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1.  Serum autoantibodies to pancreatic cancer antigens as biomarkers of pancreas cancer in a San Francisco Bay Area case-control study 
Cancer  2012;118(21):5384-5394.
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.
PMCID: PMC3414682  PMID: 22517435
Pancreatic cancer; autoantibodies; antigens; biomarkers; case-control
2.  Intake of vitamins D and A, and calcium and risk of non-Hodgkin lymphoma: San Francisco Bay Area population-based case-control study 
Nutrition and Cancer  2012;64(5):674-684.
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.
PMCID: PMC3403694  PMID: 22697504
lymphoma, non-Hodgkin; case-control studies; vitamin D; vitamin A; calcium
3.  A genome-wide association study of marginal zone lymphoma shows association to the HLA region 
Vijai, Joseph | Wang, Zhaoming | Berndt, Sonja I. | Skibola, Christine F. | Slager, Susan L. | de Sanjose, Silvia | Melbye, Mads | Glimelius, Bengt | Bracci, Paige M. | Conde, Lucia | Birmann, Brenda M. | Wang, Sophia S. | Brooks-Wilson, Angela R. | Lan, Qing | de Bakker, Paul I. W. | Vermeulen, Roel C. H. | Portlock, Carol | Ansell, Stephen M. | Link, Brian K. | Riby, Jacques | North, Kari E. | Gu, Jian | Hjalgrim, Henrik | Cozen, Wendy | Becker, Nikolaus | Teras, Lauren R. | Spinelli, John J. | Turner, Jenny | Zhang, Yawei | Purdue, Mark P. | Giles, Graham G. | Kelly, Rachel S. | Zeleniuch-Jacquotte, Anne | Ennas, Maria Grazia | Monnereau, Alain | Bertrand, Kimberly A. | Albanes, Demetrius | Lightfoot, Tracy | Yeager, Meredith | Chung, Charles C. | Burdett, Laurie | Hutchinson, Amy | Lawrence, Charles | Montalvan, Rebecca | Liang, Liming | Huang, Jinyan | Ma, Baoshan | Villano, Danylo J. | Maria, Ann | Corines, Marina | Thomas, Tinu | Novak, Anne J. | Dogan, Ahmet | Liebow, Mark | Thompson, Carrie A. | Witzig, Thomas E. | Habermann, Thomas M. | Weiner, George J. | Smith, Martyn T. | Holly, Elizabeth A. | Jackson, Rebecca D. | Tinker, Lesley F. | Ye, Yuanqing | Adami, Hans-Olov | Smedby, Karin E. | De Roos, Anneclaire J. | Hartge, Patricia | Morton, Lindsay M. | Severson, Richard K. | Benavente, Yolanda | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Diver, W. Ryan | Vajdic, Claire M. | Armstrong, Bruce K. | Kricker, Anne | Zheng, Tongzhang | Holford, Theodore R. | Severi, Gianluca | Vineis, Paolo | Ferri, Giovanni M. | Ricco, Rosalia | Miligi, Lucia | Clavel, Jacqueline | Giovannucci, Edward | Kraft, Peter | Virtamo, Jarmo | Smith, Alex | Kane, Eleanor | Roman, Eve | Chiu, Brian C. H. | Fraumeni, Joseph F. | Wu, Xifeng | Cerhan, James R. | Offit, Kenneth | Chanock, Stephen J. | Rothman, Nathaniel | Nieters, Alexandra
Nature Communications  2015;6:5751.
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10−15) and HLA-B (rs2922994, P=2.43 × 10−9) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
Marginal zone lymphoma (MZL) is a common subtype of B-cell non-Hodgkin lymphoma. Here the authors carry out a two-stage genome-wide association study in over 8,000 Europeans and identify two new MZL risk loci at chromosome 6p, implicating the major histocompatibility complex in the disease for the first time.
