James R Cerhan

Mayo Clinic - Rochester, Рочестер, Minnesota, United States

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Publications (475)3408.86 Total impact

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    ABSTRACT: Deficits in health-related quality of life (HRQOL) may be associated with worse patient experiences, outcomes and even survival. While there exists evidence to identify risk factors associated with deficits in HRQOL among patients with individual medical conditions such as cancer, it is less well established in more general populations without attention to specific illnesses. This study used patients with a wide range of medical conditions to identify contributors with the greatest influence on HRQOL deficits. Self-perceived general health and depressive symptoms were assessed using data from 21,736 Mayo Clinic Biobank (MCB) participants. Each domain was dichotomized into categories related to poor health: deficit (poor/fair for general health and ≥3 for PHQ-2 depressive symptoms) or non-deficit. Logistic regression models were used to test the association of commonly collected demographic characteristics and disease burden with each HRQOL domain, adjusting for age and gender. Gradient boosting machine (GBM) models were applied to quantify the relative influence of contributors on each HRQOL domain. The prevalence of participants with a deficit was 9.5 % for perception of general health and 4.6 % for depressive symptoms. For both groups, disease burden had the strongest influence for deficit in HRQOL (63 % for general health and 42 % for depressive symptoms). For depressive symptoms, age was equally influential. The prevalence of a deficit in general health increased slightly with age for males, but remained stable across age for females. Deficit in depressive symptoms was inversely associated with age. For both HRQOL domains, risk of a deficit was associated with higher disease burden, lower levels of education, no alcohol consumption, smoking, and obesity. Subjects with deficits were less likely to report that they were currently working for pay than those without a deficit; this association was stronger among males than females. Comorbid health burden has the strongest influence on deficits in self-perceived general health, while demographic factors show relatively minimal impact. For depressive symptoms, both age and comorbid health burden were equally important, with decreasing deficits in depressive symptoms with increasing age. For interpreting patient-reported metrics and comparison, one must account for comorbid health burden.
    Health and Quality of Life Outcomes 12/2015; 13(1):95. DOI:10.1186/s12955-015-0285-6 · 2.10 Impact Factor
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    ABSTRACT: Tumor budding in colorectal carcinoma has been associated with poor outcome in multiple studies, but the absence of an established histologic cutoff for "high" tumor budding, heterogeneity in study populations, and varying methods for assessing tumor budding have hindered widespread incorporation of this parameter in clinical reports. We used an established scoring system in a population-based cohort to determine a histologic cutoff for "high" tumor budding and confirm its prognostic significance. We retrieved hematoxylin and eosin-stained sections from 553 incident colorectal carcinoma cases. Each case was previously characterized for select molecular alterations and survival data. Interobserver agreement was assessed between 2 gastrointestinal pathologists and a group of 4 general surgical pathologists. High budding (≥10 tumor buds in a ×20 objective field) was present in 32% of cases, low budding in 46%, and no budding in 22%. High tumor budding was associated with advanced pathologic stage (P<0.001), microsatellite stability (P=0.005), KRAS mutation (P=0.010), and on multivariate analysis with a >2 times risk of cancer-specific death (hazard ratio=2.57 [1.27, 5.19]). After multivariate adjustment, by penalized smoothing splines, we found increasing tumor bud counts from 5 upward to be associated with an increasingly shortened cancer-specific survival. By this method, a tumor bud count of 10 corresponded to approximately 2.5 times risk of cancer-specific death. The interobserver agreement was good with weighted κ of 0.70 for 2 gastrointestinal pathologists over 121 random cases and 0.72 between all 6 pathologists for 20 random cases. Using an established method to assess budding on routine histologic stains, we have shown that a cutoff of 10 for high tumor budding is independently associated with a significantly worse prognosis. The reproducibility data provide support for the routine widespread implementation of tumor budding in clinical reports.
    The American journal of surgical pathology 07/2015; DOI:10.1097/PAS.0000000000000504 · 4.59 Impact Factor
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    ABSTRACT: Twenty percent of patients with follicular lymphoma (FL) experience progression of disease (POD) within 2 years of initial chemoimmunotherapy. We analyzed data from the National LymphoCare Study to identify whether prognostic FL factors are associated with early POD and whether patients with early POD are at high risk for death. In total, 588 patients with stage 2 to 4 FL received first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Two groups were defined: patients with early POD 2 years or less after diagnosis and those without POD within 2 years, the reference group. An independent validation set, 147 patients with FL who received first-line R-CHOP, was analyzed for reproducibility. Of 588 patients, 19% (n = 110) had early POD, 71% (n = 420) were in the reference group, 8% (n = 46) were lost to follow-up, and 2% (n = 12) died without POD less than 2 years after diagnosis. Five-year overall survival was lower in the early-POD group than in the reference group (50% v 90%). This trend was maintained after we adjusted for FL International Prognostic Index (hazard ratio, 6.44; 95% CI, 4.33 to 9.58). Results were similar for the validation set (FL International Prognostic Index-adjusted hazard ratio, 19.8). In patients with FL who received first-line R-CHOP, POD within 2 years after diagnosis was associated with poor outcomes and should be further validated as a standard end point of chemoimmunotherapy trials of untreated FL. This high-risk FL population warrants further study in directed prospective clinical trials. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 06/2015; DOI:10.1200/JCO.2014.59.7534 · 18.43 Impact Factor
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    ABSTRACT: The World Health Organization classification of non-Hodgkin lymphoma (NHL) was introduced in 2001. However, its incorporation into clinical practice is not well-described. We studied the distribution of NHL subtypes in adults diagnosed from 1998-2011, evaluated time trends, geo-demographic correlates, and changes in 5-year overall survival (OS). We obtained data prospectively collected by the National Cancer Data Base, which covers 70% of US cancer cases. There were 596,476 patients diagnosed with NHL. The major subtypes were diffuse large B-cell (32.5%), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; 18.6%), follicular (17.1%), marginal zone (8.3%), mantle cell (4.1%), peripheral T-cell not-otherwise-specified (1.7%), Burkitt (1.6%), hairy cell (1.1%), lymphoplasmacytic (1.1%), and NHL not-otherwise-specified (10.8%). Over the study period, the proportion of NHL not-otherwise-specified declined by half, while marginal zone lymphoma doubled. The distribution of major and rare NHL subtypes varied according to demographics but less so geographically or by type of treatment facility. We noted several novel findings among Hispanics (lower proportion of CLL/SLL, but higher Burkitt lymphoma and nasal NK/T-cell lymphoma), Asians (higher enteropathy-associated T-cell and angioimmunoblastic T-cell lymphomas), Blacks (higher hepatosplenic T-cell lymphoma), and Native Americans (similar proportions of CLL/SLL and nasal NK/T-cell lymphoma as Asians). With the exception of peripheral T-cell not-otherwise-specified and hairy cell leukemia, 5-year OS has improved for all the major NHL subtypes. This article is protected by copyright. All rights reserved. © 2015 Wiley Periodicals, Inc.
    American Journal of Hematology 06/2015; DOI:10.1002/ajh.24086 · 3.48 Impact Factor
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    ABSTRACT: Non-Hodgkin lymphoma (NHL) is an enigmatic disease with few known risk factors. Spatio-temporal epidemiologic analyses have the potential to reveal patterns that may give clues to new risk factors worthy of investigation. We sought to investigate clusters of NHL through space and time based on life course residential histories. We used residential histories from a population-based NHL case-control study of 1300 cases and 1044 controls with recruitment centers in Iowa, Detroit, Seattle, and Los Angeles, and diagnosed in 1998-2000. Novel methods for cluster detection allowing for residential mobility, called Q-statistics, were used to quantify nearest neighbor relationships through space and time over the life course to identify cancer clusters. Analyses were performed on all cases together and on two subgroups of NHL: Diffuse large B-cell lymphoma and follicular lymphoma. These more homogenous subgroups of cases might have a more common etiology that could potentially be detected in cluster analysis. Based on simulation studies designed to help account for multiple testing across space and through time, we required at least four significant cases nearby one another to declare a region a potential cluster, along with confirmatory analyses using spatial-only scanning windows (SaTScan). Evidence of a small cluster in southeastern Oakland County, MI was suggested using residences 10-18 years prior to diagnosis, and confirmed by SaTScan in a time-slice analysis 20 years prior to diagnosis, when all cases were included in the analysis. Consistent evidence of clusters was not seen in the two histologic subgroups. Suggestive evidence of a small space-time cluster in southeastern Oakland County, MI was detected in this NHL case-control study in the USA.
