Germline genetic variability in pancreatic cancer risk and prognosis.

Published on Aug 18, 2020in Seminars in Cancer Biology11.09
· DOI :10.1016/J.SEMCANCER.2020.08.003
Manuel Gentiluomo6
Estimated H-index: 6
(UniPi: University of Pisa),
Federico Canzian82
Estimated H-index: 82
(DKFZ: German Cancer Research Center)
+ 3 AuthorsDaniele Campa34
Estimated H-index: 34
(UniPi: University of Pisa)
Sources
Abstract
Pancreatic cancer (PC), particularly its most common form, pancreatic ductal adenocarcinoma (PDAC), is relatively rare but highly lethal. Knowledge about PC risk factors could in the long term contribute to early diagnosis and mortality reduction. We review the current status of research on germline genetic factors for PC risk. Genome-wide association studies (GWAS) successfully identified common loci convincingly associated with PC risk, an endeavor that is still ongoing. The function of only a handful of risk loci has being thoroughly characterized so far. Secondary analyses of existing GWAS data are being used to discover novel loci. GWAS data have also been used to study additional risk factors with a Mendelian randomization approach. Polygenic/multifactorial risk scores show much larger risks than individual variants, but their use for risk stratification in the population is not warranted yet. At the other end of the spectrum of inherited PC risk factors, rare high-penetrance variants co-segregating with the disease have been observed in familial cancer syndromes that include PC, or in families with multiple recurrence of PC alone. Rare variants predicted to have a deleterious effect on function are studied also with a case-control approach, by resequencing candidate genes or whole-exomes/whole-genomes. Telomere length and mitochondrial DNA copy number are useful additional DNA-based markers of PC susceptibility. The role of common variants in prognosis of PC patients has also been explored, albeit with more limited success than risk. Finally, genetics of pancreatic neuroendocrine tumors (PNET), a rarer and heterogeneous form of PC, is still understudied.
References282
Newest
#2Manuel Gentiluomo (UniPi: University of Pisa)H-Index: 6
Last. Daniele Campa (UniPi: University of Pisa)H-Index: 34
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Background Most cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection. Objective We generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score. Metho...
5 CitationsSource
#1Kasper A. Overbeek (EUR: Erasmus University Rotterdam)H-Index: 3
#2Mar Rodríguez-Girondo (LUMC: Leiden University Medical Center)H-Index: 13
Last. Thomas P. Potjer (LUMC: Leiden University Medical Center)H-Index: 10
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Background Pathogenic variants in the CDKN2A gene are generally associated with the development of melanoma and pancreatic ductal adenocarcinoma (PDAC), but specific genotype-phenotype correlations might exist and the extent of PDAC risk is not well established for many variants. Methods Using the Dutch national familial melanoma database, we identified all families with a pathogenic CDKN2A variant and investigated the occurrence of PDAC within these families. We also estimated the standardised ...
3 CitationsSource
#1Samantha A. Streicher (Yale University)H-Index: 6
#2Alison P. Klein (Johns Hopkins University)H-Index: 67
Last. Harvey A. Risch (Yale University)H-Index: 95
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Jews are estimated to be at increased risk of pancreatic cancer compared to non-Jews, but their observed 50-80% excess risk is not explained by known non-genetic or genetic risk factors. We conducted a GWAS in a case-control sample of American Jews, largely Ashkenazi, including 406 pancreatic cancer patients and 2332 controls, identified in the dbGaP, PanScan I/II, PanC4 and GERA data sets. We then examined resulting SNPs with P < 10-7 in an expanded sample set, of 539 full- or part-Jewish pancr...
1 CitationsSource
#1Yan Zhang (HKU: University of Hong Kong)H-Index: 12
#2Amber N. Hurson (UNC: University of North Carolina at Chapel Hill)H-Index: 1
Last. Renal Cancer Gwas (Johns Hopkins University)H-Index: 1
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Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample si...
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#1Yingsong Lin (Aichi Medical University)H-Index: 30
#2Masahiro Nakatochi (Nagoya University)H-Index: 22
Last. Keitaro Matsuo (Nagoya University)H-Index: 109
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Pancreatic cancer is the fourth leading cause of cancer-related deaths in Japan. To identify risk loci, we perform a meta-analysis of three genome-wide association studies comprising 2,039 pancreatic cancer patients and 32,592 controls in the Japanese population. Here, we identify 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P < 5.0 × 10−8), of which 16p12.3 has not been reported in the Western population. The lead single nucleotide polymorphism (SNP) at 16p12.3 is rs78193826 ...