PMCID: PMC4287989  PMID: 25569183
4.  Obesity and pancreatic cancer: overview of epidemiologic evidence and biologic mechanisms 
Molecular Carcinogenesis  2012;51(1):53-63.
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.
PMCID: PMC3348117  PMID: 22162231
body mass index; etiology; risk factor
5.  Survival in Population-based Pancreatic Cancer Patients: San Francisco Bay Area, 1995–1999 
American Journal of Epidemiology  2011;174(12):1373-1381.
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.
PMCID: PMC3276299  PMID: 22047824
cohort studies; pancreatic neoplasms; survival
6.  Genes-environment interactions in obesity- and diabetes-associated pancreatic cancer: A GWAS data analysis 
Obesity and diabetes are potentially alterable risk factors for pancreatic cancer. Genetic factors that modify the associations of obesity and diabetes with pancreatic cancer have previously not been examined at the genome-wide level.
Using GWAS genotype and risk factor data from the Pancreatic Cancer Case Control Consortium, we conducted a discovery study of 2,028 cases and 2,109 controls to examine gene-obesity and gene-diabetes interactions in relation to pancreatic cancer risk by employing the likelihood ratio test (LRT) nested in logistic regression models and Ingenuity Pathway Analysis (IPA).
After adjusting for multiple comparisons, a significant interaction of the chemokine signaling pathway with obesity (P = 3.29 × 10−6) and a near significant interaction of calcium signaling pathway with diabetes (P = 1.57 × 10−4) in modifying the risk of pancreatic cancer was observed. These findings were supported by results from IPA analysis of the top genes with nominal interactions. The major contributing genes to the two top pathways include GNGT2, RELA, TIAM1 and GNAS. None of the individual genes or SNPs except one SNP remained significant after adjusting for multiple testing. Notably, SNP rs10818684 of the PTGS1 gene showed an interaction with diabetes (P = 7.91 × 10−7) at a false discovery rate of 6%.
Genetic variations in inflammatory response and insulin resistance may affect the risk of obesity and diabetes-related pancreatic cancer. These observations should be replicated in additional large datasets.
Gene-environment interaction analysis may provide new insights into the genetic susceptibility and molecular mechanisms of obesity- and diabetes-related pancreatic cancer.
PMCID: PMC3947145  PMID: 24136929
GWAS; obesity; diabetes; interaction; pancreatic cancer; genetic susceptibility
8.  Chemokine polymorphisms and lymphoma: a pooled analysis 
Leukemia & lymphoma  2010;51(3):497-506.
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.
PMCID: PMC3443685  PMID: 20038229
Lymphoma non-Hodgkin; Chemokines; Polymorphism, genetic; Case-Control
9.  Intake of folate, vitamins B6, B12 and methionine and risk of pancreatic cancer in a large population-based case-control study 
Cancer causes & control : CCC  2009;20(8):1317-1325.
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.
PMCID: PMC3306816  PMID: 19415507
Pancreatic neoplasms; diet; micronutrients; folic acid; case-control studies
10.  Intake of fatty acids and antioxidants and pancreatic cancer in a large population-based case-control study in the San Francisco Bay Area 
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.
PMCID: PMC2930138  PMID: 20104522
Pancreatic neoplasms; nutrients; fatty acids; antioxidants; case-control studies
11.  Solvent exposure and non-Hodgkin Lymphoma: no risk in a population-based study in the San Francisco Bay Area 
The literature on environmental exposures and risk of non-Hodgkin Lymphoma(NHL) is inconsistent and no occupational exposures have been conclusively identified as causal factors. We used job exposure matrices to assess the association between occupational exposure to solvents in a population-based case-control study of NHL (N=1591 cases,N=2515 controls) in the San Francisco Bay Area between 1988 and 1995. Occupational histories were collected during in-person interviews and were coded according to the 1980 U.S. Department of Commerce Alphabetic Index of Industries and Occupations. Odds ratios (ORs) and 95% confidence intervals (CI) were adjusted for potential confounders. Our results have provided no support for an association between NHL and occupational exposure to solvents.