    Environmental Health 06/2015; 14(1):48. DOI:10.1186/s12940-015-0034-7 · 2.71 Impact Factor
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    ABSTRACT: Excess adiposity has been associated with lymphomagenesis, possibly mediated by increased cytokine production causing a chronic inflammatory state. The relationship between obesity, cytokine polymorphisms and selected mature B-cell neoplasms is reported. Data on 4979 cases and 4752 controls from nine American/European studies from the InterLymph consortium (1988-2008) were pooled. For diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL), joint associations of body mass index (from self-reported height and weight) and 12 polymorphisms in cytokines IL1A (rs1800587), IL1B (rs16944, rs1143627), IL1RN (rs454078), IL2 (rs2069762), IL6 (rs1800795, rs1800797), IL10 (rs1800890, rs1800896), TNF (rs1800629), LTA (rs909253), and CARD15 (rs2066847) were investigated using unconditional logistic regression. BMI-polymorphism interaction effects were estimated using the relative excess risk due to interaction (RERI). Obesity (BMI≥30kg m-2) was associated with DLBCL risk (OR=1.33, 95%CI 1.02-1.73), as was TNF-308GA+AA (OR=1.24, 95%CI 1.07-1.44). Together, being obese and TNF-308GA+AA increased DLBCL risk almost two-fold relative to those of normal weight and TNF-308GG (OR=1.93 95%CI 1.27-2.94), with a RERI of 0.41 (95%CI -0.05,0.84, P(interaction)=0.13). For FL and CLL/SLL, no associations with obesity or TNF-308GA+AA, either singly or jointly, were observed. No evidence of interactions between obesity and the other polymorphisms were detected. Our results suggest that cytokine polymorphisms do not generally interact with BMI to increase lymphoma risk but obesity and TNF-308GA+AA may interact to increase DLBCL risk. Studies using better measures of adiposity are needed to further investigate the interactions between obesity and TNF-308G>A in the pathogenesis of lymphoma. Copyright © 2015, American Association for Cancer Research.
    Cancer Epidemiology Biomarkers & Prevention 05/2015; DOI:10.1158/1055-9965.EPI-14-1355 · 4.32 Impact Factor
  • Cancer Research 05/2015; 75(9 Supplement):P6-07-03-P6-07-03. DOI:10.1158/1538-7445.SABCS14-P6-07-03 · 9.28 Impact Factor
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    ABSTRACT: Data from the National LymphoCare Study (a prospective, multicentre registry that enrolled follicular lymphoma (FL) patients from 2004 to 2007) were used to determine disease characteristics, treatment patterns, outcomes and prognosis for elderly FL (eFL) patients. Of 2650 FL patients, 209 (8%) were aged >80 years; these eFL patients more commonly had grade 3 disease, less frequently received chemoimmunotherapy and anthracyclines, and had lower response rates when compared to younger patients. With a median follow-up of 6.9 years, 5-year overall survival (OS) for eFL patients was 59%; 38% of deaths were lymphoma-related. No treatment produced superior OS among eFL patients. In multivariate Cox models, anaemia, B-symptoms and male sex predicted worse OS (P < 0·01); a prognostic index of these factors (0, 1 or ≥2 present) predicted OS [hazard ratio (95% CI): ≥2 vs. 0, 4·72 (2·38-9·33); 1 vs. 0, 2·63 (1·39-4·98)], with a higher concordance index (0·63) versus the Follicular Lymphoma International Prognostic Index (0·55). The index was validated in an independent cohort. In the largest prospective US-based eFL cohort, no optimal therapy was identified and nearly 40% of deaths were lymphoma-related, representing baseline outcomes in the modern era. © 2015 John Wiley & Sons Ltd.
