Screening and early diagnosis tools are lacking for pancreatic adenocarcinoma; most patients are diagnosed with metastatic disease. Autoantibodies to tumor-associated antigens (TAAs) can be present months to years before diagnosis and hold promise as biomarkers for early detection.
TAAs to pancreatic cancer autoantibodies CTDSP1, MAPK9, and NR2E3, identified as potentially promising biomarkers in exploratory studies, were evaluated in serum from participants (cases=300, controls=300) in a population-based case-control pancreatic cancer study in the San Francisco Bay Area. Patients were identified through cancer registry rapid case ascertainment, newly diagnosed from 1995-1999 and followed-up through 2008. Autoantibody levels were analyzed as continuous and grouped (quartiles) variables. Multivariable unconditional logistic regression was used to compute odds ratios (OR) as estimates of autoantibody levels associated with disease status. Kaplan-Meier product limit estimates and multivariable Cox proportional hazards regression were used to assess autoantibody levels associated with case survival duration.
Cases had higher levels of CTDSP1 (P=0.004), MAPK9 (P=0.0002), and NR2E3 (P≤0.0001) autoantibodies than controls (4th vs. 1st quartile:CTDSP1 OR=1.7, MAPK9 OR=2.5, NR2E3 OR=4.0). High BMI and tobacco use were associated with levels in controls but were not statistical confounders. High CTDSP1 levels were somewhat associated with better survival (HR=0.77, P=0.07).
Combined with previous results, our study contributes evidence that cancer-related host immune-response factors may be useful diagnostic screening tools and prognostic indicators for pancreatic cancer. Further studies are needed to critically assess the value of autoantibody panels to TAAs in diagnostic screening, prognosis and immunotherapy of pancreatic and other cancers.
Pancreatic cancer; autoantibodies; antigens; biomarkers; case-control
Several nutrients identified as potentially cancer protective have been inconsistently associated with non-Hodgkin lymphoma (NHL) risk. Dietary history data, including use of vitamin supplements, were collected using a semi-quantitative food frequency questionnaire administered during in-person interviews with 4,133 participants (2052 cases, 2081 controls) in a San Francisco Bay Area population-based case-control. Data were used to determine the association of intake levels of vitamins D, A and calcium with risk of NHL and NHL subtypes. Odds ratios (OR) and 95% confidence intervals (CI) were computed as estimates of relative risk using adjusted unconditional logistic regression. Increasing vitamin D intake from food and supplements was positively associated with NHL risk in men (5th quintile: OR=1.6, 95% CI= 1.0-2.4, Ptrend=0.07) and with diffuse large B-cell lymphoma (DLBCL) in women and men (5th quintile: OR=1.6, 95% CI=1.0-2.5, Ptrend=0.02), that was largely due to the effect in men (Ptrend=0.03). These results do not support a strong role for vitamin D intake with NHL risk with the exception of a potential association for DLBCL risk in men. Our results should be interpreted conservatively until further investigation in larger pooled studies can be conducted to better assess the role of vitamin D intake in lymphomagenesis.
lymphoma, non-Hodgkin; case-control studies; vitamin D; vitamin A; calcium
In the U.S. pancreatic cancer is characterized by a low 5-year survival rate of approximately 6%, fewer than 10% of patients diagnosed with localized disease and thus candidates for “curative” surgical resection, increasing incidence and few established risk factors. Similar statistics are observed for other industrialized nations. With new evidence to suggest that pancreatic cancer develops over a number of years, markers that can better identify high risk patients and are applicable to earlier diagnosis hold promise for improving these dire statistics. Obesity is one of the few modifiable risk factors that has been associated with increased risk of pancreatic cancer and also is related to increased risk of diabetes, a condition that in turn has been associated with pancreatic cancer development. Given recent data that nearly 70% of U.S. adults are overweight or obese, a clarification of the complex association between obesity and pancreatic cancer may disclose targets for prevention and intervention to decrease incidence and improve prognosis of this highly fatal disease. An overview of the current epidemiology and hypothesized biological mechanisms involved in the obesity-pancreatic cancer association are presented.
