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1.  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.
doi:10.1038/ncomms6751
PMCID: PMC4287989  PMID: 25569183
2.  Identification of gene–environment interactions in cancer studies using penalization 
Genomics  2013;102(4):10.1016/j.ygeno.2013.08.006.
High-throughput cancer studies have been extensively conducted, searching for genetic markers associated with outcomes beyond clinical and environmental risk factors. Gene–environment interactions can have important implications beyond main effects. The commonly-adopted single-marker analysis cannot accommodate the joint effects of a large number of markers. The existing joint-effects methods also have limitations. Specifically, they may suffer from high computational cost, do not respect the “main effect, interaction” hierarchical structure, or use ineffective techniques. We develop a penalization method for the identification of important G × E interactions and main effects. It has an intuitive formulation, respects the hierarchical structure, accommodates the joint effects of multiple markers, and is computationally affordable. In numerical study, we analyze prognosis data under the AFT (accelerated failure time) model. Simulation shows satisfactory performance of the proposed method. Analysis of an NHL (non-Hodgkin lymphoma) study with SNP measurements shows that the proposed method identifies markers with important implications and satisfactory prediction performance.
doi:10.1016/j.ygeno.2013.08.006
PMCID: PMC3869641  PMID: 23994599
Gene–environment interaction; Penalized marker identification; Cancer prognosis
3.  Role of One-carbon Metabolizing Pathway Genes and Gene-Nutrient Interaction in the Risk of Non-Hodgkin Lymphoma 
Cancer causes & control : CCC  2013;24(10):1875-1884.
Purpose
Genetic polymorphisms in one-carbon metabolizing pathway genes have been associated with risk of malignant lymphoma. However, the results have been inconsistent. The objectives of this study were to examine the potential relationship between gene-nutrient interactions and the risk of non-Hodgkin lymphoma (NHL).
Methods
We examined 25 polymorphisms in 16 one-carbon metabolism genes for their main effect and gene-nutrient interactions in relation to NHL risk among 518 incident cases and 597 population-based controls of Connecticut women enrolled between 1996 and 2000.
Results
A significantly reduced risk of NHL was associated with the homozygous TT genotype in CBS (rs234706, Ex9+33C>T) (OR = 0.51, 95%CI, 0.31–0.84), the homozygous CC genotype in MBD2 (rs603097, −2176C>T) (OR = 0.37, 95%CI, 0.17–0.79), the heterozygote AG genotype in FTHFD (rs1127717, Ex21+31A>G) (OR = 0.73, 95%CI, 0.55–0.98), and a borderline significantly reduced risk of NHL was observed for the homozygous CC genotype in MTRR (rs161870, Ex5+136T>C) (OR = 0.23, 95%CI, 0.05–1.04). The reduced risk of NHL associated with these genotypes was predominately in those with higher dietary vitamin B6 and methionine intakes, as well as with higher dietary folate intake although results were less stable. A borderline significantly increased risk of NHL was also observed for CBS (rs1801181, Ex13+41C>T), FTHFD (rs2305230, Ex10-40G>T), SHMT1 (rs1979277, Ex12+138C>T), and SHMT1 (rs1979276, Ex12+236T>C), and these associations appeared to be contingent on dietary nutrient intakes.
Conclusion
Our results suggest that variation in several one-carbon metabolizing pathway genes may influence the risk of NHL through gene-nutrient interactions involving dietary nutrient intakes.
doi:10.1007/s10552-013-0264-3
PMCID: PMC3951097  PMID: 23913011
dietary nutrients; folate; one-carbon metabolizing genes; non-Hodgkin lymphoma; cancer
4.  Interaction between Cigarette Smoking and HBV or HCV Infection on the Risk of Liver Cancer: A Meta-Analysis 
Introduction
Chronic infection with HBV and HCV as well as cigarette smoking are established risk factors of hepatocellular carcinoma (HCC), but it is unclear whether an interaction exists between these factors in causing hepatocellular carcinogenesis. We conducted a meta-analysis to evaluate the interaction of HBV and HCV infection and cigarette smoking on the risk of HCC.
Methods
We systematically searched the PUBMED and the China National Knowledge Infrastructure (CNKI) databases. A total of 16 eligible publications were identified. Cigarette smoking, and chronic HBV and HCV infections were dichotomized into present or absent. Additive (S) and multiplicative interaction indexes (V) between smoking and each of the two infections and their 95% confidence intervals (95% CI) were calculated for each study and then combined in a meta-analysis.
