Over-expression of prostate-specific membrane antigen (PSMA) in tumor tissue and serum has been linked to increased risk of biochemical recurrence in surgically treated prostate cancer patients, but no studies have assessed its association with disease-specific mortality.
We examined whether high PSMA protein expression in prostate tumor tissue was associated with lethal disease, and with tumor biomarkers of progression, among participants of two US-based cohorts (n=902, diagnosed 1983–2004). We used Cox proportional hazards regression to calculate multivariable hazard ratios (HR) and 95% confidence intervals (CI) of lethal prostate cancer, defined as disease-specific death or development of distant metastases (n=95). Partial Spearman rank correlation coefficients were used to correlate PSMA with tumor biomarkers.
During an average 13 years of follow-up, higher PSMA expression at prostatectomy was significantly associated with lethal prostate cancer (age-adjusted HRQuartile(Q)4vs.Q1=2.42; p-trend<0.01). This association was attenuated and non-significant (multivariable-adjusted HRQ4vs.Q1=1.01; p-trend=0.52) after further adjusting for Gleason score and PSA at diagnosis. High PSMA expression was significantly (p<0.05) correlated with higher Gleason score and PSA at diagnosis, increased tumor angiogenesis, lower vitamin D receptor and androgen receptor expression, and absence of ERG expression.
High tumor PSMA expression was not an independent predictor of lethal prostate cancer in the current study. PSMA expression likely captures, in part, malignant features of Gleason grade and tumor angiogenesis.
PSMA is not a strong candidate biomarker for predicting prostate cancer-specific mortality in surgically treated patients.
prostate-specific membrane antigen; prostate cancer; tumor biomarkers; prognosis; angiogenesis
Data suggest that circulating 25-hydroxyvitamin D [25(OH)D] interacts with the vitamin D receptor (VDR) to decrease proliferation and increase apoptosis for some malignancies, although evidence for prostate cancer is less clear. How VDR expression in tumor tissue may influence prostate cancer progression has not been evaluated in large studies.
Patients and Methods
We examined protein expression of VDR in tumor tissue among 841 patients with prostate cancer in relation to risk of lethal prostate cancer within two prospective cohorts, the Physicians' Health Study and Health Professionals Follow-Up Study. We also examined the association of VDR expression with prediagnostic circulating 25(OH)D and 1,25-dihydroxyvitamin D levels and with two VDR single nucleotide polymorphisms, FokI and BsmI.
Men whose tumors had high VDR expression had significantly lower prostate-specific antigen (PSA) at diagnosis (P for trend < .001), lower Gleason score (P for trend < .001), and less advanced tumor stage (P for trend < .001) and were more likely to have tumors harboring the TMPRSS2:ERG fusion (P for trend = .009). Compared with the lowest quartile, men whose tumors had the highest VDR expression had significantly reduced risk of lethal prostate cancer (hazard ratio [HR], 0.17; 95% CI, 0.07 to 0.41). This association was only slightly attenuated after adjustment for Gleason score and PSA at diagnosis (HR, 0.33; 95% CI, 0.13 to 0.83) or, additionally, for tumor stage (HR, 0.37; 95% CI, 0.14 to 0.94). Neither prediagnostic plasma vitamin D levels nor VDR polymorphisms were associated with VDR expression.
High VDR expression in prostate tumors is associated with a reduced risk of lethal cancer, suggesting a role of the vitamin D pathway in prostate cancer progression.
Epidemiologic evidence on the association of antioxidant intake and prostate cancer incidence is inconsistent. Total antioxidant intake and prostate cancer incidence has not previously been examined. Using the ferric reducing antioxidant potential (FRAP) assay, the total antioxidant content (TAC) of diet and supplements were assessed in relation to prostate cancer incidence. A prospective cohort of 47,896 men aged 40-75 years was followed from 1986 to 2008 for prostate cancer incidence (N=5,656), and they completed food frequency questionnaires (FFQ) every 4 years. A FRAP value was assigned to each item in the FFQ, and for each individual, TAC scores for diet, supplements and both (total) were calculated. Major contributors of TAC intake at baseline were: coffee (28%), fruit and vegetables (23%) and dietary supplements (23%). In multivariate analyses for dietary TAC a weak inverse association was observed; (highest versus lowest quintiles: 0.91 (0.83-1.00, p-trend=0.03) for total prostate cancer, 0.81 (0.64-1.01, p-trend=0.04) for advanced prostate cancer); this association was mainly due to coffee. No association of total TAC on prostate cancer incidence was observed. A positive association with lethal and advanced prostate cancer was observed in the highest quintile of supplemental TAC intake: 1.28 (0.98-1.65, p-trend<0.01) and 1.15 (0.92-1.43), p-trend=0.04). The weak association between dietary antioxidant intake and reduced prostate cancer incidence may be related to specific antioxidants in coffee, to non-antioxidant coffee compounds, or other effects of drinking coffee. The indication of increased risk for lethal and advanced prostate cancer with high TAC intake from supplements warrants further investigation.