PMCID: PMC2782419  PMID: 19900943
lymphoma, non-Hodgkin; case-control; occupational exposure; solvents
12.  Domestic and farm-animal exposures and risk of non-Hodgkin lymphoma in a population-based study in the San Francisco Bay Area 
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.
PMCID: PMC2946322  PMID: 18768507
lymphoma, non-Hodgkin; case-control; animal exposure; immunity; agricultural exposure
13.  Non-Hodgkin Lymphoma in Women: Reproductive Factors and Exogenous Hormone Use 
American Journal of Epidemiology  2008;168(3):278-288.
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.
PMCID: PMC2727261  PMID: 18550561
case-control studies; contraception; estrogens; hormone replacement therapy; lymphoma, non-Hodgkin; menopause; pregnancy; reproduction
14.  Allergies and Risk of Pancreatic Cancer: A Pooled Analysis From the Pancreatic Cancer Case-Control Consortium 
American Journal of Epidemiology  2013;178(5):691-700.
In order to quantify the risk of pancreatic cancer associated with history of any allergy and specific allergies, to investigate differences in the association with risk according to age, gender, smoking status, or body mass index, and to study the influence of age at onset, we pooled data from 10 case-control studies. In total, there were 3,567 cases and 9,145 controls. Study-specific odds ratios and 95% confidence intervals were calculated by using unconditional logistic regression adjusted for age, gender, smoking status, and body mass index. Between-study heterogeneity was assessed by using the Cochran Q statistic. Study-specific odds ratios were pooled by using a random-effects model. The odds ratio for any allergy was 0.79 (95% confidence interval (CI): 0.62, 1.00) with heterogeneity among studies (P < 0.001). Heterogeneity was attributable to one study; with that study excluded, the pooled odds ratio was 0.73 (95% CI: 0.64, 0.84) (Pheterogeneity = 0.23). Hay fever (odds ratio = 0.74, 95% CI: 0.56, 0.96) and allergy to animals (odds ratio = 0.62, 95% CI: 0.41, 0.94) were related to lower risk, while there was no statistically significant association with other allergies or asthma. There were no major differences among subgroups defined by age, gender, smoking status, or body mass index. Older age at onset of allergies was slightly more protective than earlier age.
PMCID: PMC3755648  PMID: 23820785
allergic rhinitis; case-control studies; hypersensitivity; pancreatic neoplasms
15.  Copy Number Variation Analysis on a Non-Hodgkin Lymphoma Case-Control Study Identifies an 11q25 Duplication Associated with Diffuse Large B-Cell Lymphoma 
PLoS ONE  2014;9(8):e105382.
Recent GWAS have identified several susceptibility loci for NHL. Despite these successes, much of the heritable variation in NHL risk remains to be explained. Common copy-number variants are important genomic sources of variability, and hence a potential source to explain part of this missing heritability. In this study, we carried out a CNV analysis using GWAS data from 681 NHL cases and 749 controls to explore the relationship between common structural variation and lymphoma susceptibility. Here we found a novel association with diffuse large B-cell lymphoma (DLBCL) risk involving a partial duplication of the C-terminus region of the LOC283177 long non-coding RNA that was further confirmed by quantitative PCR. For chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), known somatic deletions were identified on chromosomes 13q14, 11q22-23, 14q32 and 22q11.22. Our study shows that GWAS data can be used to identify germline CNVs associated with disease risk for DLBCL and somatic CNVs for CLL/SLL.
PMCID: PMC4136881  PMID: 25133503
16.  Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC4 
Cancer causes & control : CCC  2013;24(3):595-602.
The evidence of a relation between folate intake and one-carbon metabolism (OCM) with pancreatic cancer (PanCa) is inconsistent. In this study, the association between genes and single-nucleotide polymorphisms (SNPs) related to OCM and PanCa was assessed.
