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1.  Factors Associated with Hematopoietic Cell Transplantation (HCT) Among Patients in a Population Based Study of Myelodysplastic Syndrome (MDS) in Minnesota 
Annals of hematology  2015;94(10):1667-1675.
Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by dysplastic changes in the bone marrow, ineffective erythropoiesis and an increased risk of developing acute myeloid leukemia. Treatment planning for patients with MDS is a complex process and we sought to better characterize HCT outcomes and the factors that play into decision-making regarding referral of adults with MDS for definitive therapy with hematopoietic cell transplantation (HCT). Patients enrolled in a population based study of MDS between April 2010 and January 2013 who underwent HCT within the first year after enrollment were included in this analysis. Age and risk matched MDS patient controls also enrolled during that time period were used as a comparison. Survival was significantly better in the HCT group (48% vs. 21%, log-rank p-value 0.009). Non-HCT patients were more likely to have comorbidities and HCT patients were more likely to have a college degree and an income >$80,000. All three of these variables were independently associated with HCT, but none impacted survival. Patients with MDS in our study who underwent HCT had better survival than a comparable group of patients who did not undergo HCT. With refined treatment techniques more patients may be able to be considered for this therapy. More work needs to be done to determine why education and income appear to impact the decision to pursue HCT, but these factors may impact referral to an academic center where aggressive therapy like HCT is more likely to be considered.
doi:10.1007/s00277-015-2422-z
PMCID: PMC4725732  PMID: 26063191
MDS; myelodysplastic syndrome; hematopoietic cell transplantation; epidemiology
2.  Coagulation factor XII genetic variation, ex vivo thrombin generation, and stroke risk in the elderly: results from the Cardiovascular Health Study 
Background
Relationships of thrombin generation (TG) with cardiovascular disease risk are under-evaluated in population-based cohorts.
Objectives
Evaluate the relationships of TG influenced by the contact and tissue factor coagulation pathways ex vivo with common SNPs and incident cardiovascular disease and stroke.
Patients/Methods
We measured peak TG (pTG) in baseline plasma samples of Cardiovascular Health Study participants (n=5,411), both with and without inhibitory anti-FXIa antibody (pTG/FXIa−). We evaluated their associations with ~50K SNPs using the IBCv2 genotyping array, and with incident cardiovascular disease and stroke events over a median follow-up of 13.2-years.
Results
The minor allele for a SNP in the coagulation factor XII gene (F12), rs1801020, was associated with lower pTG in European-Americans (β=−34.2 nM ± 3.5 nM; p=3.3×10−22; minor allele frequency (MAF) =0.23) and African-Americans (β=−31.1 nM ± 7.9 nM; p=9.0×10−5; MAF=0.42). Lower FXIa-independent pTG (pTG/FXIa−) was associated with the F12 rs1801020 minor allele, and higher pTG/FXIa− was associated with the ABO SNP rs657152 minor allele (β=16.3 nM; p=4.3×10−9; MAF=0.37). The risk factor-adjusted ischemic stroke hazard ratio (95% confidence interval) was 1.09 (1.01, 1.17; p=0.03) for pTG, 1.06 (0.98, 1.15; p=0.17) for pTG/FXIa−, and 1.11 (1.02, 1.21; p=0.02) for FXIa-dependent pTG (pTG/FXIa+), per 1-SD increment (n=834 ischemic strokes). In a multi-cohort candidate gene analysis, rs1801020 was not associated with incident ischemic stroke (β= −0.02; (SE=0.08); p=0.81).
Conclusions
These results support the importance of contact activation pathway-dependent TG as a risk factor for ischemic stroke and indicate the importance of F12 SNPs on TG ex vivo and in vivo.
doi:10.1111/jth.13111
PMCID: PMC4946166  PMID: 26286125
Cardiovascular Diseases; Epidemiology; Factor XIIa; Single Nucleotide Polymorphisms; Thrombin
3.  Coffee consumption and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma by sex: The Liver Cancer Pooling Project 
Background
Coffee consumption has been reported to be inversely associated with hepatocellular carcinoma (HCC), the most common type of liver cancer. Caffeine has chemopreventive properties, but whether caffeine is responsible for the coffee-HCC association is not well studied. In addition, few studies have examined the relationship by sex, and no studies have examined whether there is an association between coffee and intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer.
Methods
In the Liver Cancer Pooling Project, a consortium of U.S.-based cohort studies, data from 1,212,893 individuals (HCC n=860, ICC n=260) in nine cohorts were pooled. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression.
Results
Higher coffee consumption was associated with lower risk of HCC (HR>3 cups/day vs. non-drinker, 0.73; 95% CI, 0.53-0.99; ptrend cups/day=<0.0001). More notable reduced risk was seen among women than men (pinteraction=0.07). Women who consumed more than three cups of coffee per day were at a 54% lower risk of HCC (HR, 0.46; 95% CI, 0.26-0.81), whereas men had more modest reduced risk of HCC (HR, 0.93; 95% CI, 0.63-1.37). The associations were stronger for caffeinated coffee (HR>3 cups/day vs. non-drinker, 0.71, 95% CI, 0.50-1.01) than decaffeinated coffee (HR, 0.92; 95% CI, 0.55-1.54). There was no relationship between coffee consumption and ICC.
Conclusions
These findings suggest that, in a U.S. population, coffee consumption is associated with reduced risk of HCC.
Impact
Further research into specific coffee compounds and mechanisms that may account for these associations is needed.
doi:10.1158/1055-9965.EPI-15-0137
PMCID: PMC4576990  PMID: 26126626
coffee; diet; epidemiology; hepatocellular carcinoma; intrahepatic cholangiocarcinoma
4.  Differences in Community and Academic Practice Patterns for Newly Diagnosed Myelodysplastic Syndromes (MDS) Patients 
Cancer epidemiology  2015;39(2):222-228.
