PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (46)
 

Clipboard (0)
None

Select a Filter Below

Year of Publication
Document Types
1.  Do Variants Associated with Susceptibility to Pancreatic Cancer and Type 2 Diabetes Reciprocally Affect Risk? 
PLoS ONE  2015;10(2):e0117230.
Objectives
Although type 2 diabetes mellitus is a known risk factor for pancreatic cancer, the existence of shared genetic susceptibility is largely unknown. We evaluated whether any reported genetic risk variants of either disease found by genome-wide association studies reciprocally confer susceptibility.
Methods
Data that were generated in previous genome-wide association studies (GENEVA Type 2 Diabetes; PanScan) were obtained through the National Institutes of Health database of Genotypes and Phenotypes (dbGaP). Using the PanScan datasets, we tested for association of 38 variants within 37 genomic regions known to be susceptibility factors for type 2 diabetes. We further examined whether type 2 diabetes variants predispose to pancreatic cancer risk stratified by diabetes status. Correspondingly, we examined the association of fourteen pancreatic cancer susceptibility variants within eight genomic regions in the GENEVA Type 2 Diabetes dataset.
Results
Four plausible associations of diabetes variants and pancreatic cancer risk were detected at a significance threshold of p = 0.05, and one pancreatic cancer susceptibility variant was associated with diabetes risk at threshold of p = 0.05, but none remained significant after correction for multiple comparisons.
Conclusion
Currently identified GWAS susceptibility variants are unlikely to explain the potential shared genetic etiology between Type 2 diabetes and pancreatic cancer.
doi:10.1371/journal.pone.0117230
PMCID: PMC4319943  PMID: 25658847
2.  Patients with chronic lymphocytic leukaemia and clonal deletion of both 17p13.1 and 11q22.3 have a very poor prognosis 
British journal of haematology  2013;163(3):326-333.
Summary
Detection of a 17p13.1 deletion (loss of TP53) or 11q22.3 deletion (loss of ATM), by fluorescence in situ hybridization (FISH), in chronic lymphocytic leukaemia (CLL) patients is associated with a poorer prognosis. Because TP53 and ATM are integral to the TP53 pathway, we hypothesized that 17p13.1- (17p-) and 11q22.3- (11q-) occurring in the same cell (clonal 17p-/11q-) would confer a worse prognosis than either 17p- or 11q-. We studied 2184 CLL patients with FISH (1995–2012) for the first occurrence of 17p-, 11q-, or clonal 17p-/11q-. Twenty (1%) patients had clonal 17p-/11q-, 158 (7%) had 17p- (including 4 with 17p- and 11q- in separate clones), 247 (11%) had 11q-, and 1759 (81%) had neither 17p- nor 11q-. Eleven of 15 (73%) tested patients with clonal 17p-/11q- had dysfunctional TP53 mutations. Overall survival for clonal 17p-/11q- was significantly shorter (1.9 years) than 17p- (3.1 years, p = 0.04), 11q- (4.8 years, p = <0.0001), or neither 17p- nor 11q- (9.3 years, p = <0.0001). Clonal 17p-/11q- thus conferred significantly worse prognosis, suggesting that loss of at least one copy of both TP53 and ATM causes more aggressive disease. Use of an ATM/TP53 combination FISH probe set could identify these very-high risk patients.
doi:10.1111/bjh.12534
PMCID: PMC3907074  PMID: 24032430
Chronic lymphocytic leukaemia; prognostic factors; fluorescencein situ hybridization (FISH); TP53; ATM
3.  Polymorphisms in Metabolism/Antioxidant Genes May Mediate the Effect of Dietary Intake on Pancreatic Cancer Risk 
Pancreas  2013;42(7):1043-1053.
Objectives
A source of variation for inconsistent dietary-pancreatic cancer associations may be individuals carrying constitutional metabolism/antioxidant gene variants differentially benefit compared to homozygous individuals. Seventy-six tag SNPs were genotyped in thirteen candidate genes to test differential associations with pancreatic adenocarcinoma.
Methods
A clinic-based case-control design was used to rapidly ascertain 251 cases and 970 frequency matched controls who provided blood samples and completed a 144-item food frequency questionnaire. SNPs were evaluated using a dominant genetic model and dietary categories split on controls’ median intake. Logistic regression was used to calculate odds ratios and 95% confidence intervals, adjusted for potential confounders.
Results
Significant increased associations (Bonferroni corrected P ≤ 0.0007) were observed for carriers of ≥ 1 minor allele for rs3816257 (glucosidase, alpha; acid [GAA]) and lower intake of deep-yellow vegetables (1.90[1.28,2.83]); and carriers of no minor allele for rs12807961 (catalyase [CAT]) and high total grains intake (2.48[1.50,4.09]) while those with ≥ 1 minor allele had a decreasing slope (across grains). The reference group was no minor alleles with low dietary intake.