    British Journal of Haematology 04/2015; 170(1). DOI:10.1111/bjh.13399 · 4.96 Impact Factor
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    ABSTRACT: Peripheral T-cell lymphomas (PTCLs) are generally aggressive non-Hodgkin lymphomas with poor overall survival rates following standard therapy. One-third of PTCLs express interferon regulatory factor-4 (IRF4), a tightly-regulated transcription factor involved in lymphocyte growth and differentiation. IRF4 drives tumor growth in several lymphoid malignancies and has been proposed as a candidate therapeutic target. Since direct IRF4 inhibitors are not clinically available, we sought to characterize the mechanism by which IRF4 expression is regulated in PTCLs. We demonstrated that IRF4 is constitutively expressed in PTCL cells and drives Myc expression and proliferation. Using an inhibitor screen, we identified NF-κB as a candidate regulator of IRF4 expression and cell proliferation. We then demonstrated that the NF-κB subunits, p52 and RelB, were transcriptional activators of IRF4. Further analysis showed that activation of CD30 promotes p52 and RelB activity and subsequent IRF4 expression. Finally, we showed that IRF4 transcriptionally regulates CD30 expression. Taken together, these data demonstrate a novel positive feedback loop involving CD30, NF-κB, and IRF4; further evidence for this mechanism was demonstrated in human PTCL tissue samples. Accordingly, NF-κB inhibitors may represent a clinical means to disrupt this feedback loop in IRF4-positive PTCLs. Copyright © 2015 American Society of Hematology.
    Blood 04/2015; 125(20). DOI:10.1182/blood-2014-05-578575 · 10.43 Impact Factor
  • Journal of Clinical Oncology 03/2015; 33(14). DOI:10.1200/JCO.2014.60.5535 · 18.43 Impact Factor
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    ABSTRACT: There are several suspected environmental risk factors for non-Hodgkin lymphoma (NHL). The associations between NHL and environmental chemical exposures have typically been evaluated for individual chemicals (i.e., one-by-one). We determined the association between a mixture of 27 correlated chemicals measured in house dust and NHL risk. We conducted a population-based case-control study of NHL in four National Cancer Institute - Surveillance, Epidemiology, and End Results centers: Detroit, Iowa, Los Angeles, and Seattle from 1998-2000. We used weighted quantile sum (WQS) regression to model the association of a mixture of chemicals and risk of NHL. The WQS index was a sum of weighted quartiles for 5 polychlorinated biphenyls (PCBs), 7 polycyclic aromatic hydrocarbons (PAHs), and 15 pesticides. We estimated chemical mixture weights and effects for study sites combined and for each site individually, and also for histologic subtypes of NHL. The WQS index was statistically significantly associated with NHL overall (odds ratio [OR]=1.30; 95% CI: 1.08, 1.56; p=0.006; for one quartile increase) and in the study sites of Detroit (OR=1.71; 95% CI: 1.02, 2.92; p=0.045), Los Angeles (OR=1.44; 95% CI: 1.00, 2.08; p=0.049), and Iowa (OR=1.76; 95% CI: 1.23, 2.53; p=0.002). The index was marginally statistically significant in Seattle (OR=1.39; 95% CI: 0.97, 1.99; p=0.071). The most highly-weighted chemicals for predicting risk overall were PCB congener 180 and propoxur. Highly-weighted chemicals varied by study site; PCBs were more highly-weighted in Detroit and pesticides were more highly-weighted in Iowa. An index of chemical mixtures was significantly associated with NHL. Our results show the importance of evaluating chemical mixtures when studying cancer risk.