Purpose
The heterogeneous nature of myelodysplastic syndromes (MDS) complicates therapeutic decision making, particularly for newly diagnosed disease. Factors impacting the treatment plan in this early period of disease course are poorly defined. This study determines whether therapeutic choices for newly diagnosed MDS are associated with location of treatment (community or academic), prognostic risk category, and patient age.
Methods
The Adults in Minnesota with Myelodysplastic Syndromes (AIMMS) database was utilized in this statewide, prospective population-based study conducted by the University of Minnesota (UMN), Mayo Clinic, and Minnesota Department of Health. Adult (age 20+ years) cases of MDS newly diagnosed starting in April 2010 were invited to participate. This analysis includes patients enrolled during the first study year with one-year follow-up data. Treatment choices (supportive, active, and transplant) were stratified by the international prognostic scoring system (IPSS) and the revised-IPSS (IPSS-R), then separated into groups by location of care and age (<65 or 65+ years). Academic-based care was any contact with the UMN and Mayo Clinic; community-based care was all other clinical sites.
Results
Stratification by IPSS and IPSS-R showed supportive care decreased and active care increased with advancing risk categories (p <0.0001). Comparing treatment setting, community-based care had 77% supportive and 23% active treatment; academic-based care was 36% supportive, 41% active, and 23% transplant (p <0.0001). By age groups, patients <65 years with intermediate, high, or very high risk disease by IPSS-R received 97% active care/transplant, compared to only 52% of patients age 65+.
Conclusions
Younger patients and those treated at academic centers had a more aggressive treatment approach. Whether these treatment differences convey improved disease control and mortality, and therefore should be extended more frequently to older and community-based patients, is the subject of ongoing prospective study.
doi:10.1016/j.canep.2015.01.006
PMCID: PMC4361261  PMID: 25701277
myelodysplastic syndromes; hematologic malignancies; drug therapy; bone marrow transplantation
5.  Effects of a high-caloric diet and physical exercise on brain metabolite levels: a combined proton MRS and histologic study 
Excessive intake of high-caloric diets as well as subsequent development of obesity and diabetes mellitus may exert a wide range of unfavorable effects on the central nervous system (CNS). It has been suggested that one mechanism in this context is the promotion of neuroinflammation. The potentially harmful effects of such diets were suggested to be mitigated by physical exercise. Here, we conducted a study investigating the effects of physical exercise in a cafeteria-diet mouse model on CNS metabolites by means of in vivo proton magnetic resonance spectroscopy (1HMRS). In addition postmortem histologic and real-time (RT)-PCR analyses for inflammatory markers were performed. Cafeteria diet induced obesity and hyperglycemia, which was only partially moderated by exercise. It also induced several changes in CNS metabolites such as reduced hippocampal glutamate (Glu), choline-containing compounds (tCho) and N-acetylaspartate (NAA)+N-acetyl-aspartyl-glutamic acid (NAAG) (tNAA) levels, whereas opposite effects were seen for running. No association of these effects with markers of central inflammation could be observed. These findings suggest that while voluntary wheel running alone is insufficient to prevent the unfavorable peripheral sequelae of the diet, it counteracted many changes in brain metabolites. The observed effects seem to be independent of neuroinflammation.
doi:10.1038/jcbfm.2014.231
PMCID: PMC4420876  PMID: 25564238
diabetes; exercise; 1HMRS; inflammation; obesity; spectroscopy
6.  Multi-species sequence comparison reveals conservation of ghrelin gene-derived splice variants encoding a truncated ghrelin peptide 
Endocrine  2016;52:609-617.
The peptide hormone ghrelin is a potent orexigen produced predominantly in the stomach. It has a number of other biological actions, including roles in appetite stimulation, energy balance, the stimulation of growth hormone release and the regulation of cell proliferation. Recently, several ghrelin gene splice variants have been described. Here, we attempted to identify conserved alternative splicing of the ghrelin gene by cross-species sequence comparisons. We identified a novel human exon 2-deleted variant and provide preliminary evidence that this splice variant and in1-ghrelin encode a C-terminally truncated form of the ghrelin peptide, termed minighrelin. These variants are expressed in humans and mice, demonstrating conservation of alternative splicing spanning 90 million years. Minighrelin appears to have similar actions to full-length ghrelin, as treatment with exogenous minighrelin peptide stimulates appetite and feeding in mice. Forced expression of the exon 2-deleted preproghrelin variant mirrors the effect of the canonical preproghrelin, stimulating cell proliferation and migration in the PC3 prostate cancer cell line. This is the first study to characterise an exon 2-deleted preproghrelin variant and to demonstrate sequence conservation of ghrelin gene-derived splice variants that encode a truncated ghrelin peptide. This adds further impetus for studies into the alternative splicing of the ghrelin gene and the function of novel ghrelin peptides in vertebrates.
Electronic supplementary material
The online version of this article (doi:10.1007/s12020-015-0848-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s12020-015-0848-7
PMCID: PMC4879156  PMID: 26792793
Ghrelin; Peptide hormone; Evolution; Comparative endocrinology; Alternative splicing
7.  Incidence of intracranial germ cell tumors by race in the United States, 1992–2010 
Journal of neuro-oncology  2014;120(2):381-388.
