3D genomic mapping reveals multifocality of human pancreatic precancers.

Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them challenging to study1. Critically, the number, dimensions and connectivity of human PanINs remain largely unknown, precluding important insights into early cancer development. Here, we provide a microanatomical survey of human PanINs by analysing 46 large samples of grossly normal human pancreas with a machine-learning pipeline for quantitative 3D histological reconstruction at single-cell resolution. To elucidate genetic relationships between and within PanINs, we developed a workflow in which 3D modelling guides multi-region microdissection and targeted and whole-exome sequencing. From these samples, we calculated a mean burden of 13 PanINs per cm3 and extrapolated that the normal intact adult pancreas harbours hundreds of PanINs, almost all with oncogenic KRAS hotspot mutations. We found that most PanINs originate as independent clones with distinct somatic mutation profiles. Some spatially continuous PanINs were found to contain multiple KRAS mutations; computational and in situ analyses demonstrated that different KRAS mutations localize to distinct cell subpopulations within these neoplasms, indicating their polyclonal origins. The extensive multifocality and genetic heterogeneity of PanINs raises important questions about mechanisms that drive precancer initiation and confer differential progression risk in the human pancreas. This detailed 3D genomic mapping of molecular alterations in human PanINs provides an empirical foundation for early detection and rational interception of pancreatic cancer.

Somatic loss of ATM is a late event in pancreatic tumorigenesis.

Understanding the timing and spectrum of genetic alterations that contribute to the development of pancreatic cancer is essential for effective interventions and treatments. The aim of this study was to characterize somatic ATM alterations in noninvasive pancreatic precursor lesions and invasive pancreatic adenocarcinomas from patients with and without pathogenic germline ATM variants. DNA was isolated and sequenced from the invasive pancreatic ductal adenocarcinomas and precursor lesions of patients with a pathogenic germline ATM variant. Tumor and precursor lesions from these patients as well as colloid carcinoma from patients without a germline ATM variant were immunolabeled to assess ATM expression. Among patients with a pathogenic germline ATM variant, somatic ATM alterations, either mutations and/or loss of protein expression, were identified in 75.0% of invasive pancreatic adenocarcinomas but only 7.1% of pancreatic precursor lesions. Loss of ATM expression was also detected in 31.0% of colloid carcinomas from patients unselected for germline ATM status, significantly higher than in pancreatic precursor lesions [pancreatic intraepithelial neoplasms (p = 0.0013); intraductal papillary mucinous neoplasms, p = 0.0040] and pancreatic ductal adenocarcinoma (p = 0.0076) unselected for germline ATM status. These data are consistent with the second hit to ATM being a late event in pancreatic tumorigenesis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Adaptive staffing can mitigate essential worker disease and absenteeism in an emerging epidemic.

Essential worker absenteeism has been a pressing problem in the COVID-19 pandemic. Nearly 20% of US hospitals experienced staff shortages, exhausting replacement pools and at times requiring COVID-positive healthcare workers to remain at work. To our knowledge there are no data-informed models examining how different staffing strategies affect epidemic dynamics on a network in the context of rising worker absenteeism. Here we develop a susceptible-infected-quarantined-recovered adaptive network model using pair approximations to gauge the effects of worker replacement versus redistribution of work among remaining healthy workers in the early epidemic phase. Parameterized with hospital data, the model exhibits a time-varying trade-off: Worker replacement minimizes peak prevalence in the early phase, while redistribution minimizes final outbreak size. Any "ideal" strategy requires balancing the need to maintain a baseline number of workers against the desire to decrease total number infected. We show that one adaptive strategy-switching from replacement to redistribution at epidemic peak-decreases disease burden by 9.7% and nearly doubles the final fraction of healthy workers compared to pure replacement.

Evolutionary History Mediates Population Response to Rapid Environmental Change through Within-Generational and Transgenerational Plasticity.

AbstractRapid environmental change is affecting many organisms; some are coping well, but many species are in decline. A key mechanism for facilitating success following environmental change is phenotypic plasticity. Organisms use cues to respond phenotypically to environmental conditions; many incorporate recent information (within-generation plasticity) and information from previous generations (transgenerational plasticity). We extend an existing evolutionary model where organisms utilize within-generational plasticity, transgenerational plasticity, and bet hedging to include changes in environmental regime. We show how when rapid evolution of plasticity is not possible, the effect of environmental change (altering the environment mean, variance, or autocorrelation or cue reliability) on population growth rate depends on the population's evolutionary history and past evolutionary responses to historical environmental conditions. We then evaluate the predictions that populations adapted to highly variable environments or with greater within-generational plasticity are more likely to successfully respond to environmental change. We identify when these predictions fail and show that environmental change is most detrimental when previously reliable cues become unreliable. When multiple cues become unreliable, environmental change can cause deleterious effects regardless of the population's evolutionary history. Overall, this work provides a general framework for understanding the role of plasticity in population responses to rapid environmental change.

Epichloë fungal endophyte interactions in perennial ryegrass (Lolium perenne L.) modified to accumulate foliar lipids for increased energy density.

BACKGROUND: Commercial cultivars of perennial ryegrass infected with selected Epichloë fungal endophytes are highly desirable in certain pastures as the resulting mutualistic association has the capacity to confer agronomic benefits (such as invertebrate pest deterrence) largely due to fungal produced secondary metabolites (e.g., alkaloids). In this study, we investigated T2 segregating populations derived from two independent transformation events expressing diacylglycerol acyltransferase (DGAT) and cysteine oleosin (CO) genes designed to increase foliar lipid and biomass accumulation. These populations were either infected with Epichloë festucae var. lolii strain AR1 or Epichloë sp. LpTG-3 strain AR37 to examine relationships between the introduced trait and the endophytic association. Here we report on experiments designed to investigate if expression of the DGAT + CO trait in foliar tissues of perennial ryegrass could negatively impact the grass-endophyte association and vice versa. Both endophyte and plant characters were measured under controlled environment and field conditions. RESULTS: Expected relative increases in total fatty acids of 17-58% accrued as a result of DGAT + CO expression with no significant difference between the endophyte-infected and non-infected progeny. Hyphal growth in association with DGAT + CO expression appeared normal when compared to control plants in a growth chamber. There was no significant difference in mycelial biomass for both strains AR1 and AR37, however, Epichloë-derived alkaloid concentrations were significantly lower on some occasions in the DGAT + CO plants compared to the corresponding null-segregant progenies, although these remained within the reported range for bioactivity. CONCLUSIONS: These results suggest that the mutualistic association formed between perennial ryegrass and selected Epichloë strains does not influence expression of the host DGAT + CO technology, but that endophyte performance may be reduced under some circumstances. Further investigation will now be required to determine the preferred genetic backgrounds for introgression of the DGAT + CO trait in combination with selected endophyte strains, as grass host genetics is a major determinant to the success of the grass-endophyte association in this species.

Nickel-Catalyzed O-Arylation of Primary or Secondary Aliphatic Alcohols with (Hetero)aryl Chlorides: A Comparison of Ni(I) and Ni(II) Precatalysts.

A comparative experimental and computational study examining the interplay of the ancillary ligand structure and Ni oxidation state in the Ni-catalyzed C(sp2)-O cross-coupling of (hetero)aryl chlorides and primary or secondary aliphatic alcohols is presented, focusing on PAd-DalPhos (L1)-, CyPAd-DalPhos (L2)-, PAd2-DalPhos (L3)-, and DPPF (L4)-ligated [(L)NiCl]n (n = 1 or 2) and (L)Ni(o-tol)Cl precatalysts. Both L1 and L2 were found to outperform the other ligands examined, with the latter proving to be superior overall. While Ni(II) precatalysts generally outperformed Ni(I) species, in some instances the catalytic abilities of Ni(I) precatalysts were competitive with those of Ni(II). Density-functional theory calculations indicate the favorability of a Ni(0)/Ni(II) catalytic cycle featuring turnover-limiting C-O bond reductive elimination over a Ni(I)/Ni(III) cycle involving turnover-limiting C-Cl oxidative addition.

Temporal and Probabilistic Comparisons of Epidemic Interventions.

Forecasting disease spread is a critical tool to help public health officials design and plan public health interventions. However, the expected future state of an epidemic is not necessarily well defined as disease spread is inherently stochastic, contact patterns within a population are heterogeneous, and behaviors change. In this work, we use time-dependent probability generating functions (PGFs) to capture these characteristics by modeling a stochastic branching process of the spread of a disease over a network of contacts in which public health interventions are introduced over time. To achieve this, we define a general transmissibility equation to account for varying transmission rates (e.g. masking), recovery rates (e.g. treatment), contact patterns (e.g. social distancing) and percentage of the population immunized (e.g. vaccination). The resulting framework allows for a temporal and probabilistic analysis of an intervention's impact on disease spread, which match continuous-time stochastic simulations that are much more computationally expensive. To aid policy making, we then define several metrics over which temporal and probabilistic intervention forecasts can be compared: Looking at the expected number of cases and the worst-case scenario over time, as well as the probability of reaching a critical level of cases and of not seeing any improvement following an intervention. Given that epidemics do not always follow their average expected trajectories and that the underlying dynamics can change over time, our work paves the way for more detailed short-term forecasts of disease spread and more informed comparison of intervention strategies.

Pancreatic cancer pathology viewed in the light of evolution.

One way to understand ductal adenocarcinoma of the pancreas (pancreatic cancer) is to view it as unimaginably large numbers of evolving living organisms interacting with their environment. This "evolutionary view" creates both expected and surprising perspectives in all stages of neoplastic progression. Advances in the field will require greater attention to this critical evolutionary prospective.

Endoplasmic stress-inducing variants in carboxyl ester lipase and pancreatic cancer risk.

BACKGROUND: Endoplasmic reticulum (ER) stress-inducing variants in several pancreatic secretory enzymes have been associated with pancreatic disease. Multiple variants in CEL, encoding carboxyl ester lipase, are known to cause maturity-onset diabetes of the young (MODY8) but have not been implicated in pancreatic cancer risk. METHODS: The prevalence of ER stress-inducing variants in the CEL gene was compared among pancreatic cancer cases vs. controls. Variants were identified by next-generation sequencing and confirmed by Sanger sequencing. Variants of uncertain significance (VUS) were assessed for their effect on the secretion of CEL protein and variants with reduced protein secretion were evaluated to determine if they induced endoplasmic reticulum stress. RESULTS: ER stress-inducing CEL variants were found in 34 of 986 cases with sporadic pancreatic ductal adenocarcinoma, and 21 of 1045 controls (P = 0.055). Most of the variants were either the CEL-HYB1 variant, the I488T variant, or the combined CEL-HYB1/I488T variant; one case had a MODY8 variant. CONCLUSION: This case/control analysis finds ER stress-inducing CEL variants are not associated with an increased likelihood of having pancreatic cancer.

Downregulation of 5-hydroxymethylcytosine is an early event in pancreatic tumorigenesis.

Epigenetic alterations are increasingly recognized as important contributors to the development and progression of pancreatic ductal adenocarcinoma. 5-hydroxymethylcytosine (5hmC) is an epigenetic DNA mark generated through the ten-eleven translocation (TET) enzyme-mediated pathway and is closely linked to gene activation. However, the timing of alterations in epigenetic regulation in the progression of pancreatic neoplasia is not well understood. In this study, we hypothesized that aberrant expression of ten-eleven translocation methylcytosine dioxygenase 1 (TET1) and subsequent global 5hmC alteration are linked to early tumorigenesis in the pancreas. Therefore, we evaluated alterations of 5hmC and TET1 levels using immunohistochemistry in pancreatic neoplasms (n = 380) and normal ducts (n = 118). The study cohort included representation of the full spectrum of precancerous lesions from low- and high-grade pancreatic intraepithelial neoplasia (n = 95), intraductal papillary mucinous neoplasms (all subtypes, n = 129), intraductal oncocytic papillary neoplasms (n = 12), and mucinous cystic neoplasms (n = 144). 5hmC and TET1 were significantly downregulated in all types of precancerous lesion and associated invasive pancreatic ductal adenocarcinomas compared with normal ductal epithelium (all p < 0.001), and expression of 5hmC positively correlated with expression of TET1. Importantly, downregulation of both 5hmC and TET1 was observed in most low-grade precancerous lesions. There were no clear associations between 5hmC levels and clinicopathological factors, thereby suggesting a common epigenetic abnormality across precancerous lesions. We conclude that downregulation of 5hmC and TET1 is an early event in pancreatic tumorigenesis. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Cell division rates decrease with age, providing a potential explanation for the age-dependent deceleration in cancer incidence.

A new evaluation of previously published data suggested to us that the accumulation of mutations might slow, rather than increase, as individuals age. To explain this unexpected finding, we hypothesized that normal stem cell division rates might decrease as we age. To test this hypothesis, we evaluated cell division rates in the epithelium of human colonic, duodenal, esophageal, and posterior ethmoid sinonasal tissues. In all 4 tissues, there was a significant decrease in cell division rates with age. In contrast, cell division rates did not decrease in the colon of aged mice, and only small decreases were observed in their small intestine or esophagus. These results have important implications for understanding the relationship between normal stem cells, aging, and cancer. Moreover, they provide a plausible explanation for the enigmatic age-dependent deceleration in cancer incidence in very old humans but not in mice.

A region-based gene association study combined with a leave-one-out sensitivity analysis identifies SMG1 as a pancreatic cancer susceptibility gene.

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.

Germline sequence analysis of RABL3 in a large series of pancreatic ductal adenocarcinoma patients reveals no evidence of deleterious variants.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival rate of less than 10%. Individuals with a pathogenic germline variant in a pancreatic cancer susceptibility gene are at an increased risk of developing pancreatic cancer. Understanding the inherited genetic basis of pancreatic tumor development provides a unique opportunity to improve patient care and outcomes. For example, relatives of a patients with PDAC who have a pathogenic germline variant in a pancreatic cancer susceptibility gene are eligible for disease surveillance where cancers may be detected early, and 5-year survival greatly improved. Furthermore, for some patients with PDAC and a pathogenic germline variant in a pancreatic cancer susceptibility gene, their tumors may be susceptible to specific anti-cancer therapies. Recently, RABL3 was identified as a pancreatic cancer susceptibility gene. To validate these findings and inform clinical translation, we determined the prevalence of deleterious RABL3 variants in a large cohort of 1037 patients with PDAC that had undergone either whole genome or whole exome germline sequencing. We identified two synonymous variants and four missense variants classified as variants of unknown significance. We found no pathogenic RABL3 variants, indicating that the maximum prevalence of such variants in patients with PDAC is less than 0.36% (minor allele frequency 0, 97.5% one-sided confidence interval: 0-0.0036). This finding has important implications for germline genetic testing of patients with PDAC.

(PNSiMe3 )4 (NMe)6 : A Robust Tetravalent Phosphaza-adamantane Scaffold for Molecular and Macromolecular Construction.

Tetraarylmethanes and adamantanes are important rigid covalent connectors that play a four-way scaffolding role in molecular and materials chemistry. We report the synthesis of a new tetravalent phosphaza-adamantane cage, (PNSiMe3 )4 (NMe)6 (2), that shows high thermal, air, and redox stability due to its geometry. It nevertheless participates in covalent four-fold functionalization reactions along its periphery. The combination of a robust core and reactive corona makes 2 a convenient inorganic scaffold upon which tetrahedral molecular and macromolecular chemistry can be constructed. This potential is demonstrated by the synthesis of a tetrakis(bis(phosphine)iminium) ion (in compound 3) and the first all P/N poly(phosphazene) network (5).

Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic KLF4 mutations predominantly in low-grade regions.

OBJECTIVE: Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions that can progress to invasive pancreatic cancer and are classified as low-grade or high-grade based on the morphology of the neoplastic epithelium. We aimed to compare genetic alterations in low-grade and high-grade regions of the same IPMN in order to identify molecular alterations underlying neoplastic progression. DESIGN: We performed multiregion whole exome sequencing on tissue samples from 17 IPMNs with both low-grade and high-grade dysplasia (76 IPMN regions, including 49 from low-grade dysplasia and 27 from high-grade dysplasia). We reconstructed the phylogeny for each case, and we assessed mutations in a novel driver gene in an independent cohort of 63 IPMN cyst fluid samples. RESULTS: Our multiregion whole exome sequencing identified KLF4, a previously unreported genetic driver of IPMN tumorigenesis, with hotspot mutations in one of two codons identified in >50% of the analyzed IPMNs. Mutations in KLF4 were significantly more prevalent in low-grade regions in our sequenced cases. Phylogenetic analyses of whole exome sequencing data demonstrated diverse patterns of IPMN initiation and progression. Hotspot mutations in KLF4 were also identified in an independent cohort of IPMN cyst fluid samples, again with a significantly higher prevalence in low-grade IPMNs. CONCLUSION: Hotspot mutations in KLF4 occur at high prevalence in IPMNs. Unique among pancreatic driver genes, KLF4 mutations are enriched in low-grade IPMNs. These data highlight distinct molecular features of low-grade and high-grade dysplasia and suggest diverse pathways to high-grade dysplasia via the IPMN pathway.

Examination of ATM, BRCA1, and BRCA2 promoter methylation in patients with pancreatic cancer.

BACKGROUND: Pancreatic cancer is a lethal disease with a poor 5-year survival rate. Pathogenic germline variants in the coding regions of ATM, BRCA1, and BRCA2 are found in up to 4.8% of pancreatic cancer patients. Germline promoter methylation and gene silencing arising from a germline variant or through other mechanisms have been described as a cause of tumor suppressor gene inactivation. METHODS: We measured the level of promoter methylation of the ATM, BRCA1, and BRCA2 genes in peripheral blood lymphocytes from 655 patients with pancreatic cancer using real-time PCR. RESULTS: No evidence of germline promoter methylation of any of these genes was found. Promoter methylation levels were minimal with no patient having promoter methylation greater than 3.4%, 3.3%, and 7.6% for ATM, BRCA1 and BRCA2, respectively, well below levels found in patients who have inherited promoter methylation (∼50%). CONCLUSIONS: We found no evidence of germline promoter methylation for the pancreatic susceptibility genes ATM, BRCA1 and BRCA2 in patients with pancreatic cancer. This study reveals that constitutive germline methylation of promoter CpG islands is rare in pancreatic cancer.

Molecular characterization of organoids derived from pancreatic intraductal papillary mucinous neoplasms.

Intraductal papillary mucinous neoplasms (IPMNs) are commonly identified non-invasive cyst-forming pancreatic neoplasms with the potential to progress into invasive pancreatic adenocarcinoma. There are few in vitro models with which to study the biology of IPMNs and their progression to invasive carcinoma. Therefore, we generated a living biobank of organoids from seven normal pancreatic ducts and ten IPMNs. We characterized eight IPMN organoid samples using whole genome sequencing and characterized five IPMN organoids and seven normal pancreatic duct organoids using transcriptome sequencing. We identified an average of 11,344 somatic mutations in the genomes of organoids derived from IPMNs, with one sample harboring 61,537 somatic mutations enriched for T→C transitions and T→A transversions. Recurrent coding somatic mutations were identified in 15 genes, including KRAS, GNAS, RNF43, PHF3, and RBM10. The most frequently mutated genes were KRAS, GNAS, and RNF43, with somatic mutations identified in six (75%), four (50%), and three (37.5%) IPMN organoid samples, respectively. On average, we identified 36 structural variants in IPMN derived organoids, and none had an unstable phenotype (> 200 structural variants). Transcriptome sequencing identified 28 genes differentially expressed between normal pancreatic duct organoid and IPMN organoid samples. The most significantly upregulated and downregulated genes were CