciferous (OR=0.68; p-trend=0.045) vegetables, were inversely associated with NHL risk. NHL risk was inversely associated with both hydrophilic ORAC (OR=0.61, p-trend=0.003) and lipophilic ORAC (OR=0.48, p-trend=0.0002), although after simultaneous adjustment for other antioxidants or total vegetables only the association for lipophilic ORAC remained significant. There was no striking heterogeneity in results across the common NHL subtypes. Higher antioxidant intake as estimated by the FFQ-ORAC, particularly the lipophilic component, was associated with a lower NHL risk after accounting for other antioxidant nutrients and vegetable intake, supporting this as potentially useful summary measure of total antioxidant intake.
Diet; non-Hodgkin lymphoma; vegetables; antioxidants; ORAC
While standard clinical prognostic factors predict outcome in diffuse large B-cell lymphoma (DLBCL), predicting the outcome of patients might be further refined using biological factors. We tested whether serum cytokines could provide prognostic information in DLBCL patients. Thirty cytokines were measured in pre-treatment samples from newly diagnosed DLBCL patients using a multiplex ELISA. Sixty-nine patients treated with R-CHOP plus epratuzumab were used in an initial cohort and 185 patients treated with standard R-CHOP served as a subsequent validation cohort. In the initial cohort, elevated serum IL-10 (interleukin-10; HR=6.6, p=0.022), GM-CSF (granulocyte macrophage colony-stimulating factor; HR=10.8, p=0.027) and IP-10 (interferon-inducible protein-10, CXCL10; HR=3.32, p=0.015) were associated with event-free survival (EFS). An identical analysis of the subsequent validation cohort confirmed that elevated serum levels of IP-10 were strongly associated with a poor EFS (HR=2.42, p= 0.0007); and also identified IL-8 (interleukin-8; HR=3.40, p= 0.00002) and IL-2R (interleukin-2 receptor, CD25; HR=2.59, p= 0.0012) as significantly associated with prognosis. The prognostic significance of elevated IP-10 remained significant after adjustment for the International Prognostic Index (IPI; EFS – HR 1.99, p=0.009, overall survival- HR 1.93, p=0.021). Elevated pretreatment serum IP-10 levels are therefore associated with an increased likelihood of disease relapse and an inferior survival in patients with DLBCL.
IP-10; CXCL10; cytokines; diffuse large B-cell lymphoma; prognosis
The complement pathway plays a central role in innate immunity, and also functions as a regulator of the overall immune response. We evaluated whether polymorphisms in complement genes are associated with event-free survival (EFS) in follicular (FL) and diffuse large B-cell (DLBCL) lymphoma. We genotyped 167 single nucleotide polymorphisms (SNPs) from 30 complement pathway genes in a prospective cohort study of newly diagnosed FL (N=107) and DLBCL (N=82) patients enrolled at the Mayo Clinic from 2002–2005. Cox regression was used to estimate Hazard Ratios (HRs) for individual SNPs with EFS, adjusting for FLIPI or IPI and treatment. For gene-level analyses, we used a principal components based gene-level test. In gene-level analyses for FL EFS, CFH (p=0.009), CD55 (p=0.006), CFHR5 (p=0.01), C9 (p=0.02), CFHR1 (p=0.03), and CD46 (p=0.03) were significant at p<0.05, and these genes remained noteworthy after accounting for multiple testing (q<0.15). SNPs in CFH, CFHR1, and CFHR5 showed stronger associations among patients receiving any rituximab, while SNPs from CD55 and CD46 showed stronger associations among patients who were observed. For DLBCL, only CLU (p=0.001) and C7 (p=0.03) were associated with EFS, but did not remain noteworthy after accounting for multiple testing (q>0.15). Genes from the Regulators of Complement Activation (CFH, CD55, CFHR1, CFHR5, CD46) at 1q32-q32.1, along with C9, were associated with FL EFS after adjusting for clinical variables, and if replicated, these findings add further support for the role of host innate immunity in FL prognosis.
non-Hodgkin lymphoma; complement pathway; SNPs; prognosis; prospective cohort
Childbearing at an older age has been associated with a lower risk of endometrial cancer, but whether the association is independent of the number of births or other factors remains unclear. Individual-level data from 4 cohort and 13 case-control studies in the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 8,671 cases of endometrial cancer and 16,562 controls were included in the analysis. After adjustment for known risk factors, endometrial cancer risk declined with increasing age at last birth (Ptrend < 0.0001). The pooled odds ratio per 5-year increase in age at last birth was 0.87 (95% confidence interval: 0.85, 0.90). Women who last gave birth at 40 years of age or older had a 44% decreased risk compared with women who had their last birth under the age of 25 years (95% confidence interval: 47, 66). The protective association was similar across the different age-at-diagnosis groups and for the 2 major tumor histologic subtypes (type I and type II). No effect modification was observed by body mass index, parity, or exogenous hormone use. In this large pooled analysis, late age at last birth was independently associated with a reduced risk of endometrial cancer, and the reduced risk persisted for many years.
endometrial neoplasms; parity; reproductive history
Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant precursor to multiple myeloma (MM). Though several genetic variants have been identified for MM, none have been identified for MGUS. Recently, Broderick et al. conducted a GWAS of MM and identified three novel loci at 3p22.1 (rs1052501), 7p15.3 (rs4487645) and 2p23.3 (rs6746082) associated with MM risk. We examined the association of these variants with MGUS in a clinic-based case-control study of 391 MGUS cases and 365 controls. We also attempted to replicate the reported association with MM (243 MM cases, 365 controls). We found rs1052501 associated with increased risk of both MGUS (OR=1.32; 95% CI, 1.02 to 1.72; p=0.04) and MM (OR=1.39; 95% CI, 1.04, 1.86; p=0.03). However, there were no associations with the other two loci, rs6746082 and rs4487645, for either MGUS or MM. We identified one genetic variant that may exert its influence on MM through its association with MGUS.
genetic variation; MGUS; MM; single nucleotide polymorphism
Follicular lymphoma (FL) has variable progression and survival, and improved identification of patients at high risk for progression would aid in identifying patients most likely to benefit from alternative therapy. In a sample of 244 FL cases identified during a population-based case-control study of non-Hodgkin lymphoma (NHL), we examined 6,679 tag SNPs in 488 gene regions for associations with overall FL survival. Over a median follow-up of 89 months with 65 deaths in this preliminary study, we identified 5 gene regions (BMP7, GALNT12, DUSP2, GADD45B, and ADAM17) that were associated with overall survival from FL. Results did not meet the criteria for statistical significance after adjustment for multiple hypothesis testing. These results, which support a role for host factors in determining the variable progression of FL, serve as an initial examination that can inform future studies of genetic variation and FL survival. However, they require replication in independent populations, as well as assessment in rituximab-treated patients.
follicular lymphoma; genetic variation; survival; tag SNP; case-control study
Although a few previous studies have reported positive associations between adult myeloid leukemia and a history of certain medical conditions, the etiology of most cases remains largely unknown. Our purpose was to examine associations between certain medical conditions and adult myeloid leukemia.
Using logistic regression, we evaluated associations between 16 self-reported medical conditions and myeloid leukemia in a case–control study of 670 cases [including 420 acute myeloid leukemia (AML) and 186 chronic myelogenous leukemia (CML)] and 701 population-based controls.
We observed significant positive associations between AML and ulcerative colitis (odds ratio (OR) = 3.8; 95 % confidence interval (CI), 1.1–13) and between CML and peptic ulcer (OR = 2.0; 95% CI, 1.1–3.8). A personal cancer history increased both AML (OR = 2.6; 95% CI, 1.7–3.9) and CML (OR = 3.5; 95% CI, 2.0–5.8) risk even after excluding individuals who reported prior radiation and/or chemotherapy treatment.
