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Pancreatic cancer is a leading cause of cancer death worldwide and its global burden has more than doubled over the past 25 years. The highest incidence regions for pancreatic cancer include North America, Europe and Australia, and although much of this increase is due to ageing worldwide populations, there are key modifiable risk factors for pancreatic cancer such as cigarette smoking, obesity, diabetes and alcohol intake. The prevalence of these risk factors is increasing in many global regions, resulting in increasing age-adjusted incidence rates for pancreatic cancer, but the relative contribution from these risk factors varies globally due to variation in the underlying prevalence and prevention strategies. Inherited genetic factors, although not directly modifiable, are an important component of pancreatic cancer risk, and include pathogenic variants in hereditary cancer genes, genes associated with hereditary pancreatitis, as well as common variants identified in genome-wide association studies. Identification of the genetic changes that underlie pancreatic cancer not only provides insight into the aetiology of this cancer but also provides an opportunity to guide early detection strategies. The goal of this Review is to provide an up-to-date overview of the established modifiable and inherited risk factors for pancreatic cancer. Pancreatic cancer is a leading cause of cancer death worldwide. This Review outlines the current knowledge of established pancreatic cancer risk factors, including lifestyle and inherited risk factors. Key points Smoking continues to be a leading cause of pancreatic cancer worldwide. Increasing rates of diabetes and obesity will probably result in increased rates of pancreatic cancer. Growing evidence indicates that high alcohol intake contributes to pancreatic cancer risk. Knowledge of inherited genetic factors in pancreatic cancer continues to grow and probably explains 22–33% of pancreatic cancer risk.

Pancreatic cancer is currently one of the deadliest of the solid malignancies. However, surgery to resect neoplasms of the pancreas is safer and less invasive than ever, novel drug combinations have been shown to improve survival, advances in radiation therapy have resulted in less toxicity, and enormous strides have been made in the understanding of the fundamental genetics of pancreatic cancer. These advances provide hope but they also increase the complexity of caring for patients. It is clear that multidisciplinary care that provides comprehensive and coordinated evaluation and treatment is the most effective way to manage patients with pancreatic cancer. [PUBLICATION ABSTRACT]

The publication of the “Pan-Cancer Atlas” by the Pan-Cancer Analysis of Whole Genomes Consortium, a partnership formed by The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC), provides a wonderful opportunity to reflect on where we stand in our understanding of the genetics of pancreatic cancer, as well as on the opportunities to translate this understanding to patient care. From germline variants that predispose to the development of pancreatic cancer, to somatic mutations that are therapeutically targetable, genetics is now providing hope, where there once was no hope, for those diagnosed with pancreatic cancer.

ObjectivePancreatic cancer diagnoses are frequently preceded by a new diabetes diagnosis. Screening individuals newly diagnosed with diabetes could enable the earlier detection of pancreatic cancer. We sought to estimate the risk of pancreatic cancer by age, sex, race and time since diabetes diagnosis.DesignClaims-based cohort study.SettingJohns Hopkins Medicine conducted this deidentified claims-based cohort study using the Optum Labs Data Warehouse.ParticipantsInsurance enrollees from 1/2008–9/2018 were identified as non-diabetic or newly diagnosed diabetic. Our risk set included 4 732 313 individuals (424 129 newly diabetic) in 5 844 934 enrolment periods.Primary outcome measuresTime to pancreatic cancer. Diabetes and cancer were defined using International Classification of Diseases (ICD)-9/10 codes.ResultsIndividuals with newly diagnosed diabetes were at an increased HR of pancreatic cancer, but this effect waned over time. The HR of pancreatic cancer following a diabetes diagnosis was higher in younger individuals and varied by race (lower HR in non-White individuals) (p<0.01, main effects and interactions). Thus, the probability of pancreatic cancer following a diabetes diagnosis was dependent on age, race and sex. For example, the 1-year probability of pancreatic cancer in a White male aged 75 was 0.45% (95%CI 0.41% to 0.49%) if they were newly diagnosed with diabetes and 0.090% (95%CI 0.084% to 0.096%) if they were free of diabetes. In contrast, the risk was lower at 0.15% (new-diabetic, 95% CI 0.13% to 0.16%) and 0.022% (diabetes free, 95%CI 0.020% to 0.023%) at age 55. The HR of pancreatic cancer for individuals with newly diagnosed diabetes compared with those free of diabetes was highest in the month following diagnosis (HR=14.7 and 9.6 for a 55 and 75 year old White male, respectively) but decreased in the following months, with a HR of 7.8 and 5.8 at 3 months, 5.6 and 4.1 at 6 months, and 3.9 and 2.8 at 1 year (p<0.01).ConclusionsConsideration of the age–race–sex specific probability of pancreatic cancer and time since diabetes diagnosis is necessary when evaluating the risk of pancreatic cancer following a diabetes diagnosis.