    Environmental Health Perspectives 03/2015; DOI:10.1289/ehp.1408630 · 7.98 Impact Factor
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    ABSTRACT: Background Patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or non-Hodgkin lymphoma (NHL) are at increased risk for the development of skin malignancies.Objectives This study was conducted to estimate the incidences of rare skin malignancies in patients with CLL/SLL or NHL.Methods Patients with a diagnosis of CLL/SLL or NHL recorded in the Surveillance, Epidemiology and End Results (SEER) database during 1992–2007 were identified. Diagnoses of specific skin malignancies were identified from SEER files.ResultsDuring 1992–2007, a total of 128,674 patients with first diagnoses of CLL/SLL or NHL were recorded in SEER; 4743 were excluded because follow-up data were unavailable. Among the remaining 123,931 patients, 28,964 had CLL/SLL and 94,967 had NHL. Standardized incidence ratios (SIRs) for invasive malignant melanoma, Merkel cell carcinoma, malignant fibrous histiocytoma, dermatofibrosarcoma protuberans, Kaposi's sarcoma, and sebaceous carcinoma were 2.3, 8.2, 3.6, 2.5, 2.9, and 1.4, respectively, in CLL/SLL patients and 1.6, 3.2, 1.5, 1.3, 17.6, and 0.8, respectively, in NHL patients. When invasive melanoma was stratified by patient age and sex, the highest SIR (17.8) was found in men aged 0–49 years with CLL (P < 0.001).Conclusions Patients with CLL/SLL or NHL have a higher risk for the subsequent development of rare skin cancers. Given the more aggressive nature of these malignancies in this setting, regular monitoring for the development and prompt treatment of cutaneous malignancy is prudent in patients with NHL and particularly in patients with CLL. Regular use of sun protection may decrease the morbidity associated with skin cancer in this immunosuppressed population.
    International journal of dermatology 03/2015; DOI:10.1111/ijd.12564 · 1.23 Impact Factor
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    ABSTRACT: Autoimmune conditions and immune system-related genetic variations are associated with risk of non-Hodgkin lymphoma (NHL). In a pooled analysis of 8,692 NHL cases and 9,260 controls from 14 studies (1988-2007) within the International Lymphoma Epidemiology Consortium, we evaluated the interaction between immune system genetic variants and autoimmune conditions in NHL risk. We evaluated the immunity-related single nucleotide polymorphisms rs1800629 (tumor necrosis factor gene (TNF) G308A), rs1800890 (interleukin-10 gene (IL10) T3575A), rs6457327 (human leukocyte antigen gene (HLA) class I), rs10484561 (HLA class II), and rs2647012 (HLA class II)) and categorized autoimmune conditions as primarily mediated by B-cell or T-cell responses. We constructed unconditional logistic regression models to measure associations between autoimmune conditions and NHL with stratification by genotype. Autoimmune conditions mediated by B-cell responses were associated with increased NHL risk, specifically diffuse large B-cell lymphoma (odds ratio (OR) = 3.11, 95% confidence interval (CI): 2.25, 4.30) and marginal zone lymphoma (OR = 5.80, 95% CI: 3.82, 8.80); those mediated by T-cell responses were associated with peripheral T-cell lymphoma (OR = 2.14, 95% CI: 1.35, 3.38). In the presence of the rs1800629 AG/AA genotype, B-cell-mediated autoimmune conditions increased NHL risk (OR = 3.27, 95% CI: 2.07, 5.16; P-interaction = 0.03) in comparison with the GG genotype (OR = 1.82, 95% CI: 1.31, 2.53). This interaction was consistent across major B-cell NHL subtypes, including marginal zone lymphoma (P-interaction = 0.02) and follicular lymphoma (P-interaction = 0.04). © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    American Journal of Epidemiology 02/2015; 181(6). DOI:10.1093/aje/kwu290 · 4.98 Impact Factor
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    ABSTRACT: Background:Nulliparity is an endometrial cancer risk factor, but whether or not this association is due to infertility is unclear. Although there are many underlying infertility causes, few studies have assessed risk relations by specific causes.Methods:We conducted a pooled analysis of 8153 cases and 11 713 controls from 2 cohort and 12 case-control studies. All studies provided self-reported infertility and its causes, except for one study that relied on data from national registries. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI).Results:Nulliparous women had an elevated endometrial cancer risk compared with parous women, even after adjusting for infertility (OR=1.76; 95% CI: 1.59-1.94). Women who reported infertility had an increased risk compared with those without infertility concerns, even after adjusting for nulliparity (OR=1.22; 95% CI: 1.13-1.33). Among women who reported infertility, none of the individual infertility causes were substantially related to endometrial cancer.Conclusions:Based on mainly self-reported infertility data that used study-specific definitions of infertility, nulliparity and infertility appeared to independently contribute to endometrial cancer risk. Understanding residual endometrial cancer risk related to infertility, its causes and its treatments may benefit from large studies involving detailed data on various infertility parameters.British Journal of Cancer advance online publication, 17 February 2015; doi:10.1038/bjc.2015.24 www.bjcancer.com.