Certain inflammatory medical conditions and a personal history of cancer, independent from therapy, are associated with an increased risk of myeloid leukemia.
Acute myeloid leukemia; Chronic myeloid leukemia; Autoimmune disorders; Medical conditions
Both LMO2 mRNA and protein expression in diffuse large B-cell lymphoma (DLBCL) have been associated with superior survival; however, a role for germline genetic variation in LMO2 has not been previously reported. Immunohistochemistry (IHC) for LMO2 was conducted on tumor tissue from diagnostic biopsies, and 20 tag single nucleotide polymorphisms (SNPs) from LMO2 were genotyped from germline DNA. LMO2 IHC positivity was associated with superior survival (HR=0.55; 95% CI 0.31–0.97). Four LMO2 SNPs (rs10836127, rs941940, rs750781, rs1885524) were associated with survival after adjusting for LMO2 IHC and clinical factors (p<0.05), and one of these SNPs (rs941940) was also associated with IHC positivity (p=0.02). Compared to a model with clinical factors only (c-statistic=0.676), adding the 4 SNPs (c-statistic=0.751) or LMO2 IHC (c-statistic=0.691) increased the predictive ability of the model, while inclusion of all 3 factors (c-statistic=0.754) did not meaningfully add predictive ability above a model with clinical factors and the 4 SNPs. In conclusion, germline genetic variation in LMO2 was associated with DLBCL prognosis and provided slightly stronger predictive ability relative to LMO2 IHC status.
Diffuse large B-cell lymphoma; LMO2; prognosis; single nucleotide polymorphisms
To determine the incidence of monoclonal gammopathy of undetermined significance (MGUS) in the general population and to estimate the duration of occult MGUS before first diagnosis.
To estimate incidence we used innovative methods to exploit the Olmsted County, Minnesota, MGUS prevalence data, along with follow-up from a large cohort of patients with clinically detected MGUS. The prevalence cohort consisted of 21,463 persons systematically screened for the presence or absence of MGUS. The clinical cohort consisted of 7472 patients with MGUS diagnosed at Mayo Clinic from January 1, 1990, to May 13, 2010. The incidence of MGUS was estimated using the prevalence estimates, the rate of MGUS progression, and the death rates from MGUS using Markov chain methods.
We estimate that the annual incidence of MGUS in men is 120 per 100,000 population at the age of 50 years and increases to 530 per 100,000 population at the age of 90 years. The rates for women are 60 per 100,000 population at the age of 50 years and 370 per 100,000 population at the age of 90 years. We estimate that 56% of women 70 years of age diagnosed as having MGUS have had the condition for more than 10 years, including 28% for more than 20 years. Corresponding values for men are 55% and 31%, respectively. At 60 years of age, the proportion of prevalent cases that are clinically recognized is 13%. This rate increases to 33% at the age of 80 years.
In addition to an accumulation of cases, the age-related increase in prevalence of MGUS is related to a true increase in incidence with age. When first clinically recognized, MGUS has likely been present in an undetected state for a median duration of more than 10 years.
MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; SPEP, serum protein electrophoresis
The serum free light chain (FLC) assay quantitates free immunoglobulin kappa and lambda light chains, which has prognostic value in plasma cell dyscrasias. However, there is limited data on serum FLC in lymphoid malignancies. We analyzed the association of pretreatment FLC with event-free survival (EFS) and overall survival (OS) in 100 patients with Hodgkin lymphoma (HL). Elevated polyclonal FLC were present in 30% of patients; these patients had an inferior EFS (HR = 4.84; 95% CI: 1.84–12.7) and OS (HR = 8.87; 95% CI: 2.35–33.52) compared to patients with normal FLC. Further studies of FLC in HL are warranted.
Postmenopausal hormone (PMH) therapy may reduce colorectal cancer (CRC) risk, but existing data are inconclusive.