body mass index; etiology; risk factor
Patient vital status generally is passively obtained by cancer registries, and no previous population-based studies have used extensive active follow-up to compute a more accurate overall survival rate for pancreatic cancer. Therefore, the authors used multiple active and passive follow-up methods to determine vital status and date of death for 1,954 pancreatic cancer patients diagnosed from 1995 to 1999 in a large population-based study in the San Francisco Bay Area, California. Survival rates were estimated by using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals were estimated by using multivariable Cox proportional-hazards models. Vital status was confirmed for >99% of 1,954 patients. The overall 5-year survival rate was 1.3% and was greater in patients who were younger and who had localized disease, well-differentiated tumors, and surgical resection. Shorter survival was associated with older age at diagnosis, male sex, distant/metastatic disease, and poorly differentiated tumors. Longer survival was observed for Asian/Pacific Islanders compared with non-Hispanic whites and for any active treatment regardless of tumor stage. With an almost complete follow-up, the authors observed a low overall 5-year survival rate. Although the results provide further evidence of poor survival among patients with pancreatic cancer, the data also suggest that within-stage-of-disease patients survived somewhat longer with therapy.
cohort studies; pancreatic neoplasms; survival
Folate and other methyl-group nutrients may play a key role in pancreatic carcinogenesis through their effects on DNA integrity. We examined the association between pancreatic cancer and intake of folate, vitamins B6, B12 and methionine in a large population-based case-control study.
Risk factor data were collected during in-person interviews with 532 pancreatic cancer cases diagnosed in 1995-1999 and 1701 frequency-matched controls in the San Francisco Bay Area. Dietary history and supplement use were obtained using a semi-quantitative food frequency questionnaire developed at Harvard University. Adjusted unconditional logistic regression was used to compute odds ratios (OR) and 95% confidence intervals (CI) as estimates of the relative risk.
Total folate intake was inversely associated with pancreatic cancer (5th vs. 1st quintile: OR=0.67, 95% CI=0.48-0.93, Ptrend=0.04). Increased vitamin B12 from food was positively associated with pancreatic cancer although risk estimates for quintiles 3 to 5 were similar (5th vs. 1st quintile: OR=1.9, 95% CI=1.3-2.6, Ptrend=0.001). Intake of vitamin B6 or methionine was not associated with pancreatic cancer risk.
Our study provided some support for an inverse association between folate intake and pancreatic cancer risk. The increased pancreatic cancer risk with vitamin B12 intake from food warrants further investigation.
Pancreatic neoplasms; diet; micronutrients; folic acid; case-control studies
There are no well-established modifiable risk factors for pancreatic cancer except smoking. Some dietary factors have been associated with pancreatic cancer risk and require further study. We examined the associations among intake of specific fatty acids and antioxidants and risk of pancreatic cancer in a large population-based case-control study in the San Francisco Bay Area. Unconditional logistic regression models were used to compute odds ratios (OR) and 95% confidence intervals (CI) as estimates of relative risk. Positive associations were observed for high levels of the eight individual saturated fatty acids (4th vs. 1st quartile: ORs ranged from 1.6 to 2.6; all Ptrend<0.001), monounsaturated palmitoleic and oleic fatty acids [OR=1.6 (95%CI: 1.2-2.1) and 1.4 (95%CI: 1.1-1.9); both Ptrend <0.01], and polyunsaturated linolenic acid [OR=1.5 (95%CI: 1.1-2.0); Ptrend=0.02]. Inverse associations were observed for high levels of gadolic acid [4th vs. 1st quartile: OR=0.68 (95%CI: 0.50-0.92); Ptrend=0.007] and omega-3 fatty acids [≥0.85g/day vs. 1st quartile: OR=0.47 (95%CI: 0.25-0.90)]. An inverse association also was observed for high total intake of vitamin C [4th vs. 1st quartile: OR=0.69 (95%CI: 0.51-0.94); Ptrend=0.004] and of vitamin E [OR=0.67 (95%CI: 0.49-0.92); Ptrend=0.01]. Although similar decreased risks also were observed for high supplemental intake of these two vitamins (both Ptrend<0.01), no association was observed for intake from food alone. These results support the hypotheses that a high intake of saturated and certain monounsaturated fatty acids may increase the risk of pancreatic cancer, whereas greater intake of omega-3 fatty acids, vitamins C and E may reduce the risk.