Context.—Approximately 5% to 10% of individuals with pancreatic cancer report a history of pancreatic cancer in a close family member. In addition, several known genetic syndromes, such as familial breast cancer (BRCA2), the Peutz-Jeghers syndrome, and the familial atypical multiple mole melanoma syndrome, have been shown to be associated with an increased risk of pancreatic cancer. The known genes associated with these conditions can explain only a portion of the clustering of pancreatic cancer in families, and research to identify additional susceptibility genes is ongoing. Objective.—To provide an understanding of familial pancreatic cancer and the pathology of familial exocrine pancreatic cancers. Data Sources.—Published literature on familial aggregation of pancreatic cancer and familial exocrine pancreatic tumors. Conclusions.—Even in the absence of predictive genetic testing, the collection of a careful, detailed family history is an important step in the management of all patients with pancreatic cancer. While most pancreatic cancers that arise in patients with a family history are ductal adenocarcinomas, certain subtypes of pancreatic cancer have been associated with familial syndromes. Therefore, the histologic appearance of the pancreatic cancer itself, and/or the presence and appearance of precancerous changes in the pancreas, may increase the clinical index of suspicion for a genetic syndrome.

Key Points Familial cancer registries have had a key role in our understanding of the aetiology of many cancer types, such as breast and colon cancer. As pancreatic cancer is a leading cause of cancer death and because it has the poorest prognosis of any major tumour type, familial pancreatic cancer registries are an important tool for investigating the genetic aetiology of this devastating disease. By studying the families that are enrolled in our familial pancreatic cancer registry we have been able to identify several familial pancreatic cancer susceptibility genes, conduct some of the first early detection screening trials for pancreatic cancer and have begun to understand the potential of personalized treatment for this disease. Registries also allow for the prospective follow-up of a population at a high risk of pancreatic cancer, a disease that is traditionally difficult to study owing to its rarity. The adaptive nature of family registries has allowed for the rapid adoption of new technologies, such as genome sequencing for gene discovery. Pancreatic cancer has the poorest prognosis of any major cancer type. Familial pancreatic cancer registries are important for investigating the genetic aetiology of this devastating disease and provide a unique opportunity for laboratory, population and clinical research. Pancreatic cancer is a leading cause of cancer death, and it has the poorest prognosis of any major tumour type. Familial pancreatic cancer registries are important for investigating the genetic aetiology of this devastating disease. Using data from our familial pancreatic cancer registry and other registries, this Review discusses the usefulness of family registries in the study of pancreatic and other cancers, and also how such registries provide a unique opportunity for laboratory, population and clinical research.

Age-related cataract is a major cause of blindness worldwide, and cortical cataract is the second most prevalent type of age-related cataract. Although a significant fraction of age-related cataract is heritable, the genetic basis remains to be elucidated. We report that homozygous deletion of Epha2 in two independent strains of mice developed progressive cortical cataract. Retroillumination revealed development of cortical vacuoles at one month of age; visible cataract appeared around three months, which progressed to mature cataract by six months. EPHA2 protein expression in the lens is spatially and temporally regulated. It is low in anterior epithelial cells, upregulated as the cells enter differentiation at the equator, strongly expressed in the cortical fiber cells, but absent in the nuclei. Deletion of Epha2 caused a significant increase in the expression of HSP25 (murine homologue of human HSP27) before the onset of cataract. The overexpressed HSP25 was in an underphosphorylated form, indicating excessive cellular stress and protein misfolding. The orthologous human EPHA2 gene on chromosome 1p36 was tested in three independent worldwide Caucasian populations for allelic association with cortical cataract. Common variants in EPHA2 were found that showed significant association with cortical cataract, and rs6678616 was the most significant in meta-analyses. In addition, we sequenced exons of EPHA2 in linked families and identified a new missense mutation, Arg721Gln, in the protein kinase domain that significantly alters EPHA2 functions in cellular and biochemical assays. Thus, converging evidence from humans and mice suggests that EPHA2 is important in maintaining lens clarity with age.