    British Journal of Cancer 02/2015; 112(5). DOI:10.1038/bjc.2015.24 · 4.82 Impact Factor
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    ABSTRACT: Background: Cigarette smoking (smoking), hormone therapy (MHT), and folate intake (folate) are each thought to influence colorectal cancer (CRC) risk, but the underlying molecular mechanisms remain incompletely defined. Expression of estrogen receptor beta (ESR2) has been associated with CRC stage and survival. Methods: In this prospective cohort study, we examined smoking, MHT, and folate -associated CRC risks by ESR2protein expression level among participants in the Iowa Women's Health Study (IWHS). Self-reported exposure variables were assessed at baseline. Archived, paraffin-embedded CRC tissue specimens were collected and evaluated for ESR2protein expression by immunohistochemistry. Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs) for associations between smoking, MHT, or folate and ESR2-defined CRC subtypes. Results: Informative environmental exposure and protein expression data were available for 491 incident CRC cases. Positive associations between ESR2-low and -high tumors and several smoking-related variables were noted, most prominently with average number of cigarettes per day (RR = 4.24; 95% CI = 1.81-9.91 for ESR2-low and RR=2.15; 95%CI=1.05-4.41 for ESR2-high for >40 cigarettes compared to non-smokers). For MHT, a statistically significant association with ESR2-low tumors was observed with longer duration of exposure (RR = 0.54; 95% CI = 0.26-1.13 for > 5 years compared to never use). No associations were found for folate. Conclusions: In this study, smoking and MHT were associated with ESR2expression patterns. Impact: These data support possible heterogeneous effects from smoking and MHT on ERβ-related pathways of colorectal carcinogenesis in older women. Copyright © 2015, American Association for Cancer Research.
    Cancer Epidemiology Biomarkers & Prevention 02/2015; 24(4). DOI:10.1158/1055-9965.EPI-14-0756 · 4.32 Impact Factor
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    ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) and is the most common NHL subtype diagnosed worldwide. The first large-scale genome-wide association study (GWAS) of DLBCL with over 4000 cases conducted among individuals of European ancestry recently identified five independent SNPs that achieved genome-wide significance, and two SNPs that showed a suggestive association with DLBCL risk. In order to evaluate whether Eastern Asians and individuals of European ancestry share similar genetic risk factors for this disease, we attempted to replicate these GWAS findings in a pooled series of 1124 DLBCL cases and 3596 controls from Hong Kong, South Korea, and Thailand. Three of the five genome-wide significant SNPs from the DLBCL GWAS were significantly associated with DLBCL in our study population, including the top finding from the GWAS, EXOC2 rs116446171, which achieved genome-wide significance in our data (per allele OR = 2.04, 95% CI = 1.63-2.56; ptrend = 3.9 x 10(-10) ). Additionally, we observed a significant association with PVT1 rs13255292 (per allele OR = 1.34, 95% CI = 1.19-1.52; ptrend = 2.1 x 10(-6) ), which was the second strongest finding in the GWAS, and with HLA-B rs2523607 (per allele OR = 3.05, 95% CI = 1.32-7.05; ptrend = 0.009). Our study, which provides the first evaluation in Eastern Asians of SNPs definitively associated with DLBCL risk in individuals of European ancestry, indicates that at least some of the genetic factors associated with risk of DLBCL are similar between these populations. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 01/2015; 75(15 Supplement). DOI:10.1111/ejh.12513 · 2.41 Impact Factor
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    ABSTRACT: 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.
    Nature Communications 01/2015; 6:5751. DOI:10.1038/ncomms6751 · 10.74 Impact Factor
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    ABSTRACT: Key points •We report a cell based pharmacological screening strategy to identify new therapeutic targets in mutant NRAS transformed leukemia cells. •The screen and mechanistic analysis identified a previously unknown synergy between GCK and ACK1/AKT in mutant NRAS transformed cells. Abstract Oncogenic forms of NRAS are frequently associated with hematologic malignancies and other cancers, making them important therapeutic targets. Inhibition of individual downstream effector molecules such as RAF kinase have been complicated by the rapid development of resistance or activation of bypass pathways. For the purpose of identifying novel targets in NRAS-transformed cells, we performed a chemical screen using mutant NRAS transformed Ba/F3 cells to identify compounds with selective cytotoxicity. One of the compounds identified, GNF-7, potently and selectively inhibited NRAS-dependent cells in pre-clinical models of AML and ALL. Mechanistic analysis revealed that its effects were mediated in part through combined inhibition of ACK1/AKT and of MAP4K2 (GCK). Similar to genetic "synthetic lethal" approaches, these results suggest that small molecule screens can be used to identity novel therapeutic targets in cells addicted to RAS oncogenes.
    Blood 01/2015; · 10.43 Impact Factor
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    ABSTRACT: Whole exome sequencing (WES) is increasingly being used for diagnosis without adequate information on predictive characteristics of reportable variants typically found on any given individual and correlation with clinical phenotype. In this study, we performed WES on 89 deceased individuals (mean age at death 74 years, range 28-93) from the Mayo Clinic Biobank. Significant clinical diagnoses were abstracted from electronic medical record via chart review. Variants [Single Nucleotide Variant (SNV) and insertion/deletion] were filtered based on quality (accuracy >99%, read-depth >20, alternate-allele read-depth >5, minor-allele-frequency <0.1) and available HGMD/OMIM phenotype information. Variants were defined as Tier-1 (nonsense, splice or frame-shifting) and Tier-2 (missense, predicted-damaging) and evaluated in 56 ACMG-reportable genes, 57 cancer-predisposition genes, along with examining overall genotype-phenotype correlations. Following variant filtering, 7046 total variants were identified (~79/person, 644 Tier-1, 6402 Tier-2), 161 among 56 ACMG-reportable genes (~1.8/person, 13 Tier-1, 148 Tier-2), and 115 among 57 cancer-predisposition genes (~1.3/person, 3 Tier-1, 112 Tier-2). The number of variants across 57 cancer-predisposition genes did not differentiate individuals with/without invasive cancer history (P > 0.19). Evaluating genotype-phenotype correlations across the exome, 202(3%) of 7046 filtered variants had some evidence for phenotypic correlation in medical records, while 3710(53%) variants had no phenotypic correlation. The phenotype associated with the remaining 44% could not be assessed from a typical medical record review. These data highlight significant continued challenges in the ability to extract medically meaningful predictive results from WES.