Prostate cancer; Antioxidants; Oxidative stress; Diet; Risk factors
Nutritional and genetic determinants of the one-carbon metabolism pathway have been related to risk of malignant lymphomas, but little is known about their associations with Hodgkin lymphoma risk specifically. The authors examined nutrient intake (folate, vitamin B2, vitamin B6, vitamin B12, methionine) and multivitamin use among 497 Hodgkin lymphoma patients and 638 population-based controls (Massachusetts and Connecticut, 1997–2000), and genetic variation (MTHFR 677C>T, MTHFR 1298A>C, MTR 2756A>G, SHMT1 1420C>T, TYMS 1494del6) and gene-diet interactions in a subset. Unconditional logistic regression was used to calculate multivariable odds ratios and 95% confidence intervals. Hodgkin lymphoma risk was not associated with total nutrient intake or intake from food alone (excluding supplements). Multivitamin use (odds ratio (OR) = 1.46, 95% CI: 1.09, 1.96), total vitamin B6 (ORquartile 4 vs. 1 = 1.62) (Ptrend = 0.03), and total vitamin B12 (ORquartile 4 vs. 1 = 1.75) (Ptrend = 0.02) intakes were positively associated with risk of Epstein-Barr virus-negative, but not -positive, disease. The 5 genetic variants were not significantly associated with Hodgkin lymphoma risk; no significant gene-diet interactions were observed after Bonferroni correction. Study findings do not support a strong role for nutrients and genetic variation in the one-carbon metabolism pathway in susceptibility to Hodgkin lymphoma. Associations between diet and risk of Epstein-Barr virus-negative disease require confirmation in other populations.
case-control studies; diet; folic acid; Hodgkin disease; vitamins
To study associations between single nucleotide polymorphisms (SNPs) in RNASEL, a gene implicated in inflammation and prostate cancer risk, and outcomes following radiation therapy (RT).
We followed participants in the prospective US Health Professionals Follow-Up Study treated with RT for early-stage prostate cancer. Three SNPs were genotyped based on previously determined functional and biological significance. We used multivariable Cox proportional hazards models to assess per-allele associations with the primary outcome defined as time to a composite endpoint including development of lethal prostate cancer or biochemical recurrence.
We followed 434 patients treated with RT for a median of 9 years. On multivariate analysis, the rs12757998 variant allele was associated with significantly decreased risk of the composite endpoint (HR: 0.65; 95% CI: 0.45–0.94; p = 0.02) driven by decreased biochemical recurrence (HR: 0.60; 95% CI: 0.40 – 0.89; p = 0.01) and men treated with external beam (HR: 0.58; 95% CI: 0.36 – 0.93; p = 0.02). In contrast, in 516 men from the same cohort treated with radical prostatectomy, we found no significant impact of this variant on outcome. Furthermore, the rs12757998 variant allele significantly modified the association between androgen deprivation therapy and outcomes following RT (p-interaction = 0.02).
We demonstrate an association between RNASEL SNP rs12757998 and outcome after RT for prostate cancer. This SNP is associated with increased circulating C-reactive protein and interleukin-6, suggesting a potential role for inflammation in the response to radiation. If validated, genetic predictors of outcome may help inform prostate cancer management.