Little is known about the etiology of intracranial germ cell tumors (iGCTs), although international incidence data suggest that the highest incidence rates occur in Asian countries. In this analysis, we used 1992–2010 data from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program to determine whether rates of iGCT were also high in Asian/Pacific Islanders living in the United States. Frequencies, incidence rates and survival rates were evaluated for the entire cohort and for demographic subgroups based on sex, age category (0–9 and 10–29 years), race (white, black, and Asian/Pacific Islander), and tumor location (pineal gland vs. other) as sample size permitted. Analyses were conducted using SEER*Stat 8.1.2. We observed a significantly higher incidence rate of iGCT in Asian/Pacific Islanders compared with whites (RR = 2.05, 95 % CI 1.57–2.64, RR = 3.04, 95 % CI 1.75–5.12 for males and females, respectively) in the 10–29 year age group. This difference was observed for tumors located both in the pineal gland and for tumors in other locations. Five-year relative survival differed by demographic and tumor characteristics, although these differences were not observed in comparisons limited to cases treated with radiation. Increased incidence rates of iGCT in individuals of Asian descent in the SEER registry are in agreement with data from the International Agency for Research on Cancer, where Japan and Singapore were among the countries with highest incidence. The increased incidence in individuals of Asian ancestry in the United States suggests that underlying genetic susceptibility may play a role in the etiology of iGCT.
doi:10.1007/s11060-014-1562-7
PMCID: PMC4206671  PMID: 25086758
Pediatric cancer; Germ cell tumors; Intracranial; SEER; Incidence
8.  Cross platform analysis of methylation, miRNA and stem cell gene expression data in germ cell tumors highlights characteristic differences by tumor histology 
BMC Cancer  2015;15:769.
Background
Alterations in methylation patterns, miRNA expression, and stem cell protein expression occur in germ cell tumors (GCTs). Our goal is to integrate molecular data across platforms to identify molecular signatures in the three main histologic subtypes of Type I and Type II GCTs (yolk sac tumor (YST), germinoma, and teratoma).
Methods
We included 39 GCTs and 7 paired adjacent tissue samples in the current analysis. Molecular data available for analysis include DNA methylation data (Illumina GoldenGate Cancer Methylation Panel I), miRNA expression (NanoString nCounter miRNA platform), and stem cell factor expression (SABiosciences Human Embryonic Stem Cell Array). We evaluated the cross platform correlations of the data features using the Maximum Information Coefficient (MIC).
Results
In analyses of individual datasets, differences were observed by tumor histology. Germinomas had higher expression of transcription factors maintaining stemness, while YSTs had higher expression of cytokines, endoderm and endothelial markers. We also observed differences in miRNA expression, with miR-371-5p, miR-122, miR-302a, miR-302d, and miR-373 showing elevated expression in one or more histologic subtypes. Using the MIC, we identified correlations across the data features, including six major hubs with higher expression in YST (LEFTY1, LEFTY2, miR302b, miR302a, miR 126, and miR 122) compared with other GCT.
Conclusions
While prognosis for GCTs is overall favorable, many patients experience resistance to chemotherapy, relapse and/or long term adverse health effects following treatment. Targeted therapies, based on integrated analyses of molecular tumor data such as that presented here, may provide a way to secure high cure rates while reducing unintended health consequences.
doi:10.1186/s12885-015-1796-6
PMCID: PMC4619074  PMID: 26497383
Pediatric cancer; Germ cell tumors; miRNA; Methylation; Stem cell
9.  Allergic diseases and risk of hematopoietic malignancies in a cohort of postmenopausal women: A report from the Iowa Women’s Health Study 
Background
Allergic diseases signify immune dysregulation attributable to underlying genetics and environmental exposures. Associations between various allergies and hematopoietic cancers have been observed, albeit inconsistently, however few prospective studies have examined the risk, and even fewer among older adults.
Methods
We examined risk of incident hematopoietic cancers in those reporting allergic diseases in a population-based cohort of 22,601 older women (Iowa Women’s Health Study). Self-reported allergic status, including asthma, hay fever, eczema and/or other allergies, was determined via questionnaire in 1997 (mean age=72 years, range 63–81 years). Incident cancers were ascertained by linkage with the Iowa Cancer Registry from 1997–2011. Cox proportional hazards regression was performed to estimate multivariate-adjusted hazard ratios (HR) and 95% confidence intervals (CIs) for myeloid (N=177) and lymphoid (N=437) malignancies, respectively.
Results
Allergic diseases were not associated with risk of myeloid (HR=1.00, 95% CI: 0.72–1.37) or lymphoid (HR=0.99, 95% CI: 0.81–1.22) malignancies overall, or for most allergic and malignant subtypes examined. Self-reported asthma was positively associated with development of myelodysplastic syndrome (MDS, HR=2.00, 95% CI: 0.93–4.32). In addition, there was a 30–40% decrease in risk of both lymphoid and myeloid cancers in those reporting rural residences but no association in those reporting urban residences; the interaction between residence and allergy was statistically significant for lymphoid malignancies (Pinteraction=0.05).
Conclusions and Impact
These results suggest asthma may contribute to the pathogenesis of MDS, a finding consistent with the chronic antigen stimulation hypothesis. Susceptibility differences by location of residence are concordant with the hygiene hypothesis and merit additional exploration.
doi:10.1158/1055-9965.EPI-14-0423
PMCID: PMC4154995  PMID: 24962839
Hematologic malignancy; myelodysplastic syndrome; allergies; asthma; rural residence; Iowa Women’s Health Study
10.  Interpreting the multi-biomarker disease activity score in the context of tocilizumab treatment for patients with rheumatoid arthritis 
Rheumatology International  2015;36:295-300.