Pancreatic neoplasms; nutrients; fatty acids; antioxidants; case-control studies
Meningioma is an intracranial tumor with few confirmed risk factors. Recent research points to an impact on meningioma risk from factors related to immune function and development, such as allergy, immunoglobulin E, and Varicella infection status. To further explore an association with immune function, the authors assessed individual seroreactivity to meningioma tumor-associated antigens among participants enrolled in a multicenter, population-based US case-control study of meningioma (2006–2009). Serum samples from cases (n = 349) and controls (n = 348) were screened for autoantibody reactivity to 3 proteins identified in previous studies: enolase 1 (ENO1), NK-tumor recognition protein (NKTR), and nuclear mitotic apparatus protein 1 (NUMA1). Case-control differences were not strong overall (adjusted odds ratio (OR)ENO1 (continuous) = 1.1, 95% confidence interval (CI): 0.6, 1.9 (Ptrend = 0.3); adjusted ORNKTR (continuous) = 1.3, 95% CI: 0.7, 2.4 (Ptrend = 0.02); and adjusted ORNUMA1 (continuous) = 1.1, 95% CI: 0.7, 1.8 (Ptrend = 0.06)); however, antibodies to NKTR and NUMA1 were detected at higher levels in cases than in controls, particularly among men (for men, adjusted ORENO1 (continuous) = 1.6, 95% CI: 0.5, 4.7 (Ptrend = 0.24); adjusted ORNKTR (continuous) = 4.3, 95% CI: 1.2, 15 (Ptrend = 0.009); and adjusted ORNUMA1 (continuous) = 3.6, 95% CI: 1.1, 11 (Ptrend = 0.006)). These results indicate that men with meningioma commonly react with a serologic antimeningioma response; if supported by further research, this finding suggests a distinctive etiology for meningioma in men.
autoantibodies; brain neoplasms; genetics; immunologic factors; meningioma; neurosurgery; risk factors
An important component in the analysis of genome-wide association studies involves the imputation of genotypes that have not been measured directly in the studied samples. The imputation procedure uses the linkage disequilibrium (LD) structure in the population to infer the genotype of an unobserved single nucleotide polymorphism. The LD structure is normally learned from a dense genotype map of a reference population that matches the studied population. In many instances there is no reference population that exactly matches the studied population, and a natural question arises as to how to choose the reference population for the imputation. Here we present a Coalescent-based method that addresses this issue. In contrast to the current paradigm of imputation methods, our method assigns a different reference dataset for each sample in the studied population, and for each region in the genome. This allows the flexibility to account for the diversity within populations, as well as across populations. Furthermore, because our approach treats each region in the genome separately, our method is suitable for the imputation of recently admixed populations. We evaluated our method across a large set of populations and found that our choice of reference data set considerably improves the accuracy of imputation, especially for regions with low LD and for populations without a reference population available as well as for admixed populations such as the Hispanic population. Our method is generic and can potentially be incorporated in any of the available imputation methods as an add-on.
genotype imputation; coalescent; GWAS; linkage disequilibrium; weighted panel
Interaction between CD40 and its ligand, CD154, has a key function in immune regulation. Recent experimental data support a role of deregulated CD40 signalling in lymphomagenesis. Data from earlier studies that are part of this pooling study implicate a functional polymorphism (−1C>T, rs1883832) in the TNFRSF5 gene encoding CD40 in the etiology of follicular lymphoma. Here, the association of this variant with non-Hodgkin lymphoma (NHL) risk was replicated in a European multicenter study of 855 NHL cases and 1,206 controls. In the combined analysis of 2,617 cases and 3,605 controls, carrying the TT genotype was associated with an increased risk for all NHL (OR = 1.4; p for linear trend = 0.00009), diffuse large B-cell lymphoma (OR = 1.6; p for linear trend = 0.002) and follicular lymphoma (OR = 1.6; p for linear trend = 0.001). These data suggest a possible role of this functional polymorphism in lymphomas originating within the germinal center.
lymphoma; TNFRSF5; CD40; polymorphism; epidemiology
Obesity has been consistently associated with increased risk of pancreatic cancer incidence and mortality. However, studies of obesity and overall survival in patients with pancreatic cancer are notably lacking, especially in population-based studies.
Active and passive follow-up were used to determine vital status and survival for 510 pancreatic cancer patients diagnosed from 1995–1999 in a large population-based case-control study in the San Francisco Bay Area. Survival rates were computed using Kaplan-Meier methods. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated in multivariable Cox proportional hazards models as measures of the association between pre-diagnostic obesity and pancreatic cancer survival.
An elevated hazard ratio of 1.3 (95% CI, 0.91–1.81) was observed for obese (body mass index [BMI] ≥30) compared with normal range BMI (<25) patients. Associations between overall survival and known pancreatic cancer prognostic and risk factors did not significantly vary by BMI (all P-interaction ≥0.18), yet elevated HRs consistently were observed for obese compared with normal BMI patients [localized disease at diagnosis (HR, 3.1), surgical resection (HR, 1.6), ever smokers (HR, 1.6), diabetics (HR, 3.3)]. Poor survival was observed among men, older patients, more recent and current smokers, whereas improved survival was observed for Asian/Pacific Islanders.
Our results in general provide limited support for an association between prediagnostic obesity and decreased survival in patients with pancreatic cancer. Patterns of reduced survival associated with obesity in some patient subgroups could be due to chance and require assessment in larger pooled studies.
Pancreatic cancer; obesity; survival; population-based cohort
A recent meta-analysis of three genome-wide association studies of chronic lymphocytic leukaemia (CLL) identified two common variants at the 6p21.31 locus that are associated with CLL risk. To verify and further explore the association of these variants with other non-Hodgkin lymphoma (NHL) subtypes, we genotyped 1196 CLL cases, 1699 NHL cases, and 2410 controls. We found significant associations between the 6p21.31 variants and CLL risk (rs210134: P=0.01; rs210142: P=6.8×10−3). These variants also showed a trend towards association with some of the other NHL subtypes. Our results validate the prior work and support specific genetic pathways for risk among NHL subtypes.
CLL; NHL; SNPs; BAK1; risk locus
To assess the association between animal exposures and non-Hodgkin lymphoma (NHL).
Exposure data were collected from 1,591 cases and 2,515 controls during in-person interviews in a population-based case-control study of NHL in the San Francisco Bay Area. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for potential confounders.
Pet owners had a reduced risk of NHL (OR=0.71,CI=0.52 –0.97) and diffuse large-cell and immunoblastic large-cell (DLCL;OR=0.58,CI=0.39 –0.87) compared with those who never had owned a pet. Ever having owned dogs and/or cats was associated with reduced risk of all NHL (OR=0.71,CI=0.54–0.94) and of DLCL (OR=0.60,CI=0.42–0.86). Longer duration of cat ownership (p-trend=0.008), dog ownership (p-trend=0.04), and dog and/or cat ownership (p-trend =0.004) was inversely associated with risk of NHL. Ownership of pets other than cats and dogs was associated with a reduced risk of NHL (OR=0.64,CI=0.55–0.74) and DLCL (OR=0.58,CI=0.47 –0.71). Exposure to cattle for ≥5 years was associated with an increased risk of NHL (OR=1.6,CI=1.0–2.5) as was exposure to pigs for all NHL (OR=1.8,CI=1.2–2.6) and for DLCL (OR=2.0,CI=1.2–3.4).