To evaluate associations between PMH therapy and incident CRC, overall and by molecularly defined subtypes, in the population-based Iowa Women’s Health Study of older women.
Exposure data were collected from Iowa Women’s Health Study participants (55–69 years) at baseline (1986). Archived, paraffin-embedded tissue specimens for 553 CRC cases were collected and analysed to determine microsatellite instability (MSI-L/MSS or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive) and BRAF mutation (BRAF-wildtype or BRAF-mutated) status. Multivariable Cox regression models were fit to estimate RRs and 95% CIs.
PMH therapy (ever vs never use) was inversely associated with incident CRC overall (RR=0.82; 95% CI 0.72 to 0.93), with a significantly lower risk for MSI-L/MSS tumours (RR=0.75; 95% CI 0.60 to 0.94), and borderline significantly lower risks for CIMP-negative (RR=0.79; 95% CI 0.63 to 1.01) and BRAF-wildtype (RR=0.83; 95% CI 0.66 to 1.04) tumours. For PMH therapy >5 years, the subtype-specific risk estimates for MSI-L/MSS, CIMP-negative and BRAF-wildtype tumours were: RR=0.60, 95% CI 0.40 to 0.91; RR=0.68, 95% CI 0.45 to 1.03; and RR=0.70, 95% CI 0.47 to 1.05, respectively. PMH therapy was not significantly associated with the MSI-H, CIMP-positive or BRAF-mutated CRC subtypes.
In this prospective cohort study, PMH therapy was inversely associated with distinct molecularly defined CRC subtypes, which may be related to differential effects from oestrogen and/or progestin on heterogeneous pathways of colorectal carcinogenesis.
Residence near municipal solid waste incinerators, a major historical source of dioxin emissions, has been associated with increased risk of non-Hodgkin lymphoma (NHL) in European studies. The aim of our study was to evaluate residence near industrial combustion facilities and estimates of dioxin emissions in relation to NHL risk in the United States.
We conducted a population-based case–control study of NHL (1998–2000) in four National Cancer Institute-Surveillance Epidemiology and End Results centers (Detroit, Iowa, Los Angeles, Seattle). Residential histories 15 years before diagnosis (similar date for controls) were linked to an Environmental Protection Agency database of dioxin-emitting facilities for 969 cases and 749 controls. We evaluated proximity (3 and 5 km) to 10 facility types that accounted for >85% of U.S. emissions and a distance-weighted average emission index (AEI [ng toxic equivalency quotient (TEQ)/year]).
Proximity to any dioxin-emitting facility was not associated with NHL risk (3 km OR = 1.0, 95% CI 0.8-1.3). Risk was elevated for residence near cement kilns (5 km OR = 1.7, 95% CI 0.8-3.3; 3 km OR = 3.8, 95% CI 1.1-14.0) and reduced for residence near municipal solid waste incinerators (5 km OR = 0.5, 95% CI 0.3-0.9; 3 km OR = 0.3, 95% CI 0.1-1.4). The AEI was not associated with risk of NHL overall. Risk for marginal zone lymphoma was increased for the highest versus lowest quartile (5 km OR = 2.6, 95% CI 1.0-6.8; 3 km OR = 3.0, 95% CI 1.1-8.3).
Overall, we found no association with residential exposure to dioxins and NHL risk. However, findings for high emissions and marginal zone lymphoma and for specific facility types and all NHL provide some evidence of an association and deserve future study.