    Frontiers in Genetics 01/2015; 6:244. DOI:10.3389/fgene.2015.00244
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    ABSTRACT: Abstract The optimal treatment of follicular lymphoma (FL) is not established. Rituximab is an important component of FL treatment making the impact of chemotherapy on FL less clear. We reviewed 649 FL at the University of Iowa/Mayo Clinic from 2002 to 2009 looking for the association of total dose delivery (TDD), delivered dose intensity (DDI) of cyclophosphamide and doxorubicin on survival. 337 of 649 FL received R-monotherapy/R-chemotherapy as frontline systemic therapy. After a median follow-up duration of 52.7 months, EFS and OS were similar between the two groups with a trend toward better EFS in R-chemotherapy cohort (HR=1.24, p=0.28). In the R-chemotherapy group, increased TDD and DDI of doxorubicin were associated with improved EFS only in patients who did not receive R-maintenance (HR=0.81;P=0.02 and HR=0.94;P=0.04) but not in patients who underwent R-maintenance. Cyclophosphamide was not associated with EFS. Thus, in the immunochemotherapy era, chemotherapy dose delivery tradition requires further evaluation in FL.
    Leukemia and Lymphoma 12/2014; DOI:10.3109/10428194.2014.994206 · 2.89 Impact Factor

Publication Stats

16k Citations
3,408.86 Total Impact Points

Institutions

  • 2000–2015
    • Mayo Clinic - Rochester
      • • Department of Health Science Research
      • • Department of Internal Medicine
      Рочестер, Minnesota, United States
  • 2014
    • University of Minnesota Rochester
      Рочестер, Minnesota, United States
  • 2006–2014
    • National Institutes of Health
      • • Branch of Radiation Epidemiology
      • • Division of Cancer Epidemiology and Genetics
      베서스다, Maryland, United States
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
    • University of New Mexico
      • Department of Pathology
      Albuquerque, New Mexico, United States
  • 2004–2014
    • National Cancer Institute (USA)
      • • Radiation Epidemiology
      • • Division of Cancer Epidemiology and Genetics
      베서스다, Maryland, United States
    • Mayo Foundation for Medical Education and Research
      • • Division of Epidemiology
      • • Department of Health Sciences Research
      Рочестер, Michigan, United States
    • University of Minnesota Twin Cities
      • Department of Pediatrics
      Minneapolis, Minnesota, United States
    • Moffitt Cancer Center
      • Department of Cancer Epidemiology
      Tampa, Florida, United States
  • 2011
    • Rochester College
      Rochester, New York, United States
  • 2010
    • University of California, Berkeley
      • School of Public Health
      Berkeley, California, United States
  • 1996–2010
    • University of Minnesota Duluth
      • Department of Mechanical and Industrial Engineering
      Duluth, Minnesota, United States
    • University of Florence
      Florens, Tuscany, Italy
  • 2009
    • University of Rochester
      • James P. Wilmot Cancer Center
      Rochester, NY, United States
  • 1996–2009
    • University of Iowa
      Iowa City, Iowa, United States
  • 2008
    • University of Cambridge
      • Department of Oncology
      Cambridge, England, United Kingdom
  • 2007
    • University of Milan
      Milano, Lombardy, Italy
  • 2005–2007
    • University of Washington Seattle
      Seattle, Washington, United States
    • University of California, San Diego
      San Diego, California, United States
    • University of Toronto
      Toronto, Ontario, Canada
    • University of South Florida
      Tampa, Florida, United States
  • 2003
    • University of Nebraska Medical Center
      Omaha, Nebraska, United States
  • 2002
    • University of Alabama at Birmingham
      • Division of Clinical Immunology and Rheumatology
      Birmingham, AL, United States
  • 2001
    • Columbia University
      • Department of Health and Behavior Studies
      New York, New York, United States
    • Vanderbilt University
      • Center for Health Services Research
      Нашвилл, Michigan, United States
    • National Institute of Environmental Health Sciences
      • Epidemiology Branch
      Durham, NC, United States
  • 1999
    • Utah State University
      • Department of Nutrition, Dietetics and Food Sciences
      لوگان، اوهایو, Ohio, United States
  • 1998
    • University of Southern California
      • Department of Preventive Medicine
      Los Ángeles, California, United States