The association between animal exposure and NHL warrants further investigation in pooled analyses.
lymphoma, non-Hodgkin; case-control; animal exposure; immunity; agricultural exposure
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.
Few studies of reproductive hormone exposures and non-Hodgkin lymphoma (NHL) have examined NHL subtypes. Associations between reproductive hormonal factors and risk of all NHL and of two predominant subtypes, diffuse large-cell lymphoma (DLCL) (n = 233) and follicular lymphoma (n = 173), were investigated among women (n = 581) in a large, population-based, case-control study (1,591 cases, 2,515 controls). Controls (n = 836) identified by random digit dialing were frequency matched by age and county to incident NHL cases ascertained in the San Francisco Bay Area of California in 1988–1993. Adjusted unconditional logistic regression was used to obtain odds ratios. More than four pregnancies indicated a possible lower risk of all NHL (odds ratio (OR) = 0.81, 95% confidence interval (CI): 0.55, 1.2; p-trend = 0.06) and of DLCL (OR = 0.53, 95% CI: 0.31, 0.90; p-trend = 0.01). Exclusive use of menopausal hormone therapy for ≥5 years was associated with a reduced risk of all NHL (OR = 0.68, 95% CI: 0.48, 0.98) and of DLCL (OR = 0.50, 95% CI: 0.30, 0.85). Oral contraceptive use indicated a lower risk of all NHL (OR = 0.68, 95% CI: 0.49, 0.94), and perhaps DLCL (OR = 0.79, 95% CI: 0.51, 1.2), and of follicular lymphoma (OR = 0.75, 95% CI: 0.46, 1.2). Results suggest that endogenous and exogenous reproductive hormones confer different risks by NHL subtype and are associated with a reduced risk of DLCL in women.
case-control studies; contraception; estrogens; hormone replacement therapy; lymphoma, non-Hodgkin; menopause; pregnancy; reproduction
Non-Hodgkin lymphomas (NHL) are a heterogeneous group of solid tumours of lymphoid cell origin. Three important aspects of lymphocyte development include immunity and inflammation, DNA repair, and programmed cell death. We have used a previously established case-control study of NHL to ask whether genetic variation in genes involved in these three important processes influences risk of this cancer. 118 genes in these three categories were tagged with single nucleotide polymorphisms (SNPs), which were tested for association with NHL and its subtypes. The main analysis used logistic regression (additive model) to estimate odds ratios in European-ancestry cases and controls. 599 SNPs and 1116 samples (569 cases and 547 controls) passed quality control measures and were included in analyses. Following multiple-testing correction, one SNP in MSH3, a mismatch repair gene, showed an association with diffuse large B-cell lymphoma (OR: 1.91; 95% CI: 1.41–2.59; uncorrected p = 0.00003; corrected p = 0.010). This association was not replicated in an independent European-ancestry sample set of 251 diffuse large B-cell lymphoma cases and 737 controls, indicating this result was likely a false positive. It is likely that moderate sample size, inter-subtype and other genetic heterogeneity, and small true effect sizes account for the lack of replicable findings.
Adenocarcinoma in situ (AIS, formerly bronchioloalveolar carcinoma [BAC]) is an uncommon subtype of lung adenocarcinoma and accounts for approximately 3–4% of lung cancers. Compared with other lung cancer histologies, AIS cases are less likely to be smokers, yet associations with other lung cancer risk factors and differences by gender have not been determined.
A total of 338 AIS (formerly BAC) cases and frequency matched controls from the parent study (cases=6039, controls=2073) were included in these analyses. Odds ratios and 95% confidence intervals as estimates of the relative risk were obtained from multivariable unconditional logistic regression analyses.
Risk of AIS was associated with ever smoking (OR=2.7, 95% CI: 2.1, 3.6), increased 20–30% for each 10-year increase in pack-years of smoking and decreased with increased years since quitting (P for trend <0.0001). There was no evidence that risk differed by gender but there was some suggestion that risk may differ by asbestos and by second-hand tobacco smoke exposure in whites.
There is an association between AIS and smoking that is smaller in magnitude than other subtypes of non-small cell lung cancer. Our findings suggesting that effects may differ by asbestos and second-hand tobacco smoke exposure should be interpreted conservatively and warrant validation and further evaluation in larger studies of AIS.
Adenocarcinoma in situ; case-control; epidemiology; smoking; second-hand tobacco smoke
Owing to their role in controlling the efflux of toxic compounds, transporters are central players in the process of detoxification and elimination of xenobiotics, which in turn is related to cancer risk. Among these transporters, ATP-binding cassette B1/multidrug resistance 1 (ABCB1/MDR1), ABCC2/multidrug resistance protein 2 (MRP2), and ABCG2/breast cancer resistance protein (BCRP) affect susceptibility to many hematopoietic malignancies. The maintenance of regulated expression of these transporters is governed through the activation of intracellular “xenosensors” like the nuclear receptor 1I2/pregnane X receptor (NR1I2/PXR). SNPs in genes encoding these regulators have also been implicated in the risk of several cancers. Using a tagging approach, we tested the hypothesis that common polymorphisms in the transporter genes ABCB1, ABCC2, ABCG2, and the regulator gene NR1I2 could be implicated in lymphoma risk. We selected 68 SNPs in the 4 genes, and we genotyped them in 1,481 lymphoma cases and 1,491 controls of the European cases-control study (EpiLymph) using the Illumina™ GoldenGate assay technology.Carriers of the SNP rs6857600 minor allele in ABCG2, was associated with a decrease in risk of B-cell lymphoma (B-NHL) overall (p<0.001). Furthermore, a decreased risk of chronic lymphocytic leukemia (CLL) was associated with the ABCG2 rs2231142 variant (p=0.0004), which could be replicated in an independent population. These results suggest a role for this gene in B-NHL susceptibility, especially for CLL.
Lymphoma; multidrug resistance 1 (MDR1); multidrug resistance protein 2 (MRP2); breast cancer resistance protein (BCRP); pregnane X receptor (PXR)
Recent meta-analyses of European ancestry subjects show strong evidence for association between smoking quantity and multiple genetic variants on chromosome 15q25. This meta-analysis extends the examination of association between distinct genes in the CHRNA5-CHRNA3-CHRNB4 region and smoking quantity to Asian and African American populations to confirm and refine specific reported associations.
Association results for a dichotomized cigarettes smoked per day (CPD) phenotype in 27 datasets (European ancestry (N=14,786), Asian (N=6,889), and African American (N=10,912) for a total of 32,587 smokers) were meta-analyzed by population and results were compared across all three populations.
We demonstrate association between smoking quantity and markers in the chromosome 15q25 region across all three populations, and narrow the region of association. Of the variants tested, only rs16969968 is associated with smoking (p < 0.01) in each of these three populations (OR=1.33, 95%C.I.=1.25–1.42, p=1.1×10−17 in meta-analysis across all population samples). Additional variants displayed a consistent signal in both European ancestry and Asian datasets, but not in African Americans.
The observed consistent association of rs16969968 with heavy smoking across multiple populations, combined with its known biological significance, suggests rs16969968 is most likely a functional variant that alters risk for heavy smoking. We interpret additional association results that differ across populations as providing evidence for additional functional variants, but we are unable to further localize the source of this association. Using the cross-population study paradigm provides valuable insights to narrow regions of interest and inform future biological experiments.
smoking; genetics; meta-analysis; cross-population
Follicular lymphoma (FL) is an indolent, sometimes fatal disease characterized by recurrence at progressively shorter intervals and is frequently refractive to therapy. Genome-wide association studies have identified SNPs in the human leukocyte antigen (HLA) region on chromosome 6p21.32–33 that are statistically significantly associated with FL risk. Low to medium resolution typing of single or multiple HLA genes has provided an incomplete picture of the total genetic risk imparted by this highly variable region. To gain further insight into the role of HLA alleles in lymphomagenesis and to investigate the independence of validated SNPs and HLA alleles with FL risk, high-resolution HLA typing was conducted using next-generation sequencing in 222 non-Hispanic white FL cases and 220 matched controls from a larger San Francisco Bay Area population-based case-control study of lymphoma. A novel protective association was found between the DPB1*03:01 allele and FL risk (OR=0.39, 95% CI 0.21–0.68). Extended haplotypes DRB1*01:01-DQA1*01:01-DQB1*05:01 (OR=2.01, 95% CI 1.22–3.38) and DRB1*15-DQA1*01-DQB1*06 (OR=0.55, 95% CI 0.36–0.82) also influenced FL risk. Moreover, DRB1*15-DQA1*01-DQB1*06 was highly correlated with an established FL risk locus, rs2647012. These results provide further insight into the critical roles of HLA alleles and SNPs in FL pathogenesis that involve multi-locus effects across the HLA region.
follicular lymphoma; HLA; genetic risk factors; next-generation sequencing
Although the mitochondrial genome exhibits high mutation rates, common mitochondrial DNA (mtDNA) variation has not been consistently associated with pancreatic cancer. Here, we comprehensively examined mitochondrial genomic variation by sequencing the mtDNA of participants (cases=286, controls=283) in a San Francisco Bay Area pancreatic cancer case-control study. Five common variants were associated with pancreatic cancer at nominal statistical significance (p<0.05) with the strongest finding for mt5460g in the ND2 gene (odds ratio (OR)=3.9, 95% confidence interval (CI)=1.5–10; p=0.004) which encodes an A331T substitution. Haplogroup K was nominally associated with reduced pancreatic cancer risk (OR = 0.32, CI=0.13–0.76; p=0.01) when compared with the most common haplogroup, H. A total of 19 haplogroup-specific rare variants yielded nominal statistically significant associations (p<0.05) with pancreatic cancer risk, with the majority observed in genes involved in oxidative phosphorylation. Weighted-sum statistics were used to identify an aggregate effect of variants in the 22 mitochondrial tRNAs on pancreatic cancer risk (p=0.02). While the burden of singleton variants in the HV2 and 12S RNA regions was three times higher among European haplogroup N cases than controls, the prevalence of singleton variants in ND4 and ND5 was two to three times higher among African haplogroup L cases than in controls. Together, the results of this study provide evidence that aggregated common and rare variants and the accumulation of singleton variants are important contributors to pancreatic cancer risk.
Pancreatic cancer; mitochondrial DNA; oxidative phosphorylation; DNA sequencing; epidemiology
Studies in European and East Asian populations have identified lung cancer susceptibility loci in nicotinic acetylcholine receptor (nAChR) genes on chromosome 15q25.1 which also appear to influence smoking behaviors. We sought to determine if genetic variation in nAChR genes influences lung cancer susceptibly in African-Americans, and evaluated the association of these cancer susceptibility loci with smoking behavior. A total of 1308 African-Americans with lung cancer and 1241 African-American controls from three centers were genotyped for 378 single nucleotide polymorphisms (SNPs) spanning the sixteen human nAChR genes. Associations between SNPs and the risk of lung cancer were estimated using logistic regression, adjusted for relevant covariates. Seven SNPs in three nAChR genes were significantly associated with lung cancer at a strict Bonferroni-corrected level, including a novel association on chromosome 2 near the promoter of CHRNA1 (rs3755486: OR = 1.40, 95% CI = 1.18-1.67, P = 1.0 × 10−4). Association analysis of an additional 305 imputed SNPs on 2q31.1 supported this association. Publicly available expression data demonstrated that the rs3755486 risk allele correlates with increased CHRNA1 gene expression. Additional SNP associations were observed on 15q25.1 in genes previously associated with lung cancer, including a missense variant in CHRNA5 (rs16969968: OR = 1.60, 95% CI = 1.27-2.01, P = 5.9 × 10−5). Risk alleles on 15q25.1 also correlated with an increased number of cigarettes smoked per day among the controls. These findings identify a novel lung cancer risk locus on 2q31.1 which correlates with CHRNA1 expression and replicate previous associations on 15q25.1 in African-Americans.
Lung cancer; nicotine dependence; African-Americans; genetic association; smoking
Polymorphisms in chemokine genes have been associated with human immunodeficiency virus (HIV)-related non-Hodgkin lymphoma (NHL) but are understudied in non-HIV-related NHL. Associations of NHL and NHL subtypes with polymorphisms and haplotypes in CCR5, CCR2, CCL5, CXCL12 and CX3CR1 were explored in a pooled analysis of three case-control studies (San Francisco Bay Area, California; United Kingdom; total: cases N=1610, controls N=1992). Adjusted unconditional logistic regression was used to estimate relative risks among HIV-negative non-Hispanic Caucasians. The CCR5M Δ32 deletion reduced the risk of NHL (odds ratio=0.56, 95% confidence interval=0.38-0.83) in men but not women with similar effects observed for diffuse large-cell and follicular lymphoma (FL). NHL risk also was reduced in men with the CCR2/CCR5 haplotype characterized by the CCR5 Δ32 deletion. The CCL5 −403A allele conferred reduced risks of FL and chronic lymphocytic leukemia/small lymphocytic lymphoma. Results should be interpreted conservatively. Continued investigation is warranted to confirm these findings.
Lymphoma non-Hodgkin; Chemokines; Polymorphism, genetic; Case-Control
Many effective options exist to accurately type DNA for HLA alleles. However, most of the existing methods are excessively costly in terms of overall monetary costs, DNA requirements, and proprietary software. We present a novel assay able to resolve heterozygous HLA-DQB1 allelotypes at two digits, with even greater specificity for the HLA-DQB1*06 allele family, by using the multiplexed ligation-dependent probe amplification (MLPA) technology. This assay provides more specific allele data than genome-wide analysis and is more affordable than sequencing, making it a useful intermediate for researchers seeking to accurately allelotype human DNA samples.
DQB1; genotyping; MHC class II; MLPA
Non-Hodgkin lymphoma (NHL) is a hematological malignancy of the immune system, and, as with autoimmune and inflammatory diseases (ADs), is influenced by genetic variation in the major histocompatibility complex (MHC). Persons with a history of specific ADs also have increased risk of NHL. As the coexistence of ADs and NHL could be caused by factors common to both diseases, here we examined whether some of the associated genetic signals are shared. Overlapping risk loci for NHL subytpes and several ADs were explored using data from genome-wide association studies. Several common genomic regions and susceptibility loci were identified suggesting a potential shared genetic background. Two independent MHC regions showed the main overlap, with several alleles in the human leukocyte antigen (HLA) Class II region exhibiting an opposite risk effect for follicular lymphoma and type I diabetes. These results support continued investigation to further elucidate the relationship between lymphoma and autoimmune diseases.
Non-Hodgkin lymphoma; Autoimmune diseases; Genome-wide Association Studies; Human Leukocyte Antigen
In a recent genome-wide association study of follicular lymphoma (FL), we identified novel risk alleles on chromosome 6p21.33 that appeared to be part of an extended haplotype including HLA-DRB1*0101, DQA1*0101, and DQB1*0501. To follow up on these findings, we obtained 2–4 digit HLA-DQB1 allelotypes on a subset of 265 FL cases and 757 controls using a novel assay that applies multiplexed ligation-dependent probe amplification (MLPA). We confirmed a positive association between FL and the HLA-DQB1*05 allele group (OR=1.70, 95% CI 1.28–2.27; adjusted p-value=0.013) and also identified an allele group inversely associated with FL risk, HLA-DQB1*06 (OR=0.51, 95% CI 0.38–0.69; adjusted p-value=4.46×10−5). Although these findings require verification, the role of HLA class II proteins in B-cell survival and proliferation make this a biologically plausible association.
follicular lymphoma; MHC; HLA; DQ; NHL