Results
We found a more than additive interaction between HBV infection and cigarette smoking (S=1.44, 95% CI=1.00–2.06; 9 studies) and a more than multiplicative interaction (V=1.60, 95% CI=1.16–2.20; 6 studies) between HCV infection and cigarette smoking. No publication bias was detected.
Conclusion
Smoking appears to interact with both HBV and HCV in determining HCC risk. A pooled analysis of individual subject data, with appropriate adjustment with other risk factors is warranted to confirm these results.
Impact
Chronic carriers of HBV and HCV are suggested to avoid smoking.
doi:10.1158/1055-9965.EPI-09-1297
PMCID: PMC4170071  PMID: 20447919
Cigarette smoking; HBV; HCV; HCC; interaction
5.  Polymorphisms in JAK/STAT Signaling Pathway Genes and Risk of Non-Hodgkin Lymphoma 
Leukemia research  2013;37(9):1120-1124.
Impaired function of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway genes leads to immunodeficiency and various hematopoietic disorders. We evaluated the association between genetic polymorphisms (SNPs) in 12 JAK/STAT pathway genes (JAK3, STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6, SCOS1, SCOS2, SCOS3, and SCOS4) and NHL risk in a population-based case-control study of Connecticut women. We identified three SNPs in STAT3 (rs12949918 and rs6503695) and STAT4 (rs932169) associated with NHL risk after adjustment for multiple comparison. Our results suggest that genetic variation in JAK/STAT pathway genes may play a role in lymphomagenesis and warrants further investigation.
doi:10.1016/j.leukres.2013.05.003
PMCID: PMC3998836  PMID: 23768868
JAK/STAT signaling pathway; Non-Hodgkin Lymphoma; polymorphism; case-control study
6.  A Pooled Analysis of Alcohol Consumption and Risk of Multiple Myeloma in the International Multiple Myeloma Consortium 
Background
Recent findings suggest that alcohol consumption may reduce risk of multiple myeloma (MM).
Methods
To better understand this relationship, we conducted an analysis of six case-control studies participating in the International Multiple Myeloma Consortium (1,567 cases, 7,296 controls). Summary odds ratios (ORs) and 95% confidence intervals (CI) relating different measures of alcohol consumption and MM risk were computed by unconditional logistic regression with adjustment for age, race, and study center.
Results
Cases were significantly less likely than controls to report ever drinking alcohol (men: OR 0.72, 95% CI 0.59-0.89, women: OR 0.81, 0.68-0.95). The inverse association with MM was stronger when comparing current to never drinkers (men: OR=0.57, 95% CI 0.45-0.72, women: OR=0.55, 95% CI 0.45-0.68), but null among former drinkers. We did not observe an exposure-response relationship with increasing alcohol frequency, duration or cumulative lifetime consumption. Additional adjustment for body mass index, education, or smoking did not affect our results; and the patterns of association were similar for each type of alcohol beverage examined.
Conclusions
Our study is, to our knowledge, the largest of its kind to date, and our findings suggest that alcohol consumption may be associated with reduced risk of MM.
Impact
Prospective studies, especially those conducted as pooled analyses with large sample sizes, are needed to confirm our findings and further explore whether alcohol consumption provides true biologic protection against this rare, highly fatal malignancy.
doi:10.1158/1055-9965.EPI-13-0334
PMCID: PMC3769449  PMID: 23964064
7.  Single nucleotide polymorphisms in genes encoding for CC chemokines were not associated with the risk of Non-Hodgkin Lymphoma 
Background
Chemokines play a pivotal role in immune regulation and response, and previous studies suggest an association between immune deficiency and Non-Hodgkin lymphoma (NHL).
Methods
We evaluated the association between NHL and polymorphisms in 18 genes (CCL1, CCL2, CCL5, CCL7, CCL8, CCL11, CCL13, CCL18, CCL20, CCL24, CCL26, CCR1, CCR3, CCR4, CCR6, CCR7, CCR8 and CCR9) encoding for the CC chemokines using data from a population-based case-control study of NHL conducted in Connecticut women.
Results
CCR8 was associated with diffuse large B-cell lymphoma (DLBCL) (p = 0.012) and CCL13 was associated with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) (p = 0.003) at gene level. After adjustment for multiple comparisons, none of the genes or SNPs were associated with risk of overall NHL or NHL subtypes.