Conclusions
Inter-individual variation in metabolism/antioxidant genes could interact with dietary intake to influence pancreatic cancer risk.
doi:10.1097/MPA.0b013e3182968e00
PMCID: PMC3779344  PMID: 24051964
Pancreatic cancer; dietary risk factors; interaction; case-control; genetic risk factors
4.  Diffuse Large B-Cell Lymphoma (Richter Syndrome) in Patients with Chronic Lymphocytic Leukaemia: A Cohort Study of Newly Diagnosed Patients 
British journal of haematology  2013;162(6):774-782.
Summary
Nearly all information about patients with chronic lymphocytic leukaemia (CLL) who develop diffuse large B-cell lymphoma (Richter syndrome [RS]) is derived from retrospective case series or patients treated on clinical trials. We used the Mayo Clinic CLL Database to identify patients with newly diagnosed CLL (1/2000–7/2011). Individuals who developed biopsy-proven RS during follow-up were identified. After median follow-up of 4 years, 37/1641 (2.3%) CLL patients developed RS. The rate of RS was approximately 0.5%/year. Risk of RS was associated with advanced Rai stage at diagnosis (p<0.001), high-risk FISH (p<0.0001), unmutated IGHV (p=0.003), and expression of ZAP-70 (p=0.02) and CD38 (p=0.001). The rate of RS doubled in patients treated for CLL (1%/year). Stereotyped B-cell receptors (odds-ratio=4.2; p=0.01) but not VH4–39 was associated with increased risk of RS. Treatment with combination of purine analogues and alkylating agents increased the risk of RS 3-fold (odds-ratio= 3.26, p=0.0003). Median survival after RS diagnosis was 2.1 years. The RS prognosis score stratified patients into three risk groups with median survivals of 0.5 years, 2.1 years and not reached. Both underlying characteristics of the CLL clone and subsequent CLL therapy influence the risk of RS. Survival after RS remains poor and new therapies are needed.
doi:10.1111/bjh.12458
PMCID: PMC4098845  PMID: 23841899
transformation; aggressive lymphoma; stem cell transplantation; purine analogues; RS survival score
5.  Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC4 
Cancer causes & control : CCC  2013;24(3):595-602.
Purpose
The evidence of a relation between folate intake and one-carbon metabolism (OCM) with pancreatic cancer (PanCa) is inconsistent. In this study, the association between genes and single-nucleotide polymorphisms (SNPs) related to OCM and PanCa was assessed.
Methods
Using biochemical knowledge of the OCM pathway, we identified thirty-seven genes and 834 SNPs to examine in association with PanCa. Our study included 1,408 cases and 1,463 controls nested within twelve cohorts (PanScan). The ten SNPs and five genes with lowest p values (<0.02) were followed up in 2,323 cases and 2,340 controls from eight case-control studies (PanC4) that participated in PanScan2. The correlation of SNPs with metabolite levels was assessed for 649 controls from the European Prospective Investigation into Cancer and Nutrition.
Results
When both stages were combined, we observed suggestive associations with PanCa for rs10887710 (MAT1A) (OR 1.13, 95%CI 1.04-1.23), rs1552462 (SYT9) (OR 1.27, 95%CI 1.02-1.59), and rs7074891 (CUBN) (OR 1.91, 95%CI 1.12-3.26). After correcting for multiple comparisons, no significant associations were observed in either the first or second stage. The three suggested SNPs showed no correlations with one-carbon biomarkers.
Conclusions
This is the largest genetic study to date to examine the relation between germline variations in OCM-related genes polymorphisms and the risk of PanCa. Suggestive evidence for an association between polymorphisms and PanCa was observed among the cohort-nested studies, but this did not replicate in the case-control studies. Our results do not strongly support the hypothesis that genes related to OCM play a role in pancreatic carcinogenesis.
doi:10.1007/s10552-012-0138-0
PMCID: PMC4127987  PMID: 23334854
Pancreatic cancer; One-carbon metabolism; Polymorphisms; Biomarkers; Epidemiology
6.  Meat-Related Mutagens and Pancreatic Cancer: null results from a clinic-based case-control study 
Background
Pancreatic cancer is a devastating disease for which the role of dietary factors remains inconclusive. The study objective was to evaluate risk of pancreatic cancer associated with meat preparation methods and meat-related mutagen consumption using a clinic-based case-control design.
Methods
There were 384 cases and 983 controls; subjects provided demographic information and completed a 144-item food frequency questionnaire, which was used to estimate meat mutagen intake using the National Cancer Institute's CHARRED database. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI), adjusted for factors including age, sex, cigarette smoking, body mass index, and diabetes mellitus.
Results
Overall, the findings were null with respect to meat mutagen intake and pancreatic cancer.
Conclusion
The results do not support an association between well-done meat or meat-related mutagen intake and pancreatic cancer and contrast with generally increased risks reported in previous studies.