Non-Hodgkin lymphoma; Lymphomas; Dioxins; Air pollution; Geographic information systems; Case–control study
Few risk factors for meningioma, aside from increasing age and female sex, have been identified. We investigated risk factors for meningioma in elderly women, a group with a high incidence. We evaluated associations of demographic, lifestyle, medical history, and anthropometric variables with risk of meningioma in the Iowa Women's Health Study (IWHS), a population-based, prospective cohort study. Risk factors were collected via questionnaires mailed in 1986 and 1992. Incident meningiomas were identified via linkages to Medicare. Cox regression models were used to examine the association of risk factors with meningioma incidence. The mean age at baseline of the 27,791 women in the analysis cohort was 69.3 years (range, 65.0–84.6 years). During 291,021 person-years of follow-up, 125 incident meningiomas were identified. After adjusting for age, lower levels of physical activity (relative risk [RR] , 0.68 for high versus low; P for trend = .039), greater body mass index (BMI; RR, 2.14 for ≥35 versus 19.5–24.9 kg/m2; P for trend = .0019), greater height (RR, 2.04 for >66 versus ≤62 inches; P for trend = .013), and a history of uterine fibroids (RR, 1.72; 95% confidence interval, 1.19, 2.50) were positively associated with meningioma risk in multivariate analysis. BMI at age 18 and 30 years were not associated with risk. There were no associations with menstrual or reproductive factors or other medical history and lifestyle factors. Physical activity, BMI, height, and history of uterine fibroids were associated with meningioma risk in older women. The positive association with height suggests a role for early life influences on risk, whereas the associations with BMI and physical activity suggest a role for modifiable factors later in life.
cohort studies; epidemiology; primary brain tumor; risk factors
To evaluate whether germline variations in genes involved in sex steroid biosynthesis and metabolic pathways predict time to treatment failure for patients with advanced prostate cancer undergoing androgen deprivation therapy (ADT), because there are few known clinical predictors of response.
Patients and Methods
In a cohort of 304 patients with advanced prostate cancer undergoing ADT, we genotyped 746 single-nucleotide polymorphisms (SNPs) from 72 genes from germline DNA (680 tagSNPs from 58 genes and 66 candidate SNPs from 20 genes [6 genes common in both]). Association with the primary end point of time to ADT failure was assessed using proportional hazards regression models at the gene level (for genes with tagging SNPs) and at the SNP level. False discovery rates (FDRs) of 0.10 or less were considered noteworthy to account for multiple testing.
At the gene level, TRMT11 showed the strongest association with time to ADT failure (P<.001; FDR=0.008). Two of 4 TRMT11 tagSNPs were associated with time to ADT failure. Median time to ADT failure for rs1268121 (A>G) was 3.05 years for the AA, 4.27 years for the AG, and 6.22 years for the GG genotypes (P=.002), and for rs6900796 (G>A), it was 2.42 years for the GG, 3.52 years for the AG, and 4.18 years for the AA genotypes (P<.001). No other gene level or SNP level tests had an FDR of 0.10 or less.
Genetic variation in TRMT11 was associated with time to ADT failure. Confirmation of these preliminary findings in an independent cohort is needed.
The t(14;18) chromosomal translocation is the most common cytogenetic abnormality in NHL, occurring in 70–90% of follicular lymphomas (FL) and 30–50% of diffuse large B-cell lymphomas (DLBCL). Previous t(14;18)-NHL studies have not evaluated risk factors for NHL defined by both t(14;18) status and histology. In this population-based case-control study, t(14;18) status was determined in DLBCL cases using fluorescence in situ hybridization on paraffin-embedded tumor sections. Polytomous logistic regression was used to evaluate the association between a wide variety of exposures and t(14;18)-positive (N=109) and −negative DLBCL (N=125) and FL (N=318), adjusting for sex, age, race and study center. Taller height, more lifetime surgeries, and PCB180 exposure were associated with t(14;18)-positivity. Taller individuals (3rd tertile vs. 1st tertile) had elevated risks of t(14;18)-positive DLBCL [odds ratio (OR)=1.8, 95% confidence interval (CI) 1.1–3.0] and FL (OR=1.4, 95%CI 1.0–1.9) but not t(14;18)-negative DLBCL. Similar patterns were seen for individuals with more lifetime surgeries [13+ versus 0–12 surgeries; t(14;18)-positive DLBCL OR=1.4, 95%CI 0.7–2.7; FL OR=1.6, 95%CI 1.1–2.5] and individuals exposed to PCB180 greater than 20.8 ng/g [t(14;18)-positive DLBCL OR=1.3, 95%CI 0.6–2.9; FL OR=1.7, 95%CI 1.0–2.8]. In contrast, termite treatment and high alpha-chlordane levels were associated with t(14;18)-negative DLBCL only, suggesting that these exposures do not act through t(14;18). Our findings suggest that putative associations between NHL and height, surgeries, and PCB180 may be t(14;18)-mediated and provide support for case-subtyping based on molecular and histologic subtypes. Future efforts should focus on pooling data to confirm and extend previous research on risk factors for t(14;18)-NHL subtypes.
