Gloria M Petersen

Mayo Foundation for Medical Education and Research, Рочестер, Michigan, United States

Are you Gloria M Petersen?

Claim your profile

Publications (270)2600.94 Total impact

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 × 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 × 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 × 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 × 10(-9)), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk.
    Nature Genetics 06/2015; DOI:10.1038/ng.3341
  • Gloria M. Petersen
  • Source
    Rick J. Jansen, Xiang-Lin Tan, Gloria M. Petersen
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic cancer (PC) has been estimated to have higher incidence and correspondingly higher mortality rates in more developed regions worldwide. Overall, the age-adjusted incidence rate is 4.9/105 and age-adjusted mortality rate is at 4.8/105. We review here our current knowledge of modifiable risk factors (cigarette smoking, obesity, diet, and alcohol) for PC, genetic variants implicated by genome-wide association studies, possible genetic interactions with risk factors, and prevention strategies to provide future research directions that may further our understanding of this complex disease. Cigarette smoking is consistently associated with a two-fold increased PC risk. PC associations with dietary intake have been largely inconsistent, with the potential exception of certain unsaturated fatty acids decreasing risk and well-done red meat or meat mutagens increasing risk. There is strong evidence to support that obesity (and related measures) increase risk of PC. Only the heaviest alcohol drinkers seem to be at an increased risk of PC. Currently, key prevention strategies include avoiding tobacco and excessive alcohol consumption and adopting a healthy lifestyle. Screening technologies and PC chemoprevention are likely to become more sophisticated, but may only apply to those at high risk. Risk stratification may be improved by taking into account gene environment interactions. Research on these modifiable risk factors is key to reducing the incidence of PC and understanding who in the population can be considered high risk.
    The Yale journal of biology and medicine 06/2015; 88(2):115-126.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Discriminant markers for pancreatic cancer detection are needed. We sought to identify and validate methylated DNA markers for pancreatic cancer using next-generation sequencing unbiased by known targets. At a referral center, we conducted four sequential case-control studies: discovery, technical validation, biological validation, and clinical piloting. Candidate markers were identified using variance inflated logistic regression on reduced-representation bisulfite DNA sequencing results from matched pancreatic cancers, benign pancreas, and normal colon tissues. Markers were validated technically on replicate discovery study DNA and biologically on independent, matched, blinded tissues by methylation specific PCR. Clinical testing of 6 methylation candidates and mutant KRAS was performed on secretin-stimulated pancreatic juice samples from 61 pancreatic cancer patients, 22 with chronic pancreatitis and 19 with normal pancreas on endoscopic ultrasound. Areas under receiver operating characteristics curves (AUC) for markers were calculated. Sequencing identified >500 differentially hyper-methylated regions. On independent tissues, AUC on 19 selected markers ranged between 0.73 - 0.97. Pancreatic juice AUC values for CD1D, KCNK12, CLEC11A, NDRG4, IKZF1, PKRCB and KRAS were 0.92*, 0.88, 0.85, 0.85, 0.84, 0.83 and 0.75, respectively, for pancreatic cancer compared to normal pancreas and 0.92*, 0.73, 0.76, 0.85*, 0.73, 0.77 and 0.62 for pancreatic cancer compared to chronic pancreatitis (*p=0.001 vs KRAS). We identified and validated novel DNA methylation markers strongly associated with pancreatic cancer. On pilot testing in pancreatic juice, best markers (especially CD1D) highly discriminated pancreatic cases from controls. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 05/2015; DOI:10.1158/1078-0432.CCR-14-2469
  • [Show abstract] [Hide abstract]
    ABSTRACT: The potential role of vitamin D in the aetiology of pancreatic cancer is unclear, with recent studies suggesting both positive and negative associations. We used data from 9 case-control studies from the International Pancreatic Cancer Case-Control Consortium (PanC4) to examine associations between pancreatic cancer risk and dietary vitamin D intake. Study-specific odds ratios (ORs) were estimated using multivariable logistic regression, and ORs were then pooled using a random effects model. From a subset of 4 studies, we also calculated pooled estimates of association for supplementary and total vitamin D intake. Risk of pancreatic cancer increased with dietary intake of vitamin D (per 100 international units (IU)/day: OR=1.13, 95% confidence interval (CI) 1.07-1.19, p=7.4×10(-6), p-heterogeneity=0.52; ≥230 vs <110 IU/day: OR=1.31, 95% CI 1.10-1.55, p=2.4×10(-3), p-heterogeneity=0.81), with the association possibly stronger in people with low retinol / vitamin A intake. Increased risk of pancreatic cancer was observed with higher levels of dietary vitamin D intake. Additional studies are required to determine whether or not our finding has a causal basis. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
    Annals of Oncology 05/2015; DOI:10.1093/annonc/mdv236
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT - CLPTM1L gene region on chr5p15.33. Since this region is characterized by low linkage disequilibrium (LD), we sought to identify additional SNPs could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia.We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, OR=0.85; 95% CI=0.80-0.90, P=8.3x10(-8) ). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low LD between them (r(2) =0.07, D'=0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (P=3.0x10(-5) ), rs4583925 (P=4.0x10(-5) ) and rs2735948 (P=5.0x10(-5) ). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants. This article is protected by copyright. All rights reserved. © 2015 UICC.
    International Journal of Cancer 05/2015; DOI:10.1002/ijc.29590