The multi-biomarker disease activity (MBDA) score measures 12 proteins involved in the pathophysiology of rheumatoid arthritis (RA) to assess disease activity (DA). Previous studies demonstrated correlations between MBDA and clinical DA scores with some RA therapies. In this analysis, the relationship between DA and MBDA scores and changes in MBDA component biomarkers were evaluated in tocilizumab (TCZ)-treated patients. Patients from the ACT-RAY study were included in this analysis if they had DA measures and serum collected at pre-specified time points with sufficient serum for MBDA testing at ≥1 visit. Descriptive statistics, associations between outcomes, and percentage agreement between DA categories were calculated. Seventy-eight patients were included and were similar to the ACT-RAY population. Correlations between MBDA score and DAS28-CRP were ρ = 0.50 at baseline and ρ = 0.26 at week 24. Agreement between low/moderate/high categories of MBDA score and DAS28-CRP was observed for 77.1 % of patients at baseline and 23.7 % at week 24. Mean changes from baseline to weeks 4, 12, and 24 were proportionately smaller for MBDA score than DAS28-CRP. Unlike some other MBDA biomarkers, interleukin-6 (IL-6) concentrations increased in most patients during TCZ treatment. Correlations and agreement between MBDA and DAS28-CRP or CDAI scores were lower at week 24 versus baseline. The proportionately smaller magnitude of response observed for MBDA score versus DAS28-CRP may be due to the influence of the increase in IL-6 concentrations on MBDA score. Thus, MBDA scores obtained during TCZ treatment should be interpreted cautiously and in the context of available clinical information.
doi:10.1007/s00296-015-3285-2
PMCID: PMC4723630  PMID: 26026604
Rheumatoid arthritis; Tocilizumab; Biomarker; MBDA; Interleukin-6 (IL-6); C-reactive protein (CRP)
11.  The Children’s Oncology Group Childhood Cancer Research Network (CCRN) 
Cancer  2014;120(19):3007-3015.
BACKGROUND
The Childhood Cancer Research Network (CCRN) was established within the Children’s Oncology Group (COG) in July 2008 to provide a centralized pediatric cancer research registry for investigators conducting approved etiologic and survivorship studies. The authors conducted an ecological analysis to characterize CCRN catchment at >200 COG institutions by demographic characteristics, diagnosis, and geographic location to determine whether the CCRN can serve as a population-based registry for childhood cancer.
METHODS
During 2009 to 2011, 18,580 US children newly diagnosed with cancer were registered in the CCRN. These observed cases were compared with age-specific, sex-specific, and race/ethnicity-specific expected numbers calculated from Surveillance, Epidemiology, and End Results (SEER) Program cancer incidence rates and 2010 US Census data.
RESULTS
Overall, 42% of children (18,580 observed/44,267 expected) who were diagnosed with cancer at age <20 years were registered in the CCRN, including 45%, 57%, 51%, 44%, and 24% of those diagnosed at birth, ages 1 to 4 years, ages 5 to 9 years, ages 10 to 14 years, and ages 15 to 19 years, respectively. Some malignancies were better represented in the CCRN (leukemia, 59%; renal tumors, 67%) than others (retinoblastoma, 34%). There was little evidence of differences by sex or race/ethnicity, although rates in nonwhites were somewhat lower than rates in whites.
CONCLUSIONS
Given the low observed-to-expected ratio, it will be important to identify challenges and barriers to registration to improve case ascertainment, especially for rarer diagnoses and older age groups; however, it is encouraging that some diagnoses in younger children are fairly representative of the population. Overall, the CCRN is providing centralized, real-time access to cases for research and could be used as a model for other national cooperative groups.
doi:10.1002/cncr.28813
PMCID: PMC4287245  PMID: 24889136
childhood cancer; United States; clinical trials; incidence; catchment
12.  Reproductive, lifestyle and anthropometric risk factors for cancer in elderly women 
Background
With an increasing elderly population, the United States will experience an increased cancer burden in the coming years. We evaluated associations between anthropometric, lifestyle and reproductive factors and risk of breast, ovarian, and colorectal cancer in a prospective study of postmenopausal women with a focus on diagnoses occurring among very elderly women (≥75 years).
Methods
For each cancer type, we estimated associations with relevant exposures in two age bands (< vs. ≥75 years of age). During 22 years of follow-up, 322 ovarian, 1,311 colon, 315 rectal, and 2,664 breast cancers occurred among 37,459 postmenopausal women (mean age at baseline 62 years, range 55–71 years).
Results
For ovarian cancer, we identified few significant associations in either age band. Colon cancer cases had a higher body mass index and were less likely to report estrogen or aspirin use than non-cases, yet these associations were consistent in both age bands. Few risk factors were identified for rectal cancer in women ≥75 years of age. For breast cancer, notably different patterns were revealed, with alcohol consumption associated with risk in the younger group and previous hysterectomy associated with risk only in the older group.
Conclusion
These analyses suggest some important differences in risk factors for cancer depending on age at diagnosis.
Impact
This study suggests that etiologic differences may exist in cancers occurring in the very elderly. The ongoing demographic shift in the United States provides a strong rationale for studies evaluating cancer etiology in the elderly.
doi:10.1158/1055-9965.EPI-12-0966
PMCID: PMC3617066  PMID: 23429062
cancer risk; elderly; ovarian; colorectal; breast
13.  Trends in Incidence and Survival of Pediatric and Adolescent Germ Cell Tumors in the United States, 1975-2006 
Cancer  2010;116(20):4882-4891.
Background
Pediatric germ cell tumors (GCTs) are rare and heterogeneous tumors with uncertain etiology. We used data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program to evaluate trends in incidence and survival of GCTs in boys and girls ≤ 19 years of age. Few studies have evaluated trends in pediatric GCTs. Results from these analyses may provide clues to the etiology of GCTs.