lymphoma; non-Hodgkin; case–control studies; translocation; follicular lymphoma; diffuse large B-cell lymphoma; etiology
Little is known about the causes of adult leukemia. A few small studies have reported a reduced risk associated with regular use of non-steroidal anti-inflammatory drugs (NSAIDs).
In a population-based case-control study, we evaluated analgesic use among 670 newly diagnosed myeloid leukemia cases [including 420 acute myeloid leukemias (AML) and 186 chronic myeloid leukemias (CML)] and 701 controls aged 20–79 years. Prior use of aspirin, ibuprofen, acetaminophen, other NSAIDs, and cyclooxygenase-2 (COX-2) inhibitors was assessed and included frequency, duration, and quantity. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression adjusting for potential confounders.
Regular/extra strength aspirin use was inversely associated with myeloid leukemia in women (OR=0.59, 95%CI=0.37–0.93) but not men (OR=0.85, 95%CI=0.58–1.24). In contrast, acetaminophen use was associated with an increased risk of myeloid leukemia in women only (OR=1.60, 95%CI=1.04–2.47). These relationships were stronger with increasing dose and duration. When stratified by leukemia type, aspirin use was inversely associated with AML and CML in women. No significant overall associations were found with ibuprofen or COX-2 inhibitors for either sex; however, a decreased risk was observed with other anti-inflammatory analgesic use for women with AML or CML (OR=0.47, 95%CI=0.22–0.99; OR=0.31, 95%CI=0.10–0.92, respectively).
Our results provide additional support for the chemopreventive benefits of NSAIDs, at least in women. Since leukemia ranks fifth in person years of life lost due to malignancy, further investigation is warranted.
NSAIDs may reduce, while acetaminophen may increase, myeloid leukemia risk in women.
aspirin; leukemia; NSAIDs; acetaminophen; prevention
Ingested nitrate can be endogenously reduced to nitrite, which may form N-nitroso compounds, known potent carcinogens. However, some studies have reported no or inverse associations between dietary nitrate intake and cancer risk. These associations may be confounded by a protective effect of folate, which plays a vital role in DNA repair. We evaluated the interaction of dietary and water nitrate intake with total folate intake on breast cancer risk in the Iowa Women’s Health Study. Dietary intake was assessed at study baseline. Nitrate intake from public water was assessed using a historical database on Iowa municipal water supplies. After baseline exclusions, 34,388 postmenopausal women and 2,875 incident breast cancers were included. Overall, neither dietary nor water nitrate was associated with breast cancer risk. Among those with folate intake ≥400 μg/d, breast cancer risk was significantly increased in public water users with the highest nitrate quintile (HR=1.40, 95%CI=1.05–1.87) and private well users (HR=1.38, 95%CI=1.05–1.82) compared to public water users with the lowest nitrate quintile; in contrast, there was no association among those with lower folate intake. Our findings do not support a previous report of increased risk of breast cancer among individuals with high dietary nitrate but low folate intake.