prostate cancer; radiotherapy; inflammation; outcome; single nucleotide polymorphism
Although dietary fat has been associated with prostate cancer risk, the association between specific fatty acids and prostate cancer survival remains unclear. Dietary intake of 14 fatty acids was analyzed in a population-based cohort of 525 Swedish men with prostate cancer in Örebro County (1989–1994). Multivariable hazard ratios and 95% confidence intervals for time to prostate cancer death by quartile and per standard deviation increase in intake were estimated by Cox proportional hazards regression. Additional models examined the association by stage at diagnosis (localized: T0-T2/M0; advanced: T0-T4/M1, T3-T4/M0). Among all men, those with the highest omega-3 docosahexaenoic acid and total marine fatty acid intakes were 40% less likely to die from prostate cancer (Ptrend = 0.05 and 0.04, respectively). Among men with localized prostate cancer, hazard ratios of 2.07 (95% confidence interval: 0.93, 4.59; Ptrend = 0.03) for elevated total fat, 2.39 (95% confidence interval: 1.06, 5.38) for saturated myristic acid, and 2.88 (95% confidence interval: 1.24, 6.67) for shorter chain (C4-C10) fatty acid intakes demonstrated increased risk for disease-specific mortality for the highest quartile compared with the lowest quartile. This study suggests that high intake of total fat and certain saturated fatty acids may worsen prostate cancer survival, particularly among men with localized disease. In contrast, high marine omega-3 fatty acid intake may improve disease-specific survival for all men.
fatty acids; prostatic neoplasms; survival analysis
Recent studies suggest variation in genes along the vitamin D pathway, as well as vitamin D receptor (VDR) protein levels, may be associated with prostate cancer. As serum vitamin D levels vary by season, we sought to determine whether expression of genes on the vitamin D pathway, assessed in prostate tumor tissue, do the same.
Our study incorporates mRNA expression data from 362 men in the Swedish Watchful Waiting cohort, diagnosed between 1977 and 1999, and 106 men enrolled in the US Physicians’ Health Study (PHS) diagnosed between 1983 and 2004. We also assayed for VDR protein expression among 832 men in the PHS and Health Professionals Follow-up Study cohorts. Season was characterized by date of initial tissue specimen collection categorically and by average monthly ultraviolet radiation levels. One-way analysis of variance was used to examine variation in expression levels of six genes on the vitamin D pathway – VDR, GC, CYP27A1, CYP27B1, RXRα, CYP24A1 – and VDR protein by season, adjusted for age at diagnosis and Gleason grade. Variation was also examined separately among lethal and nonlethal cases.
Tumor expression levels of the six genes did not significantly vary by season of tissue collection. No consistent patterns emerged from subgroup analyses by lethal versus nonlethal cases.
Unlike circulating levels of 25-OH vitamin D, expression levels of genes on the vitamin D pathway and VDR protein did not vary overall by season of tissue collection. Epidemiological analyses of vitamin D gene expression may not be biased by seasonality.
Vitamin D; Vitamin D receptor; prostate cancer; gene expression; seasonality; biomarkers
The safety of antioxidant supplements during radiation therapy (RT) for cancer is controversial. Antioxidants could potentially counteract the pro-oxidant effects of RT and compromise therapeutic efficacy. We performed a prospective study nested within the Physicians' Health Study (PHS) randomized trial to determine if supplemental antioxidant use during RT for prostate cancer is associated with an increased risk of prostate cancer death or metastases.
Methods and Materials
383 PHS participants received RT for prostate cancer while randomized to beta-carotene (50 mg on alternate days), or placebo. The primary endpoint was time from RT to lethal prostate cancer, defined as prostate cancer death or bone metastases. The Kaplan-Meier method was used to estimate survival probabilities, and the log-rank test to compare groups. Cox proportional hazards regression was used to estimate the effect of beta-carotene compared with placebo during RT.
With a median follow-up of 10.5 years, there was no significant difference in risk of lethal prostate cancer with use of beta-carotene during RT compared with placebo (HR=0.72; 95% CI, 0.42 to 1.24; P=0.24). After adjusting for age at RT, PSA, Gleason score, and clinical stage, the difference remained non-significant. The 10-year freedom from lethal prostate cancer was 92% (95% CI, 87-95%) in the beta-carotene group and 89% (95% CI, 84-93%) in the placebo group.
Use of the supplemental antioxidant, beta-carotene, during RT was not associated with an increased risk of prostate cancer death or metastases. This study suggests a lack of harm from supplemental beta-carotene during radiation therapy for prostate cancer.
Antioxidants; prostate cancer; vitamins; beta-carotene; outcomes
To examine whether fish and fish oil consumption across the lifespan is associated with a lower risk of prostate cancer.
The study was nested among 2268 men aged 67–96 years in the AGES-Reykjavik cohort study. In 2002 to 2006, dietary habits were assessed, for early life, midlife and later life using a validated food frequency questionnaire. Participants were followed for prostate cancer diagnosis and mortality through 2009 via linkage to nationwide cancer- and mortality registers. Adjusting for potential confounders, we used regression models to estimate odds ratios (ORs) and hazard ratios (HRs) for prostate cancer according to fish and fish oil consumption.