Using biochemical knowledge of the OCM pathway, we identified thirty-seven genes and 834 SNPs to examine in association with PanCa. Our study included 1,408 cases and 1,463 controls nested within twelve cohorts (PanScan). The ten SNPs and five genes with lowest p values (<0.02) were followed up in 2,323 cases and 2,340 controls from eight case-control studies (PanC4) that participated in PanScan2. The correlation of SNPs with metabolite levels was assessed for 649 controls from the European Prospective Investigation into Cancer and Nutrition.
When both stages were combined, we observed suggestive associations with PanCa for rs10887710 (MAT1A) (OR 1.13, 95%CI 1.04-1.23), rs1552462 (SYT9) (OR 1.27, 95%CI 1.02-1.59), and rs7074891 (CUBN) (OR 1.91, 95%CI 1.12-3.26). After correcting for multiple comparisons, no significant associations were observed in either the first or second stage. The three suggested SNPs showed no correlations with one-carbon biomarkers.
This is the largest genetic study to date to examine the relation between germline variations in OCM-related genes polymorphisms and the risk of PanCa. Suggestive evidence for an association between polymorphisms and PanCa was observed among the cohort-nested studies, but this did not replicate in the case-control studies. Our results do not strongly support the hypothesis that genes related to OCM play a role in pancreatic carcinogenesis.
PMCID: PMC4127987  PMID: 23334854
Pancreatic cancer; One-carbon metabolism; Polymorphisms; Biomarkers; Epidemiology
17.  Genetic variants in telomerase-related genes are associated with an older age at diagnosis in glioma patients: evidence for distinct pathways of gliomagenesis 
Neuro-Oncology  2013;15(8):1041-1047.
Genome-wide association studies have implicated single nucleotide polymorphisms (SNPs) in 7 genes as glioma risk factors, including 2 (TERT, RTEL1) involved in telomerase structure/function. We examined associations of these 7 established glioma risk loci with age at diagnosis among patients with glioma.
SNP genotype data were available for 2286 Caucasian glioma patients from the University of California, San Francisco (n = 1434) and the Mayo Clinic (n = 852). Regression analyses were performed to test for associations between “number of risk alleles” and “age at diagnosis,” adjusted for sex and study site and stratified by tumor grade/histology where appropriate.
Four SNPs were significantly associated with age at diagnosis. Carrying a greater number of risk alleles at rs55705857 (CCDC26) and at rs498872 (PHLDB1) was associated with younger age at diagnosis (P = 1.4 × 10−22 and P = 9.5 × 10−7, respectively). These SNPs are stronger risk factors for oligodendroglial tumors, which tend to occur in younger patients, and their association with age at diagnosis varied across tumor subtypes. In contrast, carrying more risk alleles at rs2736100 (TERT) and at rs6010620 (RTEL1) was associated with older age at diagnosis (P = 6.2 × 10−4 and P = 2.5 × 10−4, respectively). These SNPs are risk factors for all glioma grades/histologies, and their association with age at diagnosis was consistent across tumor subgroups.
Carrying a greater number of risk alleles might be expected to decrease age at diagnosis. However, glioma susceptibility conferred by variation in telomerase-related genes did not follow this pattern. This supports the hypothesis that telomerase-related mechanisms of telomere maintenance are more associated with gliomas that develop later in life than those utilizing telomerase-independent mechanisms (ie, alternative lengthening of telomeres).
PMCID: PMC3714154  PMID: 23733245
age at diagnosis; glioma; single nucleotide polymorphism; telomerase; telomere
18.  Personal Use of Hair Dye and the Risk of Certain Subtypes of Non-Hodgkin Lymphoma 
American journal of epidemiology  2008;167(11):1321-1331.