nitrate; folate; interaction; breast cancer; epidemiological
Mammographic percent density (PD) is a strong risk factor for breast cancer, but there has been relatively little systematic evaluation of other features in mammographic images that might additionally predict breast cancer risk. We evaluated the association of a large number of image texture features with risk of breast cancer using a clinic-based case-control study of digitized film mammograms, all with screening mammograms prior to breast cancer diagnosis. The sample was split into training (123 cases, 258 controls) and validation (123 cases, 264 controls) datasets. Age and body mass index (BMI)-adjusted Odds Ratios (ORs) per standard deviation change in the feature, 95% confidence intervals, and the area under the receiver operator characteristic curve (AUC) were obtained using logistic regression. A bootstrap approach was used to identify the strongest features in the training dataset, and results for features that validated in the second half of the sample were reported using the full dataset. The mean age at mammography was 64.0 ± 10.2 years, and the mean time from mammography to breast cancer was 3.7 ± 1.0 (range 2.0-5.9 years). PD was associated with breast cancer risk (OR=1.49; 1.25-1.78). The strongest features that validated from each of several classes (Markovian, run-length, Laws, wavelet and Fourier) showed similar ORs as PD and predicted breast cancer at a similar magnitude (AUC=0.58-0.60) as PD (AUC=0.58). All of these features were automatically calculated (unlike PD), and measure texture at a coarse scale. These features were moderately correlated with PD (r = 0.39-0.64), and after adjustment for PD, each of the features attenuated only slightly and retained statistical significance. However, simultaneous inclusion of these features in a model with PD did not significantly improve the ability to predict breast cancer.
mammographic density; computerized image analysis; breast cancer
The role of inherited (host) genetic susceptibility in the pathogenesis of follicular lymphoma (FL) is reviewed. First degree relatives of FL patients are at an increased risk of FL, suggesting a role for inherited factors. While there have been no linkage studies in FL families, candidate gene and genome-wide association studies have identified several risk loci which have been confirmed in independent studies. These include regions on 6p21.32-33 and TNF family members. Host genetics has also been hypothesized to influence treatment response, disease progression and overall survival. Early leads in FL prognosis include pathways that regulate immune function, antibody-dependent cellular cytotoxicity, chemotaxis, and one carbon metabolism, although few of these associations have been independently confirmed. While the use of host genetics to identify individuals at high risk of FL or to predict FL treatment response and prognosis appears to be very promising, it is not yet ready for the clinic.
follicular lymphoma; genetics; single nucleotide polymorphisms; risk; prognosis
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
The serum free light chain (FLC) assay quantitates free kappa (κ) and free lambda (λ) immunoglobulin light chains. This assay has prognostic value in plasma cell proliferative disorders. There are limited data on serum FLC in B-cell malignancies.
Patients and Methods
The association of pretreatment FLC with event-free survival (EFS) and overall survival (OS) in diffuse large B-cell lymphoma (DLBCL) was evaluated in 76 patients from the North Central Cancer Treatment Group trial N0489 (NCT00301821) and 219 patients from the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource (MER). Published reference ranges were used to define an elevated FLC or an abnormal κ:λ FLC ratio.
Elevated FLC or abnormal κ:λ FLC ratio was present in 32% and 14% of patients, respectively. Patients with elevated FLC had an inferior OS and EFS in both cohorts compared with patients with normal FLC (N0489: EFS hazard ratio [HR], 3.06; OS HR, 3.16; both P < .02; MER: EFS HR, 2.42; OS HR, 3.40; both P < .001; combined EFS HR, 2.57; OS HR, 3.74; both P < .001). All associations remained significant for EFS and OS after adjusting for the International Prognostic Index (IPI). Abnormal κ:λ FLC ratio was modestly associated with outcome in the combined group (EFS HR, 1.61; OS HR, 1.67; both P = .07), but not in patients without corresponding elevated κ or λ. Elevated FLC was the strongest predictor of outcome in multivariable models with the IPI components.
Increased serum FLC is an independent, adverse prognostic factor for EFS and OS in DLBCL and warrants further evaluation as a biomarker in DLBCL.
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