Conclusions
Our results suggest that the genes encoding for CC chemokines are not significantly associated with the risk of NHL, and further studies are needed to verify these findings.
Impact
Our data indicate that CC chemokine genes were not associated with NHL risk.
doi:10.1158/1055-9965.EPI-13-0328
PMCID: PMC3753095  PMID: 23640258
Non-Hodgkin lymphoma; CC chemokine gene; Single nucleotide polymorphism
8.  Polymorphisms in DNA Repair Pathway Genes, Body Mass Index, and Risk of Non-Hodgkin Lymphoma 
American journal of hematology  2013;88(7):606-611.
We conducted a population-based case-control study in Connecticut women to test the hypothesis that genetic variations in DNA repair pathway genes may modify the relationship between body mass index (BMI) and risk of non-Hodgkin lymphoma (NHL). Compared to those with BMI < 25, women with BMI ≥ 25 had significantly increased risk of NHL among women who carried BRCA1 (rs799917) CT/TT, ERCC2 (rs13181) AA, XRCC1 (rs1799782) CC, and WRN (rs1801195) GG genotypes, but no increase in NHL risk among women who carried BRCA1 CC, ERCC2 AC/CC, XRCC1 CT/TT, and WRN GT/TT genotypes. A significant interaction with BMI was only observed for WRN (rs1801195, P=0.004) for T-cell lymphoma and ERCC2 (rs13181, P=0.002) for diffuse large B-cell lymphoma. The results suggest that common genetic variation in DNA repair pathway genes may modify the association between BMI and NHL risk.
doi:10.1002/ajh.23463
PMCID: PMC3902049  PMID: 23619945
Non-Hodgkin lymphoma; BMI; polymorphisms; DNA repair genes
9.  Subtype of Dietary Fat in Relation to Risk of Hodgkin Lymphoma: A Population-based Case-Control Study in Connecticut and Massachusetts 
Cancer causes & control : CCC  2013;24(3):485-494.
Few epidemiological studies have examined the relationship between dietary fat, which may affect immune function, and risk of Hodgkin lymphoma (HL). The aim of this study was to test the hypothesis that high dietary intake of fat and specific subtypes of fat is associated with the risk of HL among 486 HL cases and 630 population-based controls recruited between 1997–2000 in Connecticut and Massachusetts. Unconditional logistic regression was used to calculate odds ratios (OR) and 95 % confidence intervals (CIs) stratified by age and gender. Among younger adults, HL risk was significantly and positively associated with higher intake of saturated fat (ORs for increasing quartiles= 1.3, 1.8, and 2.1; p trend = 0.04), and negatively associated with higher intake of monounsaturated fat (ORs for increasing quartiles= 0.5, 0.5, and 0.4; p trend = 0.03), after adjustment for potential confounders including lifestyle and other dietary factors. The associations with saturated fat (ORs for increasing quartile = 2.4, 3.2, and 4.4; p trend < 0.01) and monounsaturated fat (ORs for increasing quartile= 0.3, 0.6, and 0.3; p trend = 0.04) were most apparent in younger women, whereas there was no significant association between intake of total fat or any type of fat and risk of HL in older females or younger or older males. These findings show that the associations between dietary fat and risk of HL may vary by gender and age, and require confirmation in other populations.
doi:10.1007/s10552-012-0136-2
PMCID: PMC4044911  PMID: 23314676
Hodgkin lymphoma; dietary fat; saturated fat; monounsaturated fat
10.  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.
doi:10.1093/aje/kwn058
PMCID: PMC4025953  PMID: 18408225
case-control studies; hair dyes; lymphoma; non-Hodgkin
11.  Association of AMP-activated Protein Kinase with Risk and Progression of Non-Hodgkin Lymphoma 
Background
Metabolic dysregulation has been identified as an “emerging hallmark” of cancer. The heterotrimeric AMP-activated protein kinase (AMPK) complex is a central regulator of the metabolic system and an important component of the mTOR pathway and the p53 axis, making it uniquely positioned to influence carcinogenesis through its canonical functions in the metabolic arena, as well as through more traditional mechanisms such as regulation of apoptosis and angiogenesis.
Methods
We conducted a population-based genetic association study to examine the impact of mutations in AMPK subunit genes on risk of non-Hodgkin’s lymphoma (NHL). We also analyzed public microarray data to determine the expression of AMPK in NHL cells and to assess the influence of AMPK expression on overall survival in NHL patients.