Personal use of hair dye has been inconsistently linked to risk of non-Hodgkin lymphoma (NHL), perhaps because of small samples or a lack of detailed information on personal hair-dye use in previous studies. This study included 4,461 NHL cases and 5,799 controls from the International Lymphoma Epidemiology Consortium 1988–2003. Increased risk of NHL (odds ratio (OR) = 1.3, 95% confidence interval (CI): 1.1, 1.4) associated with hair-dye use was observed among women who began using hair dye before 1980. Analyses by NHL subtype showed increased risk for follicular lymphoma (FL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) but not for other NHL subtypes. The increased risks of FL (OR = 1.4, 95% CI: 1.1, 1.9) and CLL/SLL (OR = 1.5, 95% CI: 1.1, 2.0) were mainly observed among women who started using hair dyes before 1980. For women who began using hair dye in 1980 or afterward, increased FL risk was limited to users of dark-colored dyes (OR = 1.5, 95% CI: 1.1, 2.0). These results indicate that personal hair-dye use may play a role in risks of FL and CLL/SLL in women who started use before 1980 and that increased risk of FL among women who started use during or after 1980 cannot be excluded.
PMCID: PMC4025953  PMID: 18408225
case-control studies; hair dyes; lymphoma; non-Hodgkin
19.  Hepatitis C and Non-Hodgkin Lymphoma Among 4784 Cases and 6269 Controls From the International Lymphoma Epidemiology Consortium 
Background & Aims
Increasing evidence points towards a role of hepatitis C virus (HCV) infection in causing malignant lymphomas. We pooled case-control study data to provide robust estimates of the risk of non-Hodgkin’s lymphoma (NHL) subtypes after HCV infection.
The analysis included 7 member studies from the International Lymphoma Epidemiology Consortium (InterLymph) based in Europe, North America, and Australia. Adult cases of NHL (n = 4784) were diagnosed between 1988 and 2004 and controls (n = 6269) were matched by age, sex, and study center. All studies used third-generation enzyme-linked immunosorbent assays to test for antibodies against HCV in serum samples. Participants who were human immunodeficiency virus positive or were organ-transplant recipients were excluded.
HCV infection was detected in 172 NHL cases (3.60%) and in 169 (2.70%) controls (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.40–2.25). In subtype-specific analyses, HCV prevalence was associated with marginal zone lymphoma (OR, 2.47; 95% CI, 1.44–4.23), diffuse large B-cell lymphoma (OR, 2.24; 95% CI, 1.68–2.99), and lymphoplasmacytic lymphoma (OR, 2.57; 95% CI, 1.14–5.79). Notably, risk estimates were not increased for follicular lymphoma (OR, 1.02; 95% CI, 0.65–1.60).
These results confirm the association between HCV infection and NHL and specific B-NHL subtypes (diffuse large B-cell lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma).
PMCID: PMC3962672  PMID: 18387498
20.  Analysis of 60 Reported Glioma Risk SNPs Replicates Published GWAS Findings but Fails to Replicate Associations From Published Candidate-Gene Studies 
Genetic epidemiology  2012;37(2):222-228.
Genomewide association studies (GWAS) and candidate-gene studies have implicated single-nucleotide polymorphisms (SNPs) in at least 45 different genes as putative glioma risk factors. Attempts to validate these associations have yielded variable results and few genetic risk factors have been consistently replicated. We conducted a case-control study of Caucasian glioma cases and controls from the University of California San Francisco (810 cases, 512 controls) and the Mayo Clinic (852 cases, 789 controls) in an attempt to replicate previously reported genetic risk factors for glioma. Sixty SNPs selected from the literature (eight from GWAS and 52 from candidate-gene studies) were successfully genotyped on an Illumina custom genotyping panel. Eight SNPs in/near seven different genes (TERT, EGFR, CCDC26, CDKN2A, PHLDB1, RTEL1, TP53) were significantly associated with glioma risk in the combined dataset (P < 0.05), with all associations in the same direction as in previous reports. Several SNP associations showed considerable differences across histologic subtype. All eight successfully replicated associations were first identified by GWAS, although none of the putative risk SNPs from candidate-gene studies was associated in the full case-control sample (all P values > 0.05). Although several confirmed associations are located near genes long known to be involved in gliomagenesis (e.g., EGFR, CDKN2A, TP53), these associations were first discovered by the GWAS approach and are in noncoding regions. These results highlight that the deficiencies of the candidate-gene approach lay in selecting both appropriate genes and relevant SNPs within these genes.
PMCID: PMC3670948  PMID: 23280628
glioma; SNP; GWAS; candidate-gene
21.  Fine-mapping of the 5p15.33, 6p22.1-p21.31 and 15q25.1 regions identifies functional and histology-specific lung cancer susceptibility loci in African-Americans 
Genome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31 and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans refined previous association signals by utilizing the reduced linkage disequilibrium observed in African-Americans.
1308 African-American cases and 1241 African-American controls from three centers were genotyped for 760 single nucleotide polymorphisms spanning three regions, and additional SNP imputation was performed. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate.
The strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution (rs16969968: OR = 1.57, 95% CI = 1.25–1.97, P = 1.1 × 10−4) and variants in the 5′-UTR. Associations on 6p22.1-p21.31 were histology-specific and included a missense variant in BAT2 associated with squamous-cell carcinoma (rs2736158: OR = 0.64, 95% CI = 0.48–0.85, P = 1.82 × 10−3). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR = 0.82, 95% CI = 0.73–0.93, P = 1.1 × 10−3). This association was stronger among cases with adenocarcinoma (OR = 0.75, 95% CI = 0.65–0.86, P = 8.1 × 10−5).
Polymorphisms in 5p15.33, 6p22.1-p21.31 and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous-cell carcinoma.
Results implicate the BAT2, TERT and CHRNA5 genes in the pathogenesis of specific lung cancer histologies.
PMCID: PMC3565099  PMID: 23221128
Lung cancer; adenocarcinoma; squamous-cell carcinoma; fine-mapping; African-American; genetic association
22.  Genome-wide Association Study Identifies Multiple Risk Loci for Chronic Lymphocytic Leukemia 
Berndt, Sonja I. | Skibola, Christine F. | Joseph, Vijai | Camp, Nicola J. | Nieters, Alexandra | Wang, Zhaoming | Cozen, Wendy | Monnereau, Alain | Wang, Sophia S. | Kelly, Rachel S. | Lan, Qing | Teras, Lauren R. | Chatterjee, Nilanjan | Chung, Charles C. | Yeager, Meredith | Brooks-Wilson, Angela R. | Hartge, Patricia | Purdue, Mark P. | Birmann, Brenda M. | Armstrong, Bruce K. | Cocco, Pierluigi | Zhang, Yawei | Severi, Gianluca | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Burdette, Laurie | Yuenger, Jeffrey | Hutchinson, Amy | Jacobs, Kevin B. | Call, Timothy G. | Shanafelt, Tait D. | Novak, Anne J. | Kay, Neil E. | Liebow, Mark | Wang, Alice H. | Smedby, Karin E | Adami, Hans-Olov | Melbye, Mads | Glimelius, Bengt | Chang, Ellen T. | Glenn, Martha | Curtin, Karen | Cannon-Albright, Lisa A. | Jones, Brandt | Diver, W. Ryan | Link, Brian K. | Weiner, George J. | Conde, Lucia | Bracci, Paige M. | Riby, Jacques | Holly, Elizabeth A. | Smith, Martyn T. | Jackson, Rebecca D. | Tinker, Lesley F. | Benavente, Yolanda | Becker, Nikolaus | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Rabe, Kari G. | Achenbach, Sara J. | Vachon, Celine M. | Goldin, Lynn R | Strom, Sara S. | Lanasa, Mark C. | Spector, Logan G. | Leis, Jose F. | Cunningham, Julie M. | Weinberg, J. Brice | Morrison, Vicki A. | Caporaso, Neil E. | Norman, Aaron D. | Linet, Martha S. | De Roos, Anneclaire J. | Morton, Lindsay M. | Severson, Richard K. | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Trichopoulos, Dimitrios | Masala, Giovanna | Weiderpass, Elisabete | Chirlaque, María-Dolores | Vermeulen, Roel C H | Travis, Ruth C. | Giles, Graham G. | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Clavel, Jacqueline | Zheng, Tongzhang | Holford, Theodore R | Offit, Kenneth | Zelenetz, Andrew | Klein, Robert J. | Spinelli, John J. | Bertrand, Kimberly A. | Laden, Francine | Giovannucci, Edward | Kraft, Peter | Kricker, Anne | Turner, Jenny | Vajdic, Claire M. | Ennas, Maria Grazia | Ferri, Giovanni M. | Miligi, Lucia | Liang, Liming | Sampson, Joshua | Crouch, Simon | Park, Ju-hyun | North, Kari E. | Cox, Angela | Snowden, John A. | Wright, Josh | Carracedo, Angel | Lopez-Otin, Carlos | Bea, Silvia | Salaverria, Itziar | Martin, David | Campo, Elias | Fraumeni, Joseph F. | de Sanjose, Silvia | Hjalgrim, Henrik | Cerhan, James R. | Chanock, Stephen J. | Rothman, Nathaniel | Slager, Susan L.
Nature genetics  2013;45(8):868-876.
PMCID: PMC3729927  PMID: 23770605
23.  Smoking, variation in N-acetyltransferase 1 (NAT1) and 2 (NAT2), and risk of non-Hodgkin lymphoma: a pooled analysis within the InterLymph consortium 
Cancer causes & control : CCC  2012;24(1):125-134.
Studies of smoking and risk of non-Hodgkin lymphoma (NHL) have yielded inconsistent results, possibly due to subtype heterogeneity and/or genetic variation impacting the metabolism of tobacco-derived carcinogens, including substrates of the N-acetyltransferase enzymes NAT1 and NAT2.
We conducted a pooled analysis of 5,026 NHL cases and 4,630 controls from seven case–control studies in the international lymphoma epidemiology consortium to examine associations between smoking, variation in the N-acetyltransferase genes NAT1 and NAT2, and risk of NHL subtypes. Smoking data were harmonized across studies, and genetic variants in NAT1 and NAT2 were used to infer acetylation phenotype of the NAT1 and NAT2 enzymes, respectively. Pooled odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for risk of NHL and subtypes were calculated using joint fixed effects unconditional logistic regression models.
Current smoking was associated with a significant 30 % increased risk of follicular lymphoma (n = 1,176) but not NHL overall or other NHL subtypes. The association was similar among NAT2 slow (OR 1.36; 95 % CI 1.07–1.75) and intermediate/rapid (OR 1.27; 95 % CI 0.95–1.69) acetylators (pinteraction = 0.82) and also did not differ by NAT1*10 allelotype. Neither NAT2 phenotype nor NAT1*10 allelotype was associated with risk of NHL overall or NHL subtypes.
The current findings provide further evidence for a modest association between current smoking and follicular lymphoma risk and suggest that this association may not be influenced by variation in the N-acetyltransferase enzymes.
PMCID: PMC3529854  PMID: 23160945
Non-Hodgkin lymphoma; Gene environment interaction; Cigarette smoking; N-acetyltransferase; Follicular lymphoma
24.  Assessment of Autoantibodies to Meningioma in a Population-based Study 
American Journal of Epidemiology  2012;177(1):75-83.
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.
PMCID: PMC3590036  PMID: 23221727
autoantibodies; brain neoplasms; genetics; immunologic factors; meningioma; neurosurgery; risk factors
25.  A Generic Coalescent-based Framework for the Selection of a Reference Panel for Imputation 
Genetic epidemiology  2010;34(8):10.1002/gepi.20505.
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.
PMCID: PMC3876740  PMID: 21058333
genotype imputation; coalescent; GWAS; linkage disequilibrium; weighted panel

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