Among the 2268 men, we ascertained 214 prevalent and 133 incident prostate cancer cases, of which 63 had advanced disease. High fish consumption in early- and midlife was not associated with overall or advanced prostate cancer. High intake of salted or smoked fish was associated with a 2-fold increased risk of advanced prostate cancer both in early life (95% CI: 1.08, 3.62) and in later life (95% CI: 1.04, 5.00). Men consuming fish oil in later life had a lower risk of advanced prostate cancer [HR (95%CI): 0.43 (0.19, 0.95)], no association was found for early life or midlife consumption.
Salted or smoked fish may increase risk of advanced prostate cancer, whereas fish oil consumption may be protective against progression of prostate cancer in elderly men. In a setting with very high fish consumption, no association was found between overall fish consumption in early or midlife and prostate cancer risk.
Whether milk and dairy intake after a prostate cancer diagnosis is associated with a poorer prognosis is unknown. We investigated post-diagnostic milk and dairy intake in relation to risk of lethal prostate cancer (metastases and prostate cancer death) among participants in the Health Professionals Follow-Up Study.
The cohort consisted of 3,918 men diagnosed with apparently localized prostate cancer between 1986 and 2006, and followed to 2008. Data on milk and dairy intake were available from repeated questionnaires. We used Cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence intervals (CI) of the association between post-diagnostic milk and dairy intake and prostate cancer outcomes.
We ascertained 229 prostate cancer deaths and an additional 69 metastases during follow-up. In multivariate analysis, total milk and dairy intakes after diagnosis were not associated with a greater risk of lethal prostate cancer. Men with the highest versus lowest intake of whole milk were at an increased risk of progression (HR 2.15; 95% CI: 1.28-3.60; P trend<0.01). Men in the highest versus lowest quintile of low-fat dairy intake were at a decreased risk of progression (HR 0.62; 95% CI: 0.40-0.95; P trend=0.07).
With the exception of whole milk, our results suggest that milk and dairy intake after a prostate cancer diagnosis is not associated with an increased risk of lethal prostate cancer.
This is the first larger prospective study investigating the relation between post-diagnostic milk and dairy intake and risk of lethal prostate cancer.
To determine whether consumption of whole-grain; rye bread, oatmeal, and whole-wheat bread, during different periods of life, is associated with risk of prostate cancer (PCa).
In 2002 to 2006, 2,268 men, aged 67-96 years, reported their dietary habits in the AGES-Reykjavik cohort study. Dietary habits were assessed for early-, mid- , and current life using a validated food frequency questionnaire (FFQ). Through linkage to cancer- and mortality registers, we retrieved information on PCa diagnosis and mortality through 2009. We used regression models to estimate odds ratios (ORs) and hazard ratios (HRs) for PCa according to whole grain consumption, adjusted for possible confounding factors including fish-, fish liver oil-, meat-, and milk intake.
Of the 2,268 men, 347 had or were diagnosed with PCa during follow-up, 63 with advanced disease (stage 3+ or died of PCa). Daily rye bread consumption in adolescence (vs. less than daily) was associated with a decreased risk of PCa diagnosis (OR = 0.76, 95% Confidence interval (CI): 0.59-0.98), and of advanced PCa (OR = 0.47, 95% CI: 0.27-0.84). High intake of oatmeal in adolescence (≥5 vs. ≤4 times/ week) was not significantly associated with risk of PCa diagnosis (OR = 0.99, 95% CI: 0.77-1.27) nor advanced PCa (OR = 0.67, 95% CI: 0.37-1.20). Mid-, and late life consumption of rye bread, oatmeal, or whole-wheat bread was not associated with PCa risk.
Our results suggest that rye bread consumption in adolescence may be associated with reduced risk of PCa, particularly advanced disease.
adolescent; diet; epidemiology; rye bread; prostatic neoplasms; whole-grain; AGES Reykjavik study
The authors investigated whether early-life residency in certain areas of Iceland marked by distinct differences in milk intake was associated with risk of prostate cancer in a population-based cohort of 8,894 men born between 1907 and 1935. Through linkage to cancer and mortality registers, the men were followed for prostate cancer diagnosis and mortality from study entry (in waves from 1967 to 1987) through 2009. In 2002–2006, a subgroup of 2,268 participants reported their milk intake in early, mid-, and current life. During a mean follow-up period of 24.3 years, 1,123 men were diagnosed with prostate cancer, including 371 with advanced disease (stage 3 or higher or prostate cancer death). Compared with early-life residency in the capital area, rural residency in the first 20 years of life was marginally associated with increased risk of advanced prostate cancer (hazard ratio = 1.29, 95% confidence interval (CI): 0.97, 1.73), particularly among men born before 1920 (hazard ratio = 1.64, 95% CI: 1.06, 2.56). Daily milk consumption in adolescence (vs. less than daily), but not in midlife or currently, was associated with a 3.2-fold risk of advanced prostate cancer (95% CI: 1.25, 8.28). These data suggest that frequent milk intake in adolescence increases risk of advanced prostate cancer.