Results
We identified an AMPK subunit haplotype which was significantly associated with NHL (OR=5.44, 95%CI: 2.15–13.75) in women with no family history of cancer. Haplotypes in two subunits, PRKAA2 and PRKAG3, were nominally associated with the follicular and diffuse large B cell lymphoma histologic subtypes, respectively, although these associations did not retain statistical significance after correction for multiple comparisons. Further, both of these subunits were differentially expressed (p<0.05) in one or more lymphoma cell type, and higher expression of two versions of the AMPK-β subunit were significantly associated with increased five-year survival among NHL patients (p=0.001 and p=0.021).
Conclusion
These results provide evidence for AMPK involvement in the pathogenesis and progression of NHL.
Impact
These findings may lead to a novel area of research into NHL treatment and chemoprevention.
doi:10.1158/1055-9965.EPI-12-1014
PMCID: PMC3631103  PMID: 23396962
AMPK; metabolism; lymphoma
12.  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.
Methods
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.
Results
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).
Conclusions
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).
doi:10.1016/j.cgh.2008.02.011
PMCID: PMC3962672  PMID: 18387498
13.  Targetome profiling, pathway analysis and genetic association study implicate miR-202 in lymphomagenesis 
Background
miRNAs have been implicated in numerous tumorigenic pathways, and previous studies have associated miR-202 dysregulation with various cancer types, including follicular lymphoma.
Methods
The miR-202 targetome was identified by ribonucleoprotein immunoprecipitation-microarray (RIP-Chip), and functional interactions among identified targets were investigated using the Ingenuity Pathway Analysis tool. We also performed a population-based genetic association study of a polymorphism within the miR-202 stem-loop sequence and risk of non-Hodgkin lymphoma. In vitro gain-of-function experiments were further conducted to elucidate the functional significance of the variant.
Results
141 potential members of the miR-202 targetome were identified by a transcriptome-wide RIP-Chip assay. Functional interactions among identified targets suggested that miR-202 regulated genes are involved in biological pathways relevant for hematological function and cancer. Consistent with this, a genetic association analysis using human blood samples revealed a significant association between a germline mutation (rs12355840) in the miR-202 precursor sequence and follicular lymphoma (FL) risk. An in vitro functional assay further demonstrated that the variant allele resulted in diminished miR-202 levels, possibly by altering precursor processing efficiency.
Conclusions
Taken together, our findings suggest that miR-202 is involved in follicular lymphomagenesis.
Impact
These findings implicate miR-202 as a potential tumor suppressor in FL and warrant the investigation of miR-202 as a novel biomarker of FL risk.
doi:10.1158/1055-9965.EPI-12-1131-T
PMCID: PMC3905613  PMID: 23334589
miR-202; Targetome; lymphomagenesis; follicular lymphoma; pathway analysis
14.  Body Size and Risk of Hodgkin Lymphoma by Age and Gender: A Population-based Case-Control Study in Connecticut and Massachusetts 
Cancer causes & control : CCC  2012;24(2):287-295.
Purpose
Descriptive studies have indicated a rising trend in Hodgkin lymphoma (HL) incidence in young adults, especially females. Increasing evidence has suggested that some risk factors associated with HL may vary by age or gender. Recent studies have reported an increased risk of HL associated with increasing body mass index (BMI), but the results have been inconsistent. The objectives of this study were to examine whether the associations between measures of body size (height, weight, and BMI) and HL risk vary by age and/or gender.
Methods
A population-based case-control study was conducted in Connecticut and Massachusetts. A total of 567 HL cases and 679 controls were recruited in 1997–2000. Unconditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CIs).
Results
Among younger women < 35 years old, being overweight (25–29.9 kg/m2) vs. normal weight (18.5–24.9 kg/m2) was significantly associated with an increased risk of HL (OR = 2.1, 95% CI = 1.1–4.0). The risk increased with increasing weight and BMI (P trends < 0.01). Among women ≥ 35 years old, by contrast, higher weight and BMI were associated with a reduced risk of HL (P trends < 0.01). Conversely, there was no significant association between BMI and risk of HL in younger or older males.
Conclusions
These findings show that the associations between body size and risk of HL vary by gender and age, and require confirmation in other populations.
doi:10.1007/s10552-012-0100-1
PMCID: PMC3557669  PMID: 23208661
Hodgkin lymphoma; body size; body mass index; height; weight
15.  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.
doi:10.1038/ng.2652
PMCID: PMC3729927  PMID: 23770605
16.  Integrative Analysis of Cancer Prognosis Data with Multiple Subtypes Using Regularized Gradient Descent 
Genetic epidemiology  2012;10.1002/gepi.21669.