Olfactory neuroblastoma (ONB) is a rare malignant neoplasm arising in the upper portion of the sinonasal cavity. To better understand the genetic bases for ONB, here we perform whole exome and whole genome sequencing as well as single nucleotide polymorphism array analyses in a series of ONB patient samples. Deletions involving the dystrophin ( DMD ) locus are found in 12 of 14 (86%) tumors. Interestingly, one of the remaining tumors has a deletion in LAMA2 , bringing the number of ONBs with deletions of genes involved in the development of muscular dystrophies to 13 or 93%. This high prevalence implicates an unexpected functional role for genes causing hereditary muscular dystrophies in ONB. Olfactory neuroblastoma (ONB) is a rare malignant tumor whose genetic basis is poorly understood. Here the authors identify recurrent deletions involving dystrophin in the majority of ONB patient tumors examined.

Background and Objectives High mortality in pancreas ductal adenocarcinoma (PDAC) is related to delayed diagnosis and lack of cost‐effective early detection strategies. Retrospective studies have demonstrated an association between PDAC and acute pancreatitis (AP). Herein, we explore the incidence of PDAC in patients with non‐biliary and non‐alcoholic AP. Methods A population‐based, retrospective cohort study was conducted utilizing TriNetX (Cambridge, MA). Patients ≥40 years with AP (ICD‐10‐CM code: K85) and without biliary AP (K85.1), alcohol‐induced AP (K85.2) or chronic pancreatitis (K86.0, K86.1), were identified. The primary outcome was incidence of PDAC (C25) in patients at defined intervals following AP. We compared the rate of early‐stage diagnosis (stage 1–2) and surgical resection among patients with and without preceding AP. Results The incidence of PDAC ranged from 2.16% (1 year) to 3.43% (5 years). Patients with PDAC and AP in preceding year were more likely to undergo surgical resection relative to those without AP (10.1% vs. 6.3%, risk ratio 1.62: 95% confidence interval, CI 1.47–1.79). Early‐stage diagnosis of PDAC was more frequent in patients with preceding AP; however, difference was insignificant (p = 0.48; 95% CI 0.64–2.58). Conclusion AP is infrequently associated with PDAC and can precede a diagnosis of PDAC in a minority of patients without another known etiology of pancreatitis. Patients with a recent AP are more likely to undergo surgical resection of PDAC and a trend toward diagnosis at an earlier stage compared to patients with PDAC and without AP. The impact of AP‐related PDAC on survival is unknown. Understanding the risk of pancreatic cancer following an acute pancreatitis diagnosis is a critical component to early intervention for pancreatic cancer in this high‐risk population as multiple data sets have demonstrated that early detection can lead to an increased percentage of patients diagnosed with stage I disease, and hence an improved chance for cure.

Pancreatic adenocarcinoma (PC) is a lethal malignancy that is familial or associated with genetic syndromes in 10% of cases. Gene-based surveillance strategies for at-risk individuals may improve clinical outcomes. However, familial PC (FPC) is plagued by genetic heterogeneity and the genetic basis for the majority of FPC remains elusive, hampering the development of gene-based surveillance programs. The study was powered to identify genes with a cumulative pathogenic variant prevalence of at least 3%, which includes the most prevalent PC susceptibility gene, BRCA2. Since the majority of known PC susceptibility genes are involved in DNA repair, we focused on genes implicated in these pathways. We performed a region-based association study using the Mixed-Effects Score Test, followed by leave-one-out characterization of PC-associated gene regions and variants to identify the genes and variants driving risk associations. We evaluated 398 cases from two case series and 987 controls without a personal history of cancer. The first case series consisted of 109 patients with either FPC (n = 101) or PC at ≤50 years of age (n = 8). The second case series was composed of 289 unselected PC cases. We validated this discovery strategy by identifying known pathogenic BRCA2 variants, and also identified SMG1, encoding a serine/threonine protein kinase, to be significantly associated with PC following correction for multiple testing (p = 3.22x10-7). The SMG1 association was validated in a second independent series of 532 FPC cases and 753 controls (p<0.0062, OR = 1.88, 95%CI 1.17-3.03). We showed segregation of the c.4249A>G SMG1 variant in 3 affected relatives in a FPC kindred, and we found c.103G>A to be a recurrent SMG1 variant associating with PC in both the discovery and validation series. These results suggest that SMG1 is a novel PC susceptibility gene, and we identified specific SMG1 gene variants associated with PC risk.