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#1Xiaoyi Wang (Fudan University)H-Index: 4
#2Haitao Chen (Southern Medical University)H-Index: 11
Last. Jianfeng Xu (NorthShore University HealthSystem)H-Index: 5
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BACKGROUND Disease-related single nucleotide polymorphisms (SNPs) based genetic risk score (GRS) has been proven to provide independent inherited risk other than family history in multiple cancer types. AIM To evaluate the potential of GRS in the prediction of pancreatic cancer risk. METHODS In this case-control study (254 cases and 1200 controls), we aimed to evaluate the association between GRS and pancreatic ductal adenocarcinoma (PDAC) risk in the Chinese population. The GRS was calculated b...
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#1Jihye Kim (Harvard University)H-Index: 7
#2Chen Yuan (Harvard University)H-Index: 21
Last. Peter Kraft (Harvard University)H-Index: 138
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Background: Pancreatic cancer is the third leading cause of cancer death in the United States, and 80% of patients present with advanced, incurable disease. Risk markers for pancreatic cancer have been characterized, but combined models are not used clinically to identify individuals at high risk for the disease. Methods: Within a nested case–control study of 500 pancreatic cancer cases diagnosed after blood collection and 1,091 matched controls enrolled in four U.S. prospective cohorts, we char...
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#1Samuel O. Antwi (Mayo Clinic)H-Index: 8
#2William R. Bamlet (Mayo Clinic)H-Index: 43
Last. Gloria M. Petersen (Mayo Clinic)H-Index: 121
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BACKGROUND: Leukocyte telomere length (LTL) has been associated with risk of multiple cancers, but its association with pancreatic ductal adenocarcinoma (PDAC) is unclear. We investigated the association between peripheral blood LTL and PDAC risk, and examined effect modification by candidate single-nucleotide polymorphisms (SNPs) previously reported to be associated with variation in LTL. METHODS: A case-control study of 1460 PDAC cases and 1459 frequency-matched controls was performed using bi...
2 CitationsSource
#1Carol Cremin (Provincial Health Services Authority)H-Index: 4
#2Michael K.C. Lee (Provincial Health Services Authority)H-Index: 4
Last. Kasmintan A. SchraderH-Index: 25
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BACKGROUND: Recent guidelines recommend consideration of germline testing for all newly diagnosed pancreatic ductal adenocarcinoma (PDAC). The primary aim of this study was to determine the burden of hereditary cancer susceptibility in PDAC. A secondary aim was to compare genetic testing uptake rates across different modes of genetic counselling. PATIENTS AND METHODS: All patients diagnosed with PDAC in the province of British Columbia, Canada referred to a population-based hereditary cancer pro...
7 CitationsSource
#1Xin Yang (University of Cambridge)H-Index: 31
#1Xin Yang (University of Cambridge)H-Index: 8
Last. Marc Tischkowitz (University of Cambridge)H-Index: 42
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PURPOSETo estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germl...
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Cited By3
Newest
#1Laura Pistoni (UniPi: University of Pisa)H-Index: 1
#2Manuel Gentiluomo (UniPi: University of Pisa)H-Index: 6
Last. Yogesh K. Vashist (UHH: University of Hamburg)H-Index: 27
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Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated...
Source
#1Ying Zhu (University of the Sciences)H-Index: 15
#2Jianbo Tian (University of the Sciences)H-Index: 15
Last. Xiaoping Miao (University of the Sciences)H-Index: 69
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Abstract Aim This study aimed to identify the functional genes and genetic variants associated with the prognosis of pancreatic ductal adenocarcinoma (PDAC) and reveal the mechanism underlying their prognostic roles. Methods First, we implement a two-stage exome-wide association study in a total of 1070 patients to identify the genetic variant correlated with PDAC prognosis. Then we performed fine mapping through bioinformatics analysis and dual-luciferase reporter assays to reveal the causal fu...
Source
#1Manuel Gentiluomo (UniPi: University of Pisa)H-Index: 6
#2C. Corradi (UniPi: University of Pisa)H-Index: 1
Last. Gabriele Capurso (UniSR: Vita-Salute San Raffaele University)H-Index: 56
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Although pancreatic ductal adenocarcinoma (PDAC) survival is poor, there are differences in patients' response to the treatments. Detection of predictive biomarkers explaining these differences is of the utmost importance. In a recent study two genetic markers (CD44-rs353630 and CHI3L2-rs684559) were reported to be associated with survival after PDAC resection. We attempted to replicate the associations in 1856 PDAC patients (685 resected with stage I/II) from the PANcreatic Disease ReseArch (PA...
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#1C. Corradi (UniPi: University of Pisa)H-Index: 1
#2Manuel Gentiluomo (UniPi: University of Pisa)H-Index: 6
Last. Daniele Campa (UniPi: University of Pisa)H-Index: 34
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Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we inves...
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