In cancer research, high-throughput profiling studies have been extensively conducted, searching for genes/SNPs associated with prognosis. Despite seemingly significant differences, different subtypes of the same cancer (or different types of cancers) may share common susceptibility genes. In this study, we analyze prognosis data on multiple subtypes of the same cancer, but note that the proposed approach is directly applicable to the analysis of data on multiple types of cancers. We describe the genetic basis of multiple subtypes using the heterogeneity model, which allows overlapping but different sets of susceptibility genes/SNPs for different subtypes. An accelerated failure time (AFT) model is adopted to describe prognosis. We develop a regularized gradient descent approach, which conducts gene-level analysis and identifies genes that contain important SNPs associated with prognosis. The proposed approach belongs to the family of gradient descent approaches, is intuitively reasonable, and has affordable computational cost. Simulation study shows that when prognosis-associated SNPs are clustered in a small number of genes, the proposed approach outperforms alternatives with significantly more true positives and fewer false positives. We analyze an NHL (non-Hodgkin lymphoma) prognosis study with SNP measurements, and identify genes associated with the three major subtypes of NHL, namely DLBCL, FL and CLL/SLL. The proposed approach identifies genes different from using alternative approaches and has the best prediction performance.
doi:10.1002/gepi.21669
PMCID: PMC3729731  PMID: 22851516
Integrative analysis; Cancer Prognosis; Gradient descent; NHL; SNP
17.  Occupational solvent exposure, genetic variation in immune genes, and the risk for non-Hodgkin lymphoma 
Solvent exposure has been inconsistently linked to the risk for non-Hodgkin lymphoma (NHL). The aim of this study was to determine whether the association is modified by genetic variation in immune genes. A population-based case–control study involving 601 incident cases of NHL and 717 controls was carried out in 1996–2000 among women from Connecticut. Thirty single nucleotide polymorphisms in 17 immune genes were examined in relation to the associations between exposure to various solvents and the risk for NHL. The study found that polymorphism in interleukin 10 (IL10; rs1800890) modified the association between occupational exposure to organic solvents and the risk for diffuse large B-cell lymphoma (Pfor interaction=0.0058). The results remained statistically significant after adjustment for false discovery rate. Compared with women who were never occupationally exposed to any organic solvents, women who were exposed to organic solvents at least once had a significantly increased risk for diffuse large B-cell lymphoma if they carried the IL10 (rs1800890) TT genotype (odds ratio=3.31, 95% confidence interval: 1.80–6.08), but not if they carried the AT/AA genotype (odds ratio=1.14, 95% confidence interval: 0.72–1.79). No significant interactions were observed for other immune gene single nucleotide polymorphisms and various solvents in relation to NHL overall and its major subtypes. The study provided preliminary evidence supporting a role of immune gene variations in modifying the association between occupational solvent exposure and the risk for NHL.
doi:10.1097/CEJ.0b013e328354d2c1
PMCID: PMC3469764  PMID: 22609637
immune genes; non-Hodgkin lymphoma; occupational exposure; single nucleotide polymorphism; solvents
18.  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.
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s10552-012-0098-4
PMCID: PMC3529854  PMID: 23160945
Non-Hodgkin lymphoma; Gene environment interaction; Cigarette smoking; N-acetyltransferase; Follicular lymphoma
19.  Self-reported history of infections and the risk of non-Hodgkin lymphoma: an InterLymph pooled analysis 
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.
doi:10.1002/ijc.27438
PMCID: PMC3406230  PMID: 22266776
20.  Occupational Solvent Exposure, Genetic Variation of DNA Repair Genes, and Risk of Non-Hodgkin Lymphoma 
Objective
To test the hypothesis that genetic variations in DNA repair genes may modify the association between occupational exposure to solvents and the risk of non-Hodgkin lymphoma (NHL).
Methods
A population-based case-control study was conducted in Connecticut women including 518 histologically confirmed incident NHL cases and 597 controls. Unconditional logistic regression models were used to estimate odds ratios (OR) and effect modification from the 30 SNPs in 16 DNA repair genes of the association between solvent exposure and risk of NHL overall and subtypes.