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To further elucidate the anticancer mechanisms of metformin against pancreatic cancer, we evaluated the inhibitory effects of metformin on pancreatic tumorigenesis in a genetically engineered mouse model and investigated its possible anti-inflammatory and antiangiogenesis effects. Six-week-old LSL-Kras;Trp53 mice (10 per group) were administered once daily intraperitoneally with saline (control) for 1 week or metformin (125 mg/kg) for 1 week (Met_1wk) or 3 weeks (Met_3wk) before tumor initiation. All mice continued with their respective injections for 6 weeks after tumor initiation. Molecular changes were evaluated through quantitative polymerase chain reaction, immunohistochemistry, and Western blotting. At euthanasia, pancreatic tumor volume in the Met_1wk (median, 181.8 mm) and Met_3wk (median, 137.9 mm) groups was significantly lower than those in the control group (median, 481.1 mm; P = 0.001 and 0.0009, respectively). No significant difference was observed between the Met_1wk and Met_3wk groups (P = 0.51). These results were further confirmed using tumor weight and tumor burden measurements. Furthermore, metformin treatment decreased the phosphorylation of nuclear factor κB and signal transducer and activator of transcription 3 as well as the expression of specificity protein 1 transcription factor and several nuclear factor κB-regulated genes. Metformin may inhibit pancreatic tumorigenesis by modulating multiple molecular targets in inflammatory pathways.
    Pancreas 05/2015; 44(4):636-47. DOI:10.1097/MPA.0000000000000308
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic cancer (PC) is estimated to become the second leading cause of cancer death in the United States by 2020. Early detection is the key to improving survival in PC. Addressing this urgent need, the Kenner Family Research Fund conducted the inaugural Early Detection of Sporadic Pancreatic Cancer Summit Conference in 2014 in conjunction with the 45th Anniversary Meeting of the American Pancreatic Association and Japan Pancreas Society. This seminal convening of international representatives from science, practice, and clinical research was designed to facilitate challenging interdisciplinary conversations to generate innovative ideas leading to the creation of a defined collaborative strategic pathway for the future of the field. An in-depth summary of current efforts in the field, analysis of gaps in specific areas of expertise, and challenges that exist in early detection is presented within distinct areas of inquiry: Case for Early Detection: Definitions, Detection, Survival, and Challenges; Biomarkers for Early Detection; Imaging; and Collaborative Studies. In addition, an overview of efforts in familial PC is presented in an addendum to this article. It is clear from the summit deliberations that only strategically designed collaboration among investigators, institutions, and funders will lead to significant progress in early detection of sporadic PC.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.
    Pancreas 04/2015; 44(5). DOI:10.1097/MPA.0000000000000368
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although zinc transporters were shown to play roles in the development of prostate, bladder, and renal cancer, no study has evaluated the genetic variants in zinc transporter genes with risk of urological cancers. A candidate gene association study using genome-wide association study (GWAS) datasets was conducted for variants in 24 zinc transporter genes. Genotypes were analyzed using logistic regression models adjusted for covariates. The function of identified variants was assessed by using the Encyclopedia of DNA Elements (ENCODE). We further evaluated tumors for somatic change of the implicated gene(s) and the associations between identified variants and patient survival from data in The Cancer Genome Atlas (TCGA). A ZIP11 variant, rs8081059, was significantly associated with increased risk of renal cell carcinoma (odds ratios (OR) = 1.28, 95 % confidence intervals (CI) (1.13-1.45), p = 0.049). No zinc transporter variants were associated with prostate cancer risk. Four variants within ZIP11 were significantly associated with bladder cancer risk: rs11871756 (OR = 1.43, 95 % CI (1.24-1.63), p = 0.0002), rs11077654 (OR = 0.76, 95 % CI (0.68-0.85), p = 0.001), rs9913017 (OR = 0.76, 95 % CI (0.68-0.85), p = 0.002), and rs4969054 (OR = 0.78, 95 % CI (0.69-0.88), p = 0.02); the three protective variants were co-located and highly correlated. These variants were located within predicted transcribed or enhancer regions. Among the 253 bladder cancer patients in TCGA, two had tumors that contained deleterious missense mutations in ZIP11. Moreover, rs11077654 was significantly associated with survival of bladder cancer patients (p = 0.046). In conclusion, zinc transporter gene, ZIP11, may play an important role in bladder cancer. Further studies of the gene are warranted.
    Tumor Biology 04/2015; DOI:10.1007/s13277-015-3459-2
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 03/2015; 96(3):487-97. DOI:10.1016/j.ajhg.2015.01.011
  • Source
    Lang Wu, Kari G. Rabe, Gloria M. Petersen
    [Show abstract] [Hide abstract]
    ABSTRACT: 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. 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. 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. Currently identified GWAS susceptibility variants are unlikely to explain the potential shared genetic etiology between Type 2 diabetes and pancreatic cancer.
    PLoS ONE 02/2015; 10(2):e0117230. DOI:10.1371/journal.pone.0117230
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background:The dismal prognosis of patients diagnosed with pancreatic cancer points to our limited arsenal of effective anticancer therapies. Oncogenic K-RAS hyperactivation is virtually universal in pancreatic cancer, that confers drug resistance, drives aggressive tumorigenesis and rapid metastasis. Pancreatic tumours are often marked by hypovascularity, increased hypoxia and ineffective drug delivery. Thus, biomarker discovery and developing innovative means of countervailing oncogenic K-RAS activation are urgently needed.Methods:Tumour specimens from 147 pancreatic cancer patients were analysed by immunohistochemical (IHC) staining and tissue microarray (TMA). Statistical correlations between selected biomarkers and clinicopathological predictors were examined to predict survival.Results:We find that heightened hypoxia response predicts poor clinical outcome in resectable pancreatic cancer. SIAH is a tumour-specific biomarker. The combination of five biomarkers (EGFR, phospho-ERK, SIAH, Ki67 and HIF-1α) and four clinicopathological predictors (tumour size, pathological grade, margin and lymph node status) predict patient survival post surgery in pancreatic cancer.Conclusions:Combining five biomarkers in the K-RAS/Ki67/HIF-1α pathways with four clinicopathological predictors may assist to better predict survival in resectable pancreatic cancer.British Journal of Cancer advance online publication 13 January 2015; doi:10.1038/bjc.2014.659