Methods
Frequencies, incidence rates and five-year relative survival rates stratified by sex were evaluated overall and for demographic subgroups based on age (0-9 and 10-19 years), race (white, black, and other), and ethnicity (non-Hispanic and Hispanic) as sample size permitted.
Results
In whites, the incidence of GCTs was lower for females than males in the 10-19 year age group (RR=0.47, 95% CI 0.42—0.53) while the rates were similar in the 0-9 year age group. In contrast, incidence rates were higher in black females than in black males in both age groups (RR=2.01, 95%CI 1.08—3.84 in 0-9 year olds; RR=3.30, 95% CI 2.13—5.28 in 10-19 year olds). The incidence of ovarian GCT was significantly higher in Hispanic than non-Hispanic girls in the 10—19 year age group. Incidence rates increased during the study period in boys ages 10-19 (APC 1.2, 95% CI 0.4—2.1) and girls ages 0-9 (APC 1.9, 95% CI 0.3-2.5).
Conclusions
The incidence of pediatric GCTs in the United States is increasing only in certain subgroups, suggesting that the etiology is not completely overlapping in all age groups. Differences in incidence patterns by race and ethnicity merit further investigation.
doi:10.1002/cncr.25454
PMCID: PMC3931133  PMID: 20597129
pediatric cancer; germ cell tumors; SEER; incidence
14.  Decreasing Intestinal Parasites in Recent Northern California Refugees 
Beginning in 2005, the Centers for Disease Control and Prevention (CDC) expanded the overseas presumptive treatment of intestinal parasites with albendazole to include refugees from the Middle East. We surveyed the prevalence of helminths and protozoa in recent Middle Eastern refugees (2008–2010) in comparison with refugees from other geographical regions and from a previous survey (2001–2004) in Santa Clara County, California. Based on stool microscopy, helminth infections decreased, particularly in Middle Eastern refugees (0.1% versus 2.3% 2001–2004, P = 0.01). Among all refugees, Giardia intestinalis was the most common protozoan found. Protozoa infections also decreased somewhat in Middle Eastern refugees (7.2%, 2008–2010 versus 12.9%, 2001–2004, P = 0.08). Serology for Strongyloides stercoralis and Schistosoma spp. identified more infected individuals than stool exams. Helminth infections are increasingly rare in refugees to Northern California. Routine screening stool microscopy may be unnecessary in all refugees.
doi:10.4269/ajtmh.2012.12-0349
PMCID: PMC3541735  PMID: 23149583
15.  Predictors of mother and child DNA yields in buccal cell samples collected in pediatric cancer epidemiologic studies: a report from the Children’s Oncology group 
BMC Genetics  2013;14:69.
Background
Collection of high-quality DNA is essential for molecular epidemiology studies. Methods have been evaluated for optimal DNA collection in studies of adults; however, DNA collection in young children poses additional challenges. Here, we have evaluated predictors of DNA quantity in buccal cells collected for population-based studies of infant leukemia (N = 489 mothers and 392 children) and hepatoblastoma (HB; N = 446 mothers and 412 children) conducted through the Children’s Oncology Group. DNA samples were collected by mail using mouthwash (for mothers and some children) and buccal brush (for children) collection kits and quantified using quantitative real-time PCR. Multivariable linear regression models were used to identify predictors of DNA yield.
Results
Median DNA yield was higher for mothers in both studies compared with their children (14 μg vs. <1 μg). Significant predictors of DNA yield in children included case–control status (β = −0.69, 50% reduction, P = 0.01 for case vs. control children), brush collection type, and season of sample collection. Demographic factors were not strong predictors of DNA yield in mothers or children in this analysis.
Conclusions
The association with seasonality suggests that conditions during transport may influence DNA yield. The low yields observed in most children in these studies highlight the importance of developing alternative methods for DNA collection in younger age groups.
doi:10.1186/1471-2156-14-69
PMCID: PMC3751424  PMID: 23937514
DNA collection; Buccal cells; Pediatric epidemiology
16.  DNA methylation analysis reveals distinct methylation signatures in pediatric germ cell tumors 
BMC Cancer  2013;13:313.
Background
Aberrant DNA methylation is a prominent feature of many cancers, and may be especially relevant in germ cell tumors (GCTs) due to the extensive epigenetic reprogramming that occurs in the germ line during normal development.
Methods
We used the Illumina GoldenGate Cancer Methylation Panel to compare DNA methylation in the three main histologic subtypes of pediatric GCTs (germinoma, teratoma and yolk sac tumor (YST); N = 51) and used recursively partitioned mixture models (RPMM) to test associations between methylation pattern and tumor and demographic characteristics. We identified genes and pathways that were differentially methylated using generalized linear models and Ingenuity Pathway Analysis. We also measured global DNA methylation at LINE1 elements and evaluated methylation at selected imprinted loci using pyrosequencing.
Results
Methylation patterns differed by tumor histology, with 18/19 YSTs forming a distinct methylation class. Four pathways showed significant enrichment for YSTs, including a human embryonic stem cell pluripotency pathway. We identified 190 CpG loci with significant methylation differences in mature and immature teratomas (q < 0.05), including a number of CpGs in stem cell and pluripotency-related pathways. Both YST and germinoma showed significantly lower methylation at LINE1 elements compared with normal adjacent tissue while there was no difference between teratoma (mature and immature) and normal tissue. DNA methylation at imprinted loci differed significantly by tumor histology and location.
Conclusion
Understanding methylation patterns may identify the developmental stage at which the GCT arose and the at-risk period when environmental exposures could be most harmful. Further, identification of relevant genetic pathways could lead to the development of new targets for therapy.
doi:10.1186/1471-2407-13-313
PMCID: PMC3701494  PMID: 23806198
Germ Cell Tumor; Teratoma; DNA Methylation; Imprinting
17.  Vascular risk factors and cognitive impairment in a stroke-free cohort 
Neurology  2011;77(19):1729-1736.
Objective:
To examine vascular risk factors, as measured by the Framingham Stroke Risk Profile (FSRP), to predict incident cognitive impairment in a large, national sample of black and white adults age 45 years and older.
Methods:
Participants included subjects without stroke at baseline from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study with at least 2 cognitive function assessments during the follow-up (n = 23,752). Incident cognitive impairment was defined as decline from a baseline score of 5 or 6 (of possible 6 points) to the most recent follow-up score of 4 or less on the Six-item Screener (SIS). Subjects with suspected stroke during follow-up were censored.
Results:
During a mean follow-up of 4.1 years, 1,907 participants met criteria for incident cognitive impairment. Baseline FSRP score was associated with incident cognitive impairment. An adjusted model revealed that male sex (odds ratio [OR] = 1.59, 95% confidence interval [CI] 1.43–1.77), black race (OR = 2.09, 95% CI 1.88–2.35), less education (less than high school graduate vs college graduate, OR = 2.21, 95% CI 1.88–2.60), older age (10-year increments, OR = 2.11, per 10-year increase in age, 95% CI 2.05–2.18), and presence of left ventricular hypertrophy (LVH, OR = 1.29, 95% CI 1.06–1.58) were related to development of cognitive impairment. When LVH was excluded from the model, elevated systolic blood pressure was related to incident cognitive impairment.
Conclusions:
Total FSRP score, elevated blood pressure, and LVH predict development of clinically significant cognitive dysfunction. Prevention and treatment of high blood pressure may be effective in preserving cognitive health.
doi:10.1212/WNL.0b013e318236ef23
PMCID: PMC3208949  PMID: 22067959
18.  Lipoprotein-associated phospholipase A2 and future risk of subclinical disease and cardiovascular events in individuals with type 2 diabetes: the Cardiovascular Health Study 
Diabetologia  2010;54(2):329-333.
Aims/hypothesis
Type 2 diabetes is an established risk factor for cardiovascular disease (CVD). This increased risk may be due in part to the increased levels of inflammatory factors associated with diabetes. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a risk marker for CVD and has pro-inflammatory effects in atherosclerotic plaques. We therefore sought to determine whether Lp-PLA2 levels partially explain the greater prevalence of subclinical CVD and greater incidence of CVD outcomes associated with type 2 diabetes in the Cardiovascular Health Study.
Methods
We conducted a cross-sectional and prospective study of 4,062 men and women without previous CVD from the Cardiovascular Health Study (1989 to 2007). Lp-PLA2 mass and activity were measured in baseline plasma. Subclinical disease was determined at baseline and incident CVD was ascertained annually. We used logistic regression for cross-sectional analyses and Cox proportional hazards models for incident analyses.
Results
At baseline, Lp-PLA2 mass did not differ significantly by type 2 diabetes status; however, Lp-PLA2 activity was significantly higher among type 2 diabetic individuals. Baseline subclinical disease was significantly associated with baseline diabetes and this association was similar in models unadjusted or adjusted for Lp-PLA2 (OR 1.68 [95% CI 1.31–2.15] vs OR 1.67 [95% CI 1.30–2.13]). Baseline type 2 diabetes was also significantly associated with incident CVD events, including fatal CHD, fatal myocardial infarction (MI) and non-fatal MI in multivariable analyses. There were no differences in these estimates after further adjustment for Lp-PLA2 activity.
Conclusions/interpretation
In this older cohort, differences in Lp-PLA2 activity did not explain any of the excess risk for subclinical disease or CVD outcomes related to diabetes.
doi:10.1007/s00125-010-1969-4
PMCID: PMC3489174  PMID: 21103980
Cardiovascular disease; Cardiovascular Health Study; Diabetes; Lipoprotein-associated phospholipase A2; Older adults; Platelet-activating factor acetylhydrolase; Subclinical disease; Type 2 diabetes
19.  Risk of contralateral breast cancer associated with common variants in BRCA1 and BRCA2: Potential modifying effect of BRCA1/BRCA2 mutation carrier status 
Rare deleterious mutations in BRCA1 and BRCA2 are associated with an elevated risk of breast and ovarian cancer. Whether or not common variants in these genes are independently associated with risk of breast cancer remains unclear. In this study, we included 632 Caucasian women with asynchronous contralateral breast cancer (CBC, cases) and 1,221 women with unilateral breast cancer (controls) from the WECARE (Women’s Environment, Cancer And Radiation Epidemiology) Study. BRCA1 and BRCA2 deleterious mutation status was measured using denaturing high-performance liquid chromatography followed by direct sequencing, yielding including 88 BRCA1 and 60 BRCA2 deleterious mutation carriers. We also genotyped samples on the Illumina Omni1-Quad platform. We assessed the association between CBC risk and common (minor allele frequency>0.05) single nucleotide polymorphisms (SNPs) in BRCA1 (n SNPs=22) and BRCA2 (n SNPs=30) and haplotypes using conditional logistic regression accounting for BRCA1/BRCA2 mutation status. We found no significant associations between any single-SNPs or haplotypes of BRCA1 or BRCA2 and risk of CBC among all women. When we stratified by BRCA1 and BRCA2 mutation carrier status, we found suggestive evidence that risk estimates for selected SNPs in BRCA1 (rs8176318, rs1060915 and rs16940) and BRCA2 (rs11571686, rs206115 and rs206117) may differ in non-carriers and carriers of deleterious mutations in BRCA1 and BRCA2. One common haplotype on BRCA1 was inversely significantly associated with risk only among non-BRCA1 and BRCA2 carriers. The association between common variants in BRCA1 and BRCA2 and risk of CBC may differ depending on BRCA1 and BRCA2 mutation carrier status.
doi:10.1007/s10549-010-1285-1
PMCID: PMC3234998  PMID: 21161372
BRCA1; BRCA2; haplotype; polymorphism; breast cancer; contralateral
20.  Idiopathic sclerosing encapsulating peritonitis: Abdominal cocoon 
Abdominal cocoon, the idiopathic form of sclerosing encapsulating peritonitis, is a rare condition of unknown etiology that results in an intestinal obstruction due to total or partial encapsulation of the small bowel by a fibrocollagenous membrane. Preoperative diagnosis requires a high index of clinical suspicion. The early clinical features are nonspecific, are often not recognized and it is difficult to make a definite pre-operative diagnosis. Clinical suspicion may be generated by the recurrent episodes of small intestinal obstruction combined with relevant imaging findings and lack of other plausible etiologies. The radiological diagnosis of abdominal cocoon may now be confidently made on computed tomography scan. Surgery is important in the management of this disease. Careful dissection and excision of the thick sac with the release of the small intestine leads to complete recovery in the vast majority of cases.
doi:10.3748/wjg.v18.i17.1999
PMCID: PMC3342596  PMID: 22563185
Peritonitis; Sclerosis; Encapsulate; Intestinal obstruction; Computed tomography scan; Surgery
21.  Genetic variation in the retinoid X receptor and calcium-sensing receptor and risk of colorectal cancer in the Colon Cancer Family Registry 
Carcinogenesis  2010;31(8):1412-1416.
Genetic variants in the calcium/vitamin D metabolic pathway may be related to risk for colorectal cancer. While several investigations of vitamin D receptor (VDR) polymorphisms and colorectal cancer have been conducted, no studies to date have evaluated the association of genetic variation in the heterodimer partner for VDR, the retinoid X receptor (RXR). Another important gene in this pathway is the calcium-sensing receptor (CASR). Employing a discordant-sibship case–control design, we examined the association between single nucleotide polymorphisms (SNPs) in RXRA and CASR and risk for colorectal cancer overall and by colorectal subsite and microsatellite instability (MSI) status using data from the Colon Cancer Family Registry. No gene-level relationships between RXRA or CASR and colorectal cancer overall were observed. However, for RXRA SNP rs7861779, a high-interest SNP selected for study a priori, there was a statistically significantly increased risk for proximal colorectal cancer among those with at least one A allele [odds ratio (OR) = 1.42; 95% confidence interval (CI) = 1.03–1.97]. Another selected RXRA SNP, rs12004589, was significantly associated with risk of MSI-high cancers (OR = 2.27; 95% CI = 1.13–4.56). Additionally, CASR SNP rs1801726 was significantly associated with a reduced risk for rectal cancer (OR = 0.53; 95% CI = 0.29–0.96). These results provide support that RXRA SNPs rs7861779 and rs12004589 and CASR SNP rs1801726 may be important markers for colorectal neoplasia. Further work is needed to elucidate their role in the carcinogenic pathway.
doi:10.1093/carcin/bgq127
PMCID: PMC2915636  PMID: 20558521
22.  A Candidate Gene Study of Folate-Associated One Carbon Metabolism Genes and Colorectal Cancer Risk 
Background
Folate-associated one carbon metabolism (FOCM) may play an important role in colorectal carcinogenesis. Variation in FOCM genes may explain some of the underlying risk of colorectal cancer.
Methods
This study utilized data from 1,805 population-based colorectal cancer cases and 2,878 matched sibling controls from the Colon Cancer Family Registry (C-CFR). We used a comprehensive tagSNP approach to select 395 tagSNPs in 15 genes involved in folate and vitamin B12 metabolism. Genotyping was performed using the Illumina GoldenGate or Sequenom platforms. Risk factor and dietary data were collected using self-completed questionnaires. MSI status was determined using standard techniques and tumor subsite was obtained from pathology reports. The association between SNPs and colorectal cancer was assessed using conditional logistic regression with sibships as the matching factor and assuming a log additive or co-dominant model.
Results
In the log additive model, two linked (r2=0.99) tagSNPs in the DHFR gene (rs1677693 and rs1643659) were associated with a significant decrease in CRC risk after correction for multiple testing (OR=0.87; 95% CI=0.71 – 0.94; P=0.029 and OR=0.87 95% CI=0.71 – 0.95, P=0.034 for rs1677693 and rs1643659 respectively. These two linked (r2=0.99) tagSNPs and one tagSNP in the MTR gene (rs4659744) were significantly associated with reduced CRC risk only among individuals not using multivitamin supplements.
Conclusions
Overall, we found only moderate evidence that genetic variation in 15 folate pathway genes may affect CRC risk except in non multivitamin users.
Impact
This study suggests that multivitamin supplement use may modify the association between folate pathway genes and CRC risk in a post folic acid supplemented population.
doi:10.1158/1055-9965.EPI-10-0151
PMCID: PMC2950115  PMID: 20615890
Colorectal Cancer; TagSNP; Folate Supplementation; Multivitamins; Microsatellite Instability; Colon subsite; ADA; ADH1C; AHCY; AMD1; CBS; DHFR; GIF; CUBN; MAT2A; MTHFD1; MTR; MTRR; SHMT1; TCN2; TYMS
23.  Reproductive factors and risk of contralateral breast cancer by BRCA1 and BRCA2 mutation status: results from the WECARE study 
Cancer causes & control : CCC  2010;21(6):839-846.
Objective
Reproductive factors, such as early age at menarche, late age at menopause, and nulliparity are known risk factors for breast cancer. Previously, we reported these factors to be associated with risk of developing contralateral breast cancer (CBC). In this study, we evaluated the association between these factors and CBC risk among BRCA1 and BRCA2 (BRCA1/2) mutation carriers and non-carriers.
Methods
The WECARE Study is a population-based multi-center case–control study of 705 women with CBC (cases) and 1,397 women with unilateral breast cancer (controls). All participants were screened for BRCA1/2 mutations and 181 carriers were identified. Conditional logistic regression models were used to evaluate associations between reproductive factors and CBC for mutation carriers and non-carriers.
Results
None of the associations between reproductive factors and CBC risk differed between mutation carriers and non-carriers. The increase in risk with younger age at menarche and decrease in risk in women with more than two full-term pregnancies seen in non-carriers were not significantly different in carriers (adjusted RRs = 1.31, 95% CI 0.65–2.65 and 0.53, 95% CI 0.19–1.51, respectively). No significant associations between the other reproductive factors and CBC risk were observed in mutation carriers or non-carriers.
Conclusion
For two reproductive factors previously shown to be associated with CBC risk, we observed similar associations for BRCA1/2 carriers. This suggests that reproductive variables that affect CBC risk may have similar effects in mutation carriers and non-carriers.
doi:10.1007/s10552-010-9510-0
PMCID: PMC2873079  PMID: 20130978
Contralateral breast cancer; BRCA1; BRCA2; Reproductive factors
24.  Genes involved with folate uptake and distribution and their association with colorectal cancer risk 
Cancer causes & control : CCC  2009;21(4):597-608.
Folate status is an important predictor of colorectal cancer risk. Common genetic variants in genes involved in regulating cellular folate levels might also predict risk, but there are limited data on this issue. We conducted a family-based case-control association study of variants in four genes involved in folate uptake and distribution: FOLR1, FPGS, GGH, and SLC19A1, using 1,750 population-based and 245 clinic-based cases of pathologically-confirmed colorectal cancer and their unaffected relatives participating in the Colon Cancer Family Registries. Standardized questionnaires, administered to all participants, collected information on risk factors and diet. Standard molecular techniques were used to determine microsatellite instability (MSI) status on cases. tagSNPs (n=29) were selected based on coverage as assessed by pairwise r2. We found no evidence that tagSNPs in these genes were associated with risk of colorectal cancer. For the SLC19A1- rs1051266 (G80A, Arg27His) missense polymorphism, the A/A genotype was not associated with risk of colorectal cancer using population-based (OR=1.00; 95% CI=0.81–1.23) or clinic-based (OR=0.75; 95% CI=0.44–1.29) families compared to the G/A and G/G genotypes. We found no evidence that the association between any tagSNP and CRC risk was modified by multivitamin use, folic acid use and dietary folate intake and total folate intake. The odds ratios were similar, irrespective of MSI status, tumor subsite and family history of colorectal cancer. In conclusion, we found no significant evidence that genetic variants in FOLR1, GGH, FPGS and SLC19A1 are associated with the risk of colorectal cancer.
doi:10.1007/s10552-009-9489-6
PMCID: PMC2904058  PMID: 20037791
Folate; folate receptor 1 (FOLR1); solute carrier family 19 (SLC19A1); reduced folate carrier (RFC); folylpolyglutamate synthase (FPGS); gamma-glutamyl hydrolase (GGH); family-based; population-based; clinic-based; polymorphisms; colorectal cancer; case-control
25.  Case–Control Study of Overweight, Obesity, and Colorectal Cancer Risk, Overall and by Tumor Microsatellite Instability Status 
Background
Being overweight or obese is an established risk factor for colorectal cancer, more so for men than for women. Approximately 10%–20% of colorectal tumors display microsatellite instability (MSI), defined as the expansion or contraction of small repeated sequences in the DNA of tumor tissue relative to nearby normal tissue. We evaluated associations between overweight or obesity and colorectal cancer risk, overall and by tumor MSI status.
Methods
The study included 1794 case subjects with incident colorectal cancer who were identified through population-based cancer registries and 2684 of their unaffected sex-matched siblings as control subjects. Recent body mass index (BMI), BMI at age 20 years, and adult weight change were derived from self-reports of height and weight. Tumor MSI status, assessed at as many as 10 markers, was obtained for 69.7% of the case subjects and classified as microsatellite (MS)-stable (0% of markers unstable; n = 913), MSI-low (>0% but <30% of markers unstable; n = 149), or MSI-high (≥30% of markers unstable; n = 188). Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). All statistical tests were two-sided.
Results
Recent BMI, modeled in 5 kg/m2 increments, was positively associated with risk of colorectal cancer for men and women combined (OR = 1.24; 95% CI = 1.15 to 1.34), for women only (OR = 1.20; 95% CI = 1.10 to 1.32), and for men only (OR = 1.30; 95% CI = 1.15 to 1.47). There was no interaction with sex (P = .22). Recent BMI, per 5 kg/m2, was positively associated with the risk of MS-stable (OR = 1.38; 95% CI = 1.24 to 1.54) and MSI-low (OR = 1.33; 95% CI = 1.04 to 1.72) colorectal tumors, but not with the risk of MSI-high tumors (OR = 1.05; 95% CI = 0.84 to 1.31).
Conclusion
The increased risk of colorectal cancer associated with a high BMI might be largely restricted to tumors that display the more common MS-stable phenotype, suggesting further that colorectal cancer etiology differs by tumor MSI status.
doi:10.1093/jnci/djq011
PMCID: PMC2841037  PMID: 20208017

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