Results
SNPs in MGMT (rs12917) and NBS1 (rs1805794) significantly modified the association between exposure to chlorinated solvents and NHL risk (Pforinteraction = 0.0003 and 0.0048 respectively). After stratified by major NHL histological subtypes, MGMT (rs12917) modified the association between chlorinated solvents and risk of diffuse large B-cell lymphoma (Pforinteraction = 0.0027) and follicular lymphoma (Pforinteraction = 0.0024). A significant interaction was also observed between occupational exposure to benzene and BRCA2 (rs144848) for NHL overall (Pforinteraction = 0.0042).
Conclusions
Our study results suggest that genetic variations in DNA repair genes modify the association between occupational exposure to solvents and risk of NHL.
doi:10.1097/CEJ.0b013e328351c762
PMCID: PMC3397155  PMID: 22430443
Non-Hodgkin Lymphoma; Occupational Exposure; Solvents; Single Nucleotide Polymorphism; DNA Repair Genes
21.  Dietary fiber intake and risk of breast cancer by menopausal and estrogen receptor status 
European journal of nutrition  2012;52(1):217-223.
Purpose
Evaluate the hypothesis that relation of breast cancer associated with dietary fiber intakes varies by type of fiber, menopausal, and the tumor’s hormone receptor status.
Methods
A case-control study of female breast cancer was conducted in Connecticut. A total of 557 incident breast cancer cases and 536 age frequency-matched controls were included in the analysis. Information on dietary intakes was collected through in-person interviews with a semi-quantitative food frequency questionnaire and was converted into nutrient intakes. Odds ratios and 95% confidence intervals were estimated by unconditional logistic regression.
Results
Among pre-menopausal women, higher intake of soluble fiber (highest versus lowest quartile of intake) was associated with a significantly reduced risk of breast cancer (OR = 0.38, 95% CI, 0.15–0.97, Ptrend = 0.08). When further restricted to pre-menopausal women with ER− tumors, the adjusted OR for the highest quartile of intake was 0.15 (95% CI, 0.03–0.69, Ptrend = 0.02) for soluble fiber intake. Among post-menopausal women, no reduced risk of breast cancer was observed for either soluble or insoluble fiber intakes or among ER+ or ER− tumor groups.
Conclusions
The results from this study show that dietary soluble fiber intake is associated with a significantly reduced risk of ER− breast cancer among pre-menopausal women. Additional studies with larger sample size are needed to confirm these results.
doi:10.1007/s00394-012-0305-9
PMCID: PMC3709253  PMID: 22350922
Dietary fiber intake; Breast cancer; Estrogen receptor; Menopausal status; Case-control studies
22.  Potential cancer-related role of circadian gene TIMELESS suggested by expression profiling and in vitro analyses 
BMC Cancer  2013;13:498.
Background
The circadian clock and cell cycle are two global regulatory systems that have pervasive behavioral and physiological effects on eukaryotic cells, and both play a role in cancer development. Recent studies have indicated that the circadian and cell cycle regulator, TIMELESS, may serve as a molecular bridge between these two regulatory systems.
Methods
To assess the role of TIMELESS in tumorigenesis, we analyzed TIMELESS expression data from publically accessible online databases. A loss-of-function analysis was then performed using TIMELESS-targeting siRNA oligos followed by a whole-genome expression microarray and network analysis. We further tested the effect of TIMELESS down-regulation on cell proliferation rates of a breast and cervical cancer cell line, as suggested by the results of our network analysis.
Results
TIMELESS was found to be frequently overexpressed in different tumor types compared to normal controls. Elevated expression of TIMELESS was significantly associated with more advanced tumor stage and poorer breast cancer prognosis. We identified a cancer-relevant network of transcripts with altered expression following TIMELESS knockdown which contained many genes with known functions in cancer development and progression. Furthermore, we observed that TIMELESS knockdown significantly decreased cell proliferation rate.
Conclusions
Our results suggest a potential role for TIMELESS in tumorigenesis, which warrants further investigation of TIMELESS expression as a potential biomarker of cancer susceptibility and prognostic outcome.
doi:10.1186/1471-2407-13-498
PMCID: PMC3924353  PMID: 24161199
TIMELESS; Circadian gene; Cell cycle; Tumorigenesis; Expression profiling
23.  Sexual Functioning among Testicular Cancer Survivors: A Case-Control Study in the U.S. 
Objective
Sexual function among testicular cancer survivors is a concern because affected men are of reproductive age when diagnosed. We conducted a case-control study among United States military men to examine whether testicular cancer survivors experienced impaired sexual function.
Methods
A total of 246 testicular cancer cases and 236 ethnicity and age matched controls were enrolled in the study in 2008-2009. The Brief Male Sexual Function Inventory (BMSFI) was used to assess sexual function.
Results
Compared to controls, cases scored significantly lower on sex drive (5.77 vs. 5.18), erection (9.40 vs. 8.63), ejaculation (10.83 vs. 9.90), and problem assessment (10.55 vs. 9.54). Cases were significantly more likely to have impaired erection (OR 1.72; 95% CI 1.11-2.64), ejaculation (OR 2.27; 95% CI 1.32-3.91), and problem assessment (OR 2.36; 95% CI 1.43-3.90). In histology and treatment analysis, nonseminoma, chemotherapy and radiation treated cases risk of erectile dysfunction, delayed ejaculation, and/or problem assessment were greater when compared to controls.
Conclusion
This study provides evidence that testicular cancer survivors are more likely to have impaired sexual functioning compared to demographically matched controls. The observed impaired sexual functioning appeared to vary by treatment regimen and histologic subtype.
doi:10.1016/j.jpsychores.2012.02.011
PMCID: PMC3374934  PMID: 22691563
Testicular cancer; sexual function; military men
24.  Methyl bromide exposure and cancer risk in the Agricultural Health Study 
Cancer causes & control : CCC  2012;23(6):807-818.
Purpose
Methyl bromide is a genotoxic soil fumigant with high acute toxicity, but unknown human carcinogenicity. Although many countries have reduced methyl bromide use because of its ozone depleting properties, some uses remain in the United States and other countries, warranting further investigation of human health effects.
Methods
We used Poisson regression to calculate rate ratios (RR) and 95% confidence intervals (CI) for associations between methyl bromide use and all cancers combined and 12 specific sites among 53,588 Agricultural Health Study (AHS) pesticide applicators with follow-up from 1993–2007. We also evaluated interactions with a family history for four common cancers (prostate, lung, colon, and lymphohematopoietic). We categorized methyl bromide exposure based on lifetime days applied weighted by an intensity score.
Results
A total of 7,814 applicators (14.6%) used methyl bromide, predominantly before enrollment. Based on 15 exposed cases, stomach cancer risk increased monotonically with increasing methyl bromide use (RR=1.42; 95% CI: 0.51–3.95 and RR=3.13; 95% CI: 1.25–7.80 for low and high use compared with no use; ptrend=0.02). No other sites displayed a significant monotonic pattern. Although we previously observed an association with prostate cancer (follow-up through 1999), the association did not persist with longer follow-up. We observed a non-significant elevated risk of prostate cancer with methyl bromide use among those with a family history of prostate cancer, but the interaction with a family history did not achieve statistical significance.
Conclusions
Our results provide little evidence of methyl bromide associations with cancer risk for most sites examined; however, we observed a significant exposure-dependent increase in stomach cancer risk. Small numbers of exposed cases and declining methyl bromide use might have influenced our findings. Further study is needed in more recently exposed populations to expand on these results.
doi:10.1007/s10552-012-9949-2
PMCID: PMC3430844  PMID: 22527160
methyl bromide; fumigant; pesticide; cancer
25.  Yale Lung Cancer Model 
The age-period-cohort model is known to provide an excellent description of the temporal trends in lung cancer incidence and mortality. This analytic approach is extended to include the contribution of carcinogenesis models for smoking. Usefulness of this strategy is that it offers a way to temporally calibrate a model that is fitted to population data and it can be readily adopted for the consideration of many different models. In addition, it provides diagnostics that can suggest temporal limitations of a particular carcinogenesis model in describing population rates. Alternative carcinogenesis models can be embedded within this framework. The two stage clonal expansion model is implemented here. The model was used to estimate the impact of tobacco control following dissemination of knowledge of the harmful effects of cigarette smoking by comparing the observed number of lung cancer deaths to those expected if there had been no control compared to an ideal of complete control in 1965. Results indicate that 35.2% and 26.5% of lung cancer deaths that could have been avoided actually were for males and females, respectively.
doi:10.1111/j.1539-6924.2011.01754.x
PMCID: PMC3662537  PMID: 22882886
Age-period-cohort calibration; lung cancer; cigarette smoking; population risk; two-stage clonal expansion model

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