adolescent; diet; Iceland; milk; prostatic neoplasms; risk factors
We examined patient-reported outcomes among prostate cancer patients managed by watchful waiting (WW) in a nationwide cohort.
Materials and Methods
We collected treatment information and patient-reported outcomes from 1230 prostate cancer patients diagnosed with T1-T2 prostate cancer in the Physicians’ Health Study; 125 were initially managed by WW. Cox proportional-hazards regression was used to identify predictors of treatment initiation among WW patients. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) to assess disease-targeted quality of life by initial treatment or WW.
At 7.3 years’ mean follow-up, 41% of WW patients remained free of treatment while 34% underwent radiotherapy or brachytherapy, 16% underwent primary hormonal therapy, and 10% underwent prostatectomy. Younger age, higher clinical stage, higher Gleason score, and higher PSA at diagnosis predicted progression to treatment. Watchful waiting compared to immediate treatment was associated with less urinary incontinence (3.5% vs 10%) and impotence (68% vs 78%) but more common obstructive urinary symptoms (22% vs 13%) in univariate analyses (p< 0.05 for each), with incontinence and impotence differences remaining significant after adjustment for age, comorbidity, and time after cancer diagnosis. Quality of life outcomes among men who underwent delayed treatment after initially waiting were not worse than among men who underwent immediate treatment.
Our findings suggest quality of life benefits subsequent to WW among select patients with early-stage prostate cancer compared to men treated immediately following diagnosis. Younger age and greater cancer severity at diagnosis predicted progression to treatment.
watchful waiting; prostate cancer; prospective study; quality of life; outcomes
Coffee contains many biologically active compounds, including caffeine and phenolic acids, that have potent antioxidant activity and can affect glucose metabolism and sex hormone levels. Because of these biological activities, coffee may be associated with a reduced risk of prostate cancer.
We conducted a prospective analysis of 47 911 men in the Health Professionals Follow-up Study who reported intake of regular and decaffeinated coffee in 1986 and every 4 years thereafter. From 1986 to 2006, 5035 patients with prostate cancer were identified, including 642 patients with lethal prostate cancers, defined as fatal or metastatic. We used Cox proportional hazards models to assess the association between coffee and prostate cancer, adjusting for potential confounding by smoking, obesity, and other variables. All P values were from two-sided tests.
The average intake of coffee in 1986 was 1.9 cups per day. Men who consumed six or more cups per day had a lower adjusted relative risk for overall prostate cancer compared with nondrinkers (RR = 0.82, 95% confidence interval [CI] = 0.68 to 0.98, Ptrend = .10). The association was stronger for lethal prostate cancer (consumers of more than six cups of coffee per day: RR = 0.40, 95% CI = 0.22 to 0.75, Ptrend = .03). Coffee consumption was not associated with the risk of nonadvanced or low-grade cancers and was only weakly inversely associated with high-grade cancer. The inverse association with lethal cancer was similar for regular and decaffeinated coffee (each one cup per day increment: RR = 0.94, 95% CI = 0.88 to 1.01, P = .08 for regular coffee and RR = 0.91, 95% CI = 0.83 to 1.00, P = .05 for decaffeinated coffee). The age-adjusted incidence rates for men who had the highest (≥6 cups per day) and lowest (no coffee) coffee consumption were 425 and 519 total prostate cancers, respectively, per 100 000 person-years and 34 and 79 lethal prostate cancers, respectively, per 100 000 person-years.
We observed a strong inverse association between coffee consumption and risk of lethal prostate cancer. The association appears to be related to non-caffeine components of coffee.
Laboratory evidence suggests that vitamin D might influence prostate cancer prognosis.