    British Journal of Cancer 01/2015; 112(3). DOI:10.1038/bjc.2014.659
  • [Show abstract] [Hide abstract]
    ABSTRACT: & Aims: We investigated the prevalence of germline mutations in APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, and TP53 in patients with pancreatic cancer. The Ontario Pancreas Cancer Study enrolls consenting participants with pancreatic cancer from a province-wide electronic pathology database; 708 probands were enrolled from April 2003 through August 2012. To improve precision of BRCA2 prevalence estimates, 290 probands were randomly selected from 3 strata, based on family history of breast and/or ovarian cancer, pancreatic cancer, or neither. Germline DNA was analyzed by next-generation sequencing using a custom multiple-gene panel. Mutation prevalence estimates were calculated from the sample for the entire cohort. Eleven pathogenic mutations were identified: 3 in ATM, 1 in BRCA1, 2 in BRCA2, 1 in MLH1, 2 in MSH2, 1 in MSH6, and 1 in TP53. The prevalence of mutations in all 13 genes was 3.8% (95% confidence interval, 2.1%-5.6%). Carrier status was significantly associated with breast cancer in the proband or first-degree relative (P<.01), and colorectal cancer in the proband or first-degree relative (P<.01), but not family history of pancreatic cancer, age of diagnosis, or stage at diagnosis. Of patients with a personal or family history of breast and colorectal cancer, 10.7% (4.4%-17.0%) and 11.1% (3.0%-19.1%) carried pathogenic mutations, respectively. A small but clinically important proportion of pancreatic cancer is associated with mutations in known predisposition genes. The heterogeneity of mutations identified in this study demonstrates the value of using a multiple-gene panel in pancreatic cancer. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
    Gastroenterology 12/2014; 148(3). DOI:10.1053/j.gastro.2014.11.042
  • Molecular Cancer Research 12/2014; 12(12 Supplement):A26-A26. DOI:10.1158/1557-3125.RASONC14-A26
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Whole exome sequencing (WES) provides an unprecedented opportunity to identify the potential aetiological role of rare functional variants in human complex diseases. Large-scale collaborations have generated germline WES data on patients with a number of diseases, especially cancer, but less often on healthy controls under the same sequencing procedures. These data can be a valuable resource for identifying new disease susceptibility loci if study designs are appropriately applied. This review describes suggested strategies and technical considerations when focusing on case-only study designs that use WES data in complex disease scenarios. These include variant filtering based on frequency and functionality, gene prioritisation, interrogation of different data types and targeted sequencing validation. We propose that if case-only WES designs were applied in an appropriate manner, new susceptibility genes containing rare variants for human complex diseases can be detected.
    Journal of Medical Genetics 11/2014; DOI:10.1136/jmedgenet-2014-102697
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose:Pancreatic cancer (PC) frequently causes diabetes. We recently proposed adrenomedullin (AM) as a candidate mediator of pancreatic β-cell dysfunction in PC. How PC-derived AM reaches β-cells remote from the cancer to induce β-cell dysfunction is unknown. We tested a novel hypothesis that PC sheds AM-containing exosomes into circulation which are transported to β-cells and impair insulin secretion. Experimental Design:We characterized exosomes from conditioned media of PC-cell lines (n=5) and portal/peripheral venous blood of PC patients (n=20). Western blot analysis showed the presence of AM in PC-Exosomes. We determined the effect of AM-containing PC-Exosomes on insulin secretion from INS-1 β-cells and human islets, and showed how exosomes internalize into β-cells. We studied the interaction between β-cell AM receptors and AM present in PC-Exosomes. In addition, we studied the effect of AM on endoplasmic reticulum (ER) stress response genes and reactive oxygen/nitrogen species generation in β-cells. Results:Exosomes were found to be the predominant extracellular vesicles secreted by PC into culture media and human plasma. PC-Exosomes contained AM and CA19-9, readily entered β-cells through caveolin-mediated endocytosis or macropinocytosis, and inhibited insulin secretion. AM in PC-Exosomes interacted with its receptor on β-cells. AM receptor blockade abrogated the inhibitory effect of exosomes on insulin secretion. β-cells exposed to AM or PC-Exosomes showed upregulation of ER stress genes and increased reactive oxygen/nitrogen species. Conclusions:Pancreatic cancer causes paraneoplastic β-cell dysfunction by shedding AM+/CA19-9+ exosomes into circulation that inhibit insulin secretion, likely through AM-induced ER stress and failure of the UPR.
    Clinical Cancer Research 10/2014; 21(7). DOI:10.1158/1078-0432.CCR-14-2022
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic neuroendocrine tumors (PNETs) are uncommon, and little is known about their risk factors and association with other cancers. We evaluated whether the following risk factors known to be associated with pancreatic adenocarcinoma are also associated with PNETs: smoking, alcohol use, family history of PNET, and other cancers, and personal history of diabetes as potential risk factors.
    Pancreas 10/2014; DOI:10.1097/MPA.0000000000000234
  • Cancer Research 10/2014; 74(19 Supplement):5102-5102. DOI:10.1158/1538-7445.AM2014-5102