Impact
These data contribute to evidence regarding pancreatic cancer and potentially carcinogenic compounds in meat.
doi:10.1158/1055-9965.EPI-13-0343
PMCID: PMC3702664  PMID: 23632817
7.  Nutrients from Fruit and Vegetable Consumption Reduce the Risk of Pancreatic Cancer 
Purpose
Pancreatic cancer is a devastating disease for which the role of dietary factors remains inconclusive. Our objective was to evaluate the risk of pancreatic cancer associated with nutrients found in fruits and vegetables and nutrient supplementation using a clinic-based case-control design.
Methods
Our study included 384 rapidly ascertained cases and 983 controls frequency-matched on age at time of recruitment (in 5-year increments), race, sex, and region of residence. All subjects provided demographic information and completed a 144-item food frequency questionnaire in which they reported no change to their diet within 5 years prior to entering the study. Logistic regression was used to calculate odds ratios (OR) and 95% CIs, adjusted for age, sex, smoking, body mass index, energy intake, and alcohol consumption.
Results
Results show a significant (trend p-value < 0.05) inverse association between pancreatic cancer and nutrient/supplement groupings in a dose-dependent manner including magnesium, potassium, selenium, alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein and zeaxanthin, niacin, total alpha-tocopherol, total vitamin A activity, vitamin B6, and vitamin C. Adjusting for diabetes or total sugar intake did not result in significant changes.
Conclusion
We conclude that most nutrients obtained through consumption of fruits and vegetables may reduce the risk of developing pancreatic cancer.
doi:10.1007/s12029-012-9441-y
PMCID: PMC3694591  PMID: 23620017
Pancreatic Cancer; Diet; Nutrients; Case-control; Fruits; Vegetables
8.  Mapping of the IRF8 gene identifies a 3’ UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-Hodgkin lymphoma subtypes 
Background
Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly-correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk.
Methods
To refine the genetic association of CLL risk, we performed Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then performed fine-mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes.
Results
The strongest association with CLL risk was observed with a common SNP located within the 3’ UTR of IRF8 (rs1044873, log additive odds ratio = 0.7, P=1.81×10−6). This SNP was not associated with the other NHL subtypes (all P>0.05).
Conclusions
We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology.
Impact
These data provide support that a functional variant within the 3’ UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk.
doi:10.1158/1055-9965.EPI-12-1217
PMCID: PMC3596428  PMID: 23307532
CLL; NHL; SNPs; IRF8; risk locus
9.  Statin and Non-steroidal Anti-inflammatory Drug (NSAID) Use In Relation to Clinical Outcome Among Patients with Rai Stage 0 Chronic Lymphocytic Leukemia (CLL) 
Leukemia & lymphoma  2010;51(7):1233-1240.
Statins and nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications. In vitro studies suggest that statins and NSAIDs may have potential as anti-cancer therapies in low grade non-Hodgkin lymphomas including chronic lymphocytic leukemia (CLL) and a recent observational study found statin use was associated with improved event free survival in patients with follicular lymphoma. Other studies have suggested that statins reduce the efficacy of rituximab by inhibiting binding to CD20. We therefore conducted an observational cohort study of 686 patients with newly diagnosed Rai stage 0 CLL to evaluate whether statin or NSAID use was related to their clinical outcome or influenced the efficacy of rituximab therapy. At diagnosis, 136 (20%) patients took statins and 230 (34%) scheduled daily aspirin, ibuprofen, or naproxen. No difference in time to treatment was observed based on statin or NSAID use. Among patients receiving a rituximab containing first-line therapy, no difference in time to salvage treatment was observed based on statin use. Although previous studies suggested statins may improve event free survival among patients with follicular lymphoma, we find no impact of statins on time to initial therapy in this large study of patients with Rai stage 0 CLL. The in vitro observation that statins reduce rituximab efficacy does not appear to have clinical significance in CLL care.
doi:10.3109/10428194.2010.486877
PMCID: PMC3913168  PMID: 20496995
10.  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
11.  Age at Diagnosis and the Utility of Prognostic Testing in Patients with Chronic Lymphocytic Leukemia (CLL) 
Cancer  2010;116(20):4777-4787.
PURPOSE
To analyze the survival of CLL patients relative to age-matched individuals in the general population and determined the age-stratified utility of prognostic testing.
METHODS
All 2487 patients diagnosed with CLL between January 1995 and June 2008 and cared for in the Mayo Division of Hematology were categorized by age at diagnosis and evaluated for differences in clinical characteristics, time to first treatment(TFT), and overall survival(OS).
RESULTS
Among Rai stage 0 patients, survival was shorter than the age-matched general population for patients age<55 years(p<0.001), 55-64 years(p<0.001), and 65-74 years(p<0.001) but not those age≥75 at diagnosis(p=NS). CD38, IGHV mutation, and ZAP-70 each predicted TFT independent of stage for all age groups(all p <0.04) but had less value for predicting OS, particularly as age increased. IGHV and FISH predicted OS independent of stage for patients
CONCLUSIONS
Survival of CLL patients age<75 is shorter than the age-matched general population regardless of disease stage. Among patients age<75, the simple combinations of stage and IGHV or stage and FISH identifies those with excess risk of death relative to the age-matched population. Although useful for predicting TFT independent of stage for patients of all ages, prognostic testing had little utility for predicting OS independent of stage among patients age≥75.
doi:10.1002/cncr.25292
PMCID: PMC3902481  PMID: 20578179
Cancer  2011;118(7):1827-1837.
Background
The impact of physicians’ disease-specific expertise on patient outcome is unknown. While previous studies suggest a survival advantage for cancer patients cared for at high volume centers, these observations may simply reflect referral bias or better access to advanced technologies, clinical trials, and multidisciplinary support at large centers.
Methods
We evaluated time to first treatment(TTFT) and overall survival(OS) of patients with newly diagnosed chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL) at a single academic center based on whether they were cared for by a hematologist/oncologist who sub-specializes in CLL(CLL hematologist) or a hematologist/oncologist with expertise in other areas(non-CLL hematologist).
Results
Among 1309 newly diagnosed patients with CLL cared for between 1999–2009, 773(59%) were cared for by CLL hematologists and 536 were cared for by non-CLL hematologists. Among early stage patients(Rai 0-I), median TTFT(9.2 vs. 6.1 years; p<0.001) and OS(10.5 years vs. 8.8 years; p<0.001) were superior for patients cared for by CLL hematologists. For all patients, OS was superior for patients cared for by CLL hematologists(10.5 years vs. 8.4 years; p=0.001). Physician’s disease-specific expertise remained an independent predictor of OS after adjusting for age, stage, sex, and lymphocyte count. Patients seen by a CLL hematologist were also more likely participate in clinical trials(48% vs. 16%; p<0.001).
Conclusion
Physician disease-specific expertise appears to influence outcome in patients with CLL. To the greatest extent possible, patients should be cared for by a hematologist/oncologist expert in the care of their specific malignancy. When not possible, practice guidelines developed by disease-specific experts should be followed.
doi:10.1002/cncr.26474
PMCID: PMC3893049  PMID: 22009554
chronic lymphocytic lymphoma(CLL); small lymphocytic lymphoma (SLL); prognosis; physician expertise
British journal of haematology  2012;159(5):572-576.
Summary
A recent meta-analysis of three genome-wide association studies of chronic lymphocytic leukaemia (CLL) identified two common variants at the 6p21.31 locus that are associated with CLL risk. To verify and further explore the association of these variants with other non-Hodgkin lymphoma (NHL) subtypes, we genotyped 1196 CLL cases, 1699 NHL cases, and 2410 controls. We found significant associations between the 6p21.31 variants and CLL risk (rs210134: P=0.01; rs210142: P=6.8×10−3). These variants also showed a trend towards association with some of the other NHL subtypes. Our results validate the prior work and support specific genetic pathways for risk among NHL subtypes.
doi:10.1111/bjh.12070
PMCID: PMC3614403  PMID: 23025533
CLL; NHL; SNPs; BAK1; risk locus
Human genetics  2012;131(9):10.1007/s00439-012-1183-1.
Adenocarcinoma of the pancreas is a significant cause of cancer mortality, and up to 10 % of cases appear to be familial. Heritable genomic copy number variants (CNVs) can modulate gene expression and predispose to disease. Here, we identify candidate predisposition genes for familial pancreatic cancer (FPC) by analyzing germline losses or gains present in one or more high-risk patients and absent in a large control group. A total of 120 FPC cases and 1,194 controls were genotyped on the Affymetrix 500K array, and 36 cases and 2,357 controls were genotyped on the Affymetrix 6.0 array. Detection of CNVs was performed by multiple computational algorithms and partially validated by quantitative PCR. We found no significant difference in the germline CNV profiles of cases and controls. A total of 93 non-redundant FPC-specific CNVs (53 losses and 40 gains) were identified in 50 cases, each CNV present in a single individual. FPC-specific CNVs overlapped the coding region of 88 RefSeq genes. Several of these genes have been reported to be differentially expressed and/or affected by copy number alterations in pancreatic adenocarcinoma. Further investigation in high-risk subjects may elucidate the role of one or more of these genes in genetic predisposition to pancreatic cancer.
doi:10.1007/s00439-012-1183-1
PMCID: PMC3808836  PMID: 22665139
PLoS ONE  2013;8(9):e72311.
Purpose
We developed an absolute risk model to identify individuals in the general population at elevated risk of pancreatic cancer.
Patients and Methods
Using data on 3,349 cases and 3,654 controls from the PanScan Consortium, we developed a relative risk model for men and women of European ancestry based on non-genetic and genetic risk factors for pancreatic cancer. We estimated absolute risks based on these relative risks and population incidence rates.
Results
Our risk model included current smoking (multivariable adjusted odds ratio (OR) and 95% confidence interval: 2.20 [1.84–2.62]), heavy alcohol use (>3 drinks/day) (OR: 1.45 [1.19–1.76]), obesity (body mass index >30 kg/m2) (OR: 1.26 [1.09–1.45]), diabetes >3 years (nested case-control OR: 1.57 [1.13–2.18], case-control OR: 1.80 [1.40–2.32]), family history of pancreatic cancer (OR: 1.60 [1.20–2.12]), non-O ABO genotype (AO vs. OO genotype) (OR: 1.23 [1.10–1.37]) to (BB vs. OO genotype) (OR 1.58 [0.97–2.59]), rs3790844(chr1q32.1) (OR: 1.29 [1.19–1.40]), rs401681(5p15.33) (OR: 1.18 [1.10–1.26]) and rs9543325(13q22.1) (OR: 1.27 [1.18–1.36]). The areas under the ROC curve for risk models including only non-genetic factors, only genetic factors, and both non-genetic and genetic factors were 58%, 57% and 61%, respectively. We estimate that fewer than 3/1,000 U.S. non-Hispanic whites have more than a 5% predicted lifetime absolute risk.
Conclusion
Although absolute risk modeling using established risk factors may help to identify a group of individuals at higher than average risk of pancreatic cancer, the immediate clinical utility of our model is limited. However, a risk model can increase awareness of the various risk factors for pancreatic cancer, including modifiable behaviors.
doi:10.1371/journal.pone.0072311
PMCID: PMC3772857  PMID: 24058443
Carcinogenesis  2012;33(7):1384-1390.
Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case–control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10−6, 1.6 × 10−5, 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10−5), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H. pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.
doi:10.1093/carcin/bgs151
PMCID: PMC3405651  PMID: 22523087
Background
Cancer is a shared family experience that might provide an opportunity for lifestyle change among at-risk family members. The purpose of this study was to assess receptivity and preferences for cancer risk reduction programs among at-risk family members with two or more relatives affected with pancreas cancer.
Methods
We surveyed 401 at-risk family members in an existing pancreatic cancer family registry. Participants completed a mailed survey which examined demographic, medical, and psychosocial correlates of willingness to participate in lifestyle cancer risk reduction programs. Multivariable generalized estimating equation approaches were used to model preferences.
Results
Overall, 85% (n = 342) of at-risk family members were receptive to lifestyle cancer risk reduction programs. Participant preferred programs focused on nutrition (36%, n = 116) and weight management (33%, n = 108), with Web/Internet (46%, n = 157) being the most preferred delivery channel. Most respondents preferred to participate in programs with their family or friends (74%, n = 182), rather than alone (25%, n = 85). In multivariable analysis, younger age (p = 0.008) and higher perceived likelihood of developing cancer (p = 0.03) were associated with willingness to participate in lifestyle programs.
Conclusions
Family members of those with pancreatic cancer are receptive to cancer risk reduction programs focusing on nutrition and weight management delivered via the internet. Further research is indicated to determine how to best incorporate a family-based approach when designing lifestyle intervention programs.
doi:10.1186/1897-4287-11-3
PMCID: PMC3691837  PMID: 23724897
Pancreatic cancer; Family; Health behavior change; Perceived risk; Risk reduction; Lifestyle
Cancer causes & control : CCC  2011;22(12):1613-1625.
Objective
Studies on fruit, vegetable, fiber, and grain consumption and pancreatic cancer risk are inconclusive. We used a clinic-based case–control study specifically designed to address limitations of both cohort and case–control studies to examine the relationship.
Methods
Participants were excluded who reported changing their diet within 5 years prior to study entry. And 384 rapidly ascertained cases and 983 controls (frequency matched on age (±5 years), race, sex, and residence) completed epidemiologic surveys and 144-item food frequency questionnaires. Odds ratios (OR) and 95% confidence intervals were calculated using logistic regression adjusted for age, sex, smoking, body mass index, energy intake, and alcohol consumption.
Results
Comparing highest to lowest quintiles, we observed significant inverse associations (OR < 0.8) with significant trends (ptrend < 0.05) for citrus, melon, and berries, other fruits, dark green vegetables, deep yellow vegetables, tomato, other vegetables, dry bean and pea, insoluble fiber, soluble fiber, whole grains, and orange/grapefruit juice, and an increased association with non-whole grains. Results were similar after adjusting for diabetes or total sugar intake.
Conclusions
We provide evidence that lower consumption of fruits, vegetables, whole grains, and fiber is associated with having pancreatic cancer. This may have a role in developing prevention strategies.
doi:10.1007/s10552-011-9838-0
PMCID: PMC3522747  PMID: 21915615
Diet; Risk; Questionnaire; Pancreatic cancer
Jacobs, Kevin B | Yeager, Meredith | Zhou, Weiyin | Wacholder, Sholom | Wang, Zhaoming | Rodriguez-Santiago, Benjamin | Hutchinson, Amy | Deng, Xiang | Liu, Chenwei | Horner, Marie-Josephe | Cullen, Michael | Epstein, Caroline G | Burdett, Laurie | Dean, Michael C | Chatterjee, Nilanjan | Sampson, Joshua | Chung, Charles C | Kovaks, Joseph | Gapstur, Susan M | Stevens, Victoria L | Teras, Lauren T | Gaudet, Mia M | Albanes, Demetrius | Weinstein, Stephanie J | Virtamo, Jarmo | Taylor, Philip R | Freedman, Neal D | Abnet, Christian C | Goldstein, Alisa M | Hu, Nan | Yu, Kai | Yuan, Jian-Min | Liao, Linda | Ding, Ti | Qiao, You-Lin | Gao, Yu-Tang | Koh, Woon-Puay | Xiang, Yong-Bing | Tang, Ze-Zhong | Fan, Jin-Hu | Aldrich, Melinda C | Amos, Christopher | Blot, William J | Bock, Cathryn H | Gillanders, Elizabeth M | Harris, Curtis C | Haiman, Christopher A | Henderson, Brian E | Kolonel, Laurence N | Le Marchand, Loic | McNeill, Lorna H | Rybicki, Benjamin A | Schwartz, Ann G | Signorello, Lisa B | Spitz, Margaret R | Wiencke, John K | Wrensch, Margaret | Wu, Xifeng | Zanetti, Krista A | Ziegler, Regina G | Figueroa, Jonine D | Garcia-Closas, Montserrat | Malats, Nuria | Marenne, Gaelle | Prokunina-Olsson, Ludmila | Baris, Dalsu | Schwenn, Molly | Johnson, Alison | Landi, Maria Teresa | Goldin, Lynn | Consonni, Dario | Bertazzi, Pier Alberto | Rotunno, Melissa | Rajaraman, Preetha | Andersson, Ulrika | Freeman, Laura E Beane | Berg, Christine D | Buring, Julie E | Butler, Mary A | Carreon, Tania | Feychting, Maria | Ahlbom, Anders | Gaziano, J Michael | Giles, Graham G | Hallmans, Goran | Hankinson, Susan E | Hartge, Patricia | Henriksson, Roger | Inskip, Peter D | Johansen, Christoffer | Landgren, Annelie | McKean-Cowdin, Roberta | Michaud, Dominique S | Melin, Beatrice S | Peters, Ulrike | Ruder, Avima M | Sesso, Howard D | Severi, Gianluca | Shu, Xiao-Ou | Visvanathan, Kala | White, Emily | Wolk, Alicja | Zeleniuch-Jacquotte, Anne | Zheng, Wei | Silverman, Debra T | Kogevinas, Manolis | Gonzalez, Juan R | Villa, Olaya | Li, Donghui | Duell, Eric J | Risch, Harvey A | Olson, Sara H | Kooperberg, Charles | Wolpin, Brian M | Jiao, Li | Hassan, Manal | Wheeler, William | Arslan, Alan A | Bas Bueno-de-Mesquita, H | Fuchs, Charles S | Gallinger, Steven | Gross, Myron D | Holly, Elizabeth A | Klein, Alison P | LaCroix, Andrea | Mandelson, Margaret T | Petersen, Gloria | Boutron-Ruault, Marie-Christine | Bracci, Paige M | Canzian, Federico | Chang, Kenneth | Cotterchio, Michelle | Giovannucci, Edward L | Goggins, Michael | Bolton, Judith A Hoffman | Jenab, Mazda | Khaw, Kay-Tee | Krogh, Vittorio | Kurtz, Robert C | McWilliams, Robert R | Mendelsohn, Julie B | Rabe, Kari G | Riboli, Elio | Tjønneland, Anne | Tobias, Geoffrey S | Trichopoulos, Dimitrios | Elena, Joanne W | Yu, Herbert | Amundadottir, Laufey | Stolzenberg-Solomon, Rachael Z | Kraft, Peter | Schumacher, Fredrick | Stram, Daniel | Savage, Sharon A | Mirabello, Lisa | Andrulis, Irene L | Wunder, Jay S | García, Ana Patiño | Sierrasesúmaga, Luis | Barkauskas, Donald A | Gorlick, Richard G | Purdue, Mark | Chow, Wong-Ho | Moore, Lee E | Schwartz, Kendra L | Davis, Faith G | Hsing, Ann W | Berndt, Sonja I | Black, Amanda | Wentzensen, Nicolas | Brinton, Louise A | Lissowska, Jolanta | Peplonska, Beata | McGlynn, Katherine A | Cook, Michael B | Graubard, Barry I | Kratz, Christian P | Greene, Mark H | Erickson, Ralph L | Hunter, David J | Thomas, Gilles | Hoover, Robert N | Real, Francisco X | Fraumeni, Joseph F | Caporaso, Neil E | Tucker, Margaret | Rothman, Nathaniel | Pérez-Jurado, Luis A | Chanock, Stephen J
Nature genetics  2012;44(6):651-658.
In an analysis of 31,717 cancer cases and 26,136 cancer-free controls drawn from 13 genome-wide association studies (GWAS), we observed large chromosomal abnormalities in a subset of clones from DNA obtained from blood or buccal samples. Mosaic chromosomal abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of size >2 Mb were observed in autosomes of 517 individuals (0.89%) with abnormal cell proportions between 7% and 95%. In cancer-free individuals, the frequency increased with age; 0.23% under 50 and 1.91% between 75 and 79 (p=4.8×10−8). Mosaic abnormalities were more frequent in individuals with solid-tumors (0.97% versus 0.74% in cancer-free individuals, OR=1.25, p=0.016), with a stronger association for cases who had DNA collected prior to diagnosis or treatment (OR=1.45, p=0.0005). Detectable clonal mosaicism was common in individuals for whom DNA was collected at least one year prior to diagnosis of leukemia compared to cancer-free individuals (OR=35.4, p=3.8×10−11). These findings underscore the importance of the role and time-dependent nature of somatic events in the etiology of cancer and other late-onset diseases.
doi:10.1038/ng.2270
PMCID: PMC3372921  PMID: 22561519
Leukemia & lymphoma  2010;51(4):620-627.
Treatment of autoimmune cytopenia complicating progressive chronic lymphocytic leukemia (CLL) is constrained by intolerance of myelosuppression and the risk of exacerbation of autoimmune cytopenia by purine analogs particularly when used as single agents. We report on 20 such patients treated with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). Autoimmune cytopenia responded in 19 patients (14 complete remissions (CR), five partial remissions (PR)) with a median time to next treatment (TTT) for autoimmune cytopenia of 21.7 months. Progressive CLL responded in 17 patients (nine CR/complete clinical response, eight PR) with a median TTT of 27.7 months. Five patients have not required any re-treatment at 15–30 months. Grade 3–4 toxicities were infections (n = 3) and drug-induced pneumonitis (n = 1). No patient required blood cell transfusions after cycle 1 of therapy. We conclude that R-CVP is effective and tolerable therapy for autoimmune cytopenia complicating progressive CLL, but the duration of response is suboptimal.
doi:10.3109/10428191003682767
PMCID: PMC3448550  PMID: 20302386
Chronic lymphocytic leukemia; autoimmune hemolytic anemia; immune thrombocytopenia; pure red blood cell aplasia; therapy
Background
Although the increased risk of developing pancreatic cancer (PC) in families with a strong history of the disease is well known, characteristics and outcomes of patients with familial PC is not described well.
Aims
This study aims to evaluate outcomes following resection in patients with familial PC.
Methods
We studied 208 patients who underwent resection of PC from 2000 to 2007 and had prospectively completed family history questionnaires for the Biospecimen Resource for Pancreas Research at our institution. We compared clinical characteristics and outcomes of familial and sporadic PC patients.
Results
Familial (N=15) and sporadic PC patients (N=193) did not have significantly different demographics, pre-operative CA19-9, pre-operative weight loss, R0 status, or T-staging (all p ≥ 0.05). Familial PC patients had lower pre-operative total serum bilirubin concentrations (p=0.03) and lesions outside of the pancreatic head more frequently (p=0.02) than sporadic PC patients. There was no difference in survival at 2 years between familial and sporadic PC patients (p=0.52).
Conclusions
Familial PC patients appear to develop tumors outside of the pancreatic head more frequently than sporadic PC patients. This difference in tumor distribution may be due to a broader area of cancer susceptibility within the pancreas for familial PC patients.
doi:10.1007/s11605-011-1417-x
PMCID: PMC3410546  PMID: 21359597
Pancreatic cancer; Familial cancer syndrome; Familial pancreatic cancer
Pancreas  2011;40(5):768-772.
Objectives
New-onset diabetes mellitus (DM) may herald pancreatic cancer (PaC). We determined if changes in body weight distinguished PaC-associated DM (PaCDM) from type 2 DM.
Methods
Amongst Olmsted County residents, we identified 29 PaCDM and 43 type 2 DM subjects who had serial fasting blood glucose (FBG) measurements, new-onset DM and no cancer-specific symptoms at DM onset. We compared body weight (kg) and FBG (mg/dl) at DM onset, 1–2 years prior and at index date in the two groups.
Results
FBG values were similar prior to and at the onset of DM. Prior to onset of DM, PaCDM and type 2 DM had similar body weight (P=.80). However, at onset of DM 59% of PaCDM lost weight vs. 30% of type 2 DM (P =.02). At onset of DM, 56% of type 2 DM gained weight vs. 31% of PaCDM (P=.04). By index date, PaCDM lost more weight than type 2 DM (8.3±8.3 vs. 0.8±4.8 kg,P<.01).
Conclusions
While new-onset primary type 2 DM is typically associated with weight gain, weight loss frequently precedes onset of PaCDM. The paradoxical development of diabetes in the face of ongoing weight loss may be an important clue to understanding the pathogenesis of PaCDM.
doi:10.1097/MPA.0b013e318220816a
PMCID: PMC3118443  PMID: 21654538
Pancreatic cancer; New-onset diabetes mellitus; zinc alpha-2 glycoprotein
Background
Pancreatic cancer (PC) is considered the most lethal cancer and approximately 10% of PC is hereditary. The purpose of the study was to assess attitudes of at-risk family members with two or more relatives affected with pancreas cancer (PC) toward PC risk and future screening options.
Methods
At-risk family members and primary care controls were surveyed regarding perceived PC risk, PC worry/concern, attitude toward cancer screening, screening test accuracy, and intentions regarding PC screening via blood testing or more invasive endoscopic ultrasound (EUS).
Results
PC family members reported greater perceived risk of PC than controls (54% vs. 6%, respectively, p < 0.0001). PC family members also reported higher levels of PC worry/concern than controls (p < 0.0001), although 19% of PC family members indicated they were “not at all concerned” about getting PC. PC family members indicated greater acceptance of a false-negative result on a PC screening test relative to controls (12% vs. 8%, p = 0.02). Both groups reported high (>89%) receptivity to the potential PC screening options presented, though receptivity was greater among PC family members as compared to controls (p < 0.0001) for EUS. In multivariable analyses, degree of PC concern (p < 0.0001) was associated with intention to screen for PC by blood test and EUS, while perceived PC risk was associated with likelihood of undergoing EUS only (p < 0.0001).
Conclusions
Receptivity to screening options for PC appears high. Clinicians should address behavioral and genetic risk factors for PC and foster appropriate concern regarding PC risk among at-risk individuals.
doi:10.1186/1897-4287-10-8
PMCID: PMC3410777  PMID: 22738386
Pancreatic cancer; Health behavior; Perceived risk; Screening intentions
Germline mutations in CDKN2A have been reported in pancreatic cancer families, but genetic counseling for pancreatic cancer risk has been limited by lack of information on CDKN2A mutation carriers outside of selected pancreatic or melanoma kindreds. Lymphocyte DNA from consecutive, unselected white non-Hispanic patients with pancreatic adenocarcinoma was used to sequence CDKN2A. Frequencies of mutations that alter the coding of p16INK4 or p14ARF were quantified overall and in subgroups. Penetrance and likelihood of carrying mutations by family history were estimated. Among 1537 cases, 9 (0.6%) carried germline mutations in CDKN2A, including three previously unreported mutations. CDKN2A mutation carriers were more likely to have a family history of pancreatic cancer (P=0.003) or melanoma (P=0.03), and a personal history of melanoma (P=0.01). Among cases who reported having a first-degree relative with pancreatic cancer or melanoma, the carrier proportions were 3.3 and 5.3%, respectively. Penetrance for mutation carriers by age 80 was calculated to be 58% for pancreatic cancer (95% confidence interval (CI) 8–86%), and 39% for melanoma (95% CI 0–80). Among cases who ever smoked cigarettes, the risk for pancreatic cancer was higher for carriers compared with non-carriers (HR 25.8, P=2.1 × 10−13), but among nonsmokers, this comparison did not reach statistical significance. Germline mutations in CDKN2A among unselected pancreatic cancer patients are uncommon, although notably penetrant, especially among smokers. Carriers of germline mutations of CDKN2A should be counseled to avoid tobacco use to decrease risk of pancreatic cancer in addition to taking measures to decrease melanoma risk.
doi:10.1038/ejhg.2010.198
PMCID: PMC3060321  PMID: 21150883
cyclin-dependent kinase inhibitor p16; genes; p16; pancreatic neoplasms
Monoclonal B cell lymphocytosis (MBL) is a hematologic condition wherein small B cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and “CLL-like” MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. Ninety-one unique MBL clones were detected: 73 CLL-like MBL (CD5+CD20dimsIgdim), 11 atypical MBL (CD5+CD20+sIg+), and 7 CD5neg MBL (CD5negCD20+sIgneg). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b, and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70, and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on 7 CLL-like MBL, and showed activation of B cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders.
doi:10.1038/leu.2011.117
PMCID: PMC3164475  PMID: 21617698

Results 1-25 (46)