[Show abstract][Hide abstract] ABSTRACT: The genetic basis underlying the majority of hereditary pancreatic adenocarcinoma (PC) is unknown. Since DNA repair genes are widely implicated in gastrointestinal malignancies, including PC, we hypothesized that there are novel DNA repair PC susceptibility genes. As germline DNA repair gene mutations may lead to PC subtypes with selective therapeutic responses, we also hypothesized that there is an overall survival (OS) difference in mutation carriers versus non-carriers. We therefore interrogated the germline exomes of 109 high-risk PC cases for rare protein-truncating variants (PTVs) in 513 putative DNA repair genes. We identified PTVs in 41 novel genes among 36 kindred. Additional genetic evidence for causality was obtained for 17 genes, with FAN1, NEK1 and RHNO1 emerging as the strongest candidates. An OS difference was observed for carriers versus non-carriers of PTVs with early stage (≤IIB) disease. This adverse survival trend in carriers with early stage disease was also observed in an independent series of 130 PC cases. We identified candidate DNA repair PC susceptibility genes and suggest that carriers of a germline PTV in a DNA repair gene with early stage disease have worse survival.
Cancer Letters 01/2016; 370(2):302-312. DOI:10.1016/j.canlet.2015.10.030 · 5.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Research biobanks are heterogeneous and exist to manage diverse biosample types with the goal of facilitating and serving biomedical discovery. The perspectives of biobank managers are reviewed, and the perspectives of two biobank directors, one with experience in institutional biobanks and the other with national cooperative group banks, are presented. Most research biobanks are not designed, nor do they have the resources, to return research results and incidental findings to participants or their families.
The Journal of Law Medicine & Ethics 10/2015; 43(3):523-528. DOI:10.1111/jlme.12294 · 1.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genomic research results and incidental findings with health implications for a research participant are of potential interest not only to the participant, but also to the participant's family. Yet investigators lack guidance on return of results to relatives, including after the participant's death. In this paper, a national working group offers consensus analysis and recommendations, including an ethical framework to guide investigators in managing this challenging issue, before and after the participant's death.
The Journal of Law Medicine & Ethics 10/2015; 43(3):440-463. DOI:10.1111/jlme.12288 · 1.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Data are lacking with regard to participants' perspectives on return of genetic research results to relatives, including after the participant's death. This paper reports descriptive results from 3,630 survey respondents: 464 participants in a pancreatic cancer biobank, 1,439 family registry participants, and 1,727 healthy individuals. Our findings indicate that most participants would feel obligated to share their results with blood relatives while alive and would want results to be shared with relatives after their death.
The Journal of Law Medicine & Ethics 10/2015; 43(3):464-475. DOI:10.1111/jlme.12289 · 1.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. METHODS: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. RESULTS: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE =0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. CONCLUSION: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
JNCI Journal of the National Cancer Institute 10/2015; 107(12). DOI:10.1093/jnci/djv279 · 12.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exposure to various chemicals and heavy metals has been associated with risk of different cancers; however, data on whether such exposures may increase the risk of pancreatic cancer (PC) are very limited and inconclusive. We examined PC risk with self-reported exposures to chemicals and heavy metals.
The design was a clinic-based, case-control study of data collected from 2000 to 2014 at Mayo Clinic in Rochester, Minnesota, USA. Cases were rapidly ascertained patients diagnosed with pancreatic ductal adenocarcinoma (n = 2,092). Controls were cancer-free patients in primary care clinics (n = 2,353), frequency-matched to cases on age, race, sex, and state/region of residence. Cases and controls completed identical risk factor questionnaires, which included yes/no questions about regular exposure to pesticides, asbestos, benzene, chlorinated hydrocarbons, chromium, and nickel. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CI) comparing those who affirmed exposure to each of the chemicals/heavy metals to those who reported no regular exposure, adjusting for potential confounders.
Self-reported regular exposure to pesticides was associated with increased odds of PC (OR 1.21, 95 % CI 1.02-1.44). Regular exposure to asbestos (OR 1.54, 95 % CI 1.23-1.92), benzene (OR 1.70, 95 % CI 1.23-2.35), and chlorinated hydrocarbons (OR 1.63, 95 % CI 1.32-2.02) also was associated with higher odds of PC. Chromium and nickel exposures were not significantly associated with PC.
These findings add to the limited data suggesting that exposure to pesticides, asbestos, benzene, and chlorinated hydrocarbons may increase PC risk. They further support the importance of implementing strategies that reduce exposure to these substances.
Cancer Causes and Control 08/2015; 26(11). DOI:10.1007/s10552-015-0652-y · 2.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Familial pancreatic cancer kindreds contain at least two affected first-degree relatives. Comprehensive data are needed to assist clinical risk assessment and genetic testing.
Germ-line DNA samples from 727 unrelated probands with positive family history (521 met criteria for familial pancreatic cancer) were tested in compliance with the Clinical Laboratory Improvement Amendments for mutations in BRCA1 and BRCA2 (including analysis of deletions and rearrangements), PALB2, and CDKN2A. We compared prevalence of deleterious mutations between familial pancreatic cancer probands and nonfamilial pancreatic cancer probands (kindreds containing at least two affected biological relatives, but not first-degree relatives). We also examined the impact of family history on breast and ovarian cancers and melanoma.
Prevalence of deleterious mutations (excluding variants of unknown significance) among familial pancreatic cancer probands was: BRCA1, 1.2%; BRCA2, 3.7%; PALB2, 0.6%; and CDKN2A, 2.5%. Four novel deleterious mutations were detected. Familial pancreatic cancer probands carry more mutations in the four genes (8.0%) than nonfamilial pancreatic cancer probands (3.5%) (odds ratio: 2.40; 95% confidence interval: 1.06-5.44; P = 0.03). The probability of testing positive for deleterious mutations in any of the four genes ranges up to 10.4%, depending on family history of cancers. BRCA2 and CDKN2A account for the majority of mutations in familial pancreatic cancer.
Genetic testing of multiple relevant genes in probands with a positive family history is warranted, particularly for familial pancreatic cancer.
Genetics in Medicine 07/2015; 17(7):569-577. DOI:10.1038/gim.2014.153 · 7.33 Impact Factor
[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.
[Show abstract][Hide abstract] ABSTRACT: Evidence on the association between vitamin D status and pancreatic cancer risk is inconsistent. This inconsistency may be partially attributable to variation in vitamin D regulating genes. We selected 11 vitamin D-related genes (GC, DHCR7, CYP2R1, VDR, CYP27B1, CYP24A1, CYP27A1, RXRA, CRP2, CASR and CUBN) totaling 213 single nucleotide polymorphisms (SNPs), and examined associations with pancreatic adenocarcinoma. Our study included 3,583 pancreatic cancer cases and 7,053 controls from the genome-wide association studies of pancreatic cancer PanScans-I-III. We used the Adaptive Joint Test and the Adaptive Rank Truncated Product statistic for pathway and gene analyses, and unconditional logistic regression for SNP analyses, adjusting for age, sex, study and population stratification. We examined effect modification by circulating vitamin D concentration (≤50, >50 nmol/L) for the most significant SNPs using a subset of cohort cases (n = 713) and controls (n = 878). The vitamin D metabolic pathway was not associated with pancreatic cancer risk (p = 0.830). Of the individual genes, none were associated with pancreatic cancer risk at a significance level of p<0.05. SNPs near the VDR (rs2239186), LRP2 (rs4668123), CYP24A1 (rs2762932), GC (rs2282679), and CUBN (rs1810205) genes were the top SNPs associated with pancreatic cancer (p-values 0.008-0.037), but none were statistically significant after adjusting for multiple comparisons. Associations between these SNPs and pancreatic cancer were not modified by circulating concentrations of vitamin D. These findings do not support an association between vitamin D-related genes and pancreatic cancer risk. Future research should explore other pathways through which vitamin D status might be associated with pancreatic cancer risk.
PLoS ONE 06/2015; 10(6):e0129983. DOI:10.1371/journal.pone.0129983 · 3.23 Impact Factor
[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: 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.
[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.