We examined the associations between prediagnostic plasma levels of 25(OH)vitamin D [25(OH)D] and 1,25(OH)2vitamin D [1,25(OH)2D] and mortality among 1822 participants of the Health Professionals Follow-up Study and Physicians' Health Study who were diagnosed with prostate cancer. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of total mortality (n = 595) and lethal prostate cancer (death from prostate cancer or development of bone metastases; n = 202). In models adjusted for age at diagnosis, BMI, physical activity, and smoking, we observed a HR of 1.22 (95% CI: 0.97, 1.54) for total mortality, comparing men in the lowest to the highest quartile of 25(OH)D. There was no association between 1,25(OH)2D and total mortality. Men with the lowest 25(OH)D quartile were more likely to die of their cancer (HR: 1.59; 95% CI: 1.06, 2.39) compared to those in the highest quartile (Ptrend = 0.006). This association was largely explained by the association between low 25(OH)D levels and advanced cancer stage and higher Gleason score, suggesting that these variables may mediate the influence of 25(OH)D on prognosis. The association also tended to be stronger among patients with samples collected within five years of cancer diagnosis. 1,25(OH)2D levels were not associated with lethal prostate cancer.
Although potential bias of less advanced disease due to more screening activity among men with high 25(OH)D levels cannot be ruled out, higher prediagnostic plasma 25(OH)D might be associated with improved prostate cancer prognosis.
To examine consequences of deferred treatment (DT) as initial management of prostate cancer (PCa) in a contemporary, prospective cohort of American men diagnosed with PCa.
Participants and Methods
We evaluated deferred treatment for PCa in the Health Professionals Follow-up Study, a prospective study of 51,529 men. Cox proportional hazards models were used to calculate hazard ratios (HRs) for time to eventual treatment among men who deferred treatment for more than 1 year after diagnosis. HRs for time to metastasis or death as a result of PCa were compared between patients who deferred treatment and those who underwent immediate treatment within 1 year of diagnosis.
From among 3,331 cohort participants diagnosed with PCa from 1986 to 2007, 342 (10.3%) initially deferred treatment. Of these, 174 (51%) remained untreated throughout follow-up (mean 7.7 years); the remainder were treated an average of 3.9 years after diagnosis. Factors associated with progression to treatment among DT patients included younger age, higher clinical stage, higher Gleason score, and higher prostate-specific antigen at diagnosis. We observed similar rates for development of metastases (n = 20 and n = 199; 7.2 v 8.1 per 1,000 person-years; P = .68) and death as a result of PCa (n = 8 and n = 80; 2.4 v 2.6 per 1,000 person-years; P = .99) for DT and immediate treatment, respectively.
In this nationwide cohort, more than half the men who opted for DT remained without treatment for 7.7 years after diagnosis. Older men and men with lesser cancer severity at diagnosis were more likely to remain untreated. PCa mortality did not differ between DT and active treatment patients.
We found that regular use of aspirin may reduce the risk of Hodgkin lymphoma (HL), a common cancer of adolescents and young adults in the US. To explore possible biological mechanisms underlying this association, we investigated whether polymorphic variation in genes involved in nuclear factor (NF)-κB activation and inhibition, other inflammatory pathways, and aspirin metabolism influences HL risk. Twenty single nucleotide polymorphisms (SNPs) in seven genes were genotyped in DNA from 473 classical HL cases and 373 controls enrolled between 1997 and 2000 in a population-based case-control study in the Boston, Massachusetts, metropolitan area and the state of Connecticut. We selected target genes and SNPs primarily using a candidate-SNP approach and estimated haplotypes using the expectation-maximization algorithm. We used multivariable logistic regression to estimate odds ratios (ORs) for associations with HL risk. HL risk was significantly associated with rs1585215 in NFKB1 (AG vs. AA: OR=2.1, 95% confidence interval [CI]=1.5–2.9; GG vs. AA: OR=3.5, 95% CI=2.2–5.7, Ptrend=1.7×10−8) and with NFKB1 haplotypes (Pglobal=6.0×10−21). Similar associations were apparent across categories of age, sex, tumor Epstein-Barr virus status, tumor histology, and regular aspirin use, although statistical power was limited for stratified analyses. Nominally significant associations with HL risk were detected for SNPs in NFKBIA and CYP2C9. HL risk was not associated with SNPs in IKKA/CHUK, PTGS2/COX2, UDP1A6, or LTC4S. In conclusion, genetic variation in the NF-κB pathway appears to influence risk of HL. Pooled studies are needed to detect any heterogeneity in the association with NF-κB across HL subgroups, including aspirin users and non-users.
Hodgkin lymphoma; genetic polymorphism; nuclear factor kappa B; NFKB1 protein; aspirin; case-control