Publication Stats

18k Citations
2,600.94 Total Impact Points


  • 2008–2015
    • Mayo Foundation for Medical Education and Research
      • Department of Health Sciences Research
      Рочестер, Michigan, United States
    • Washington University in St. Louis
      San Luis, Missouri, United States
  • 2001–2015
    • Mayo Clinic - Rochester
      • • Department of Health Science Research
      • • Department of Gastroenterology and Hepatology
      Рочестер, Minnesota, United States
  • 2013
    • National Institutes of Health
      • Branch of Epidemiology (EPI)
      베서스다, Maryland, United States
  • 2012
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
  • 2006–2012
    • National Cancer Institute (USA)
      • Division of Cancer Epidemiology and Genetics
      Bethesda, MD, United States
    • Creighton University
      Omaha, Nebraska, United States
  • 1991–2012
    • Johns Hopkins University
      • • Division of Gastroenterology
      • • Department of Medicine
      • • Department of Epidemiology
      Baltimore, Maryland, United States
  • 2009
    • Hospital Clínic de Barcelona
      Barcino, Catalonia, Spain
  • 2005
    • Nevada cancer institute
      Las Vegas, Nevada, United States
  • 2002
    • University of Michigan
      • Division of Molecular Medicine & Genetics
      Ann Arbor, Michigan, United States
  • 1996–2000
    • Johns Hopkins Bloomberg School of Public Health
      • Department of Epidemiology
      Baltimore, Maryland, United States
  • 1997–1999
    • Johns Hopkins Medicine
      • Department of Pathology
      Baltimore, MD, United States
  • 1998
    • Indiana University Bloomington
      Bloomington, Indiana, United States
  • 1992
    • University of Helsinki
      • Department of Medical Genetics
      Helsinki, Province of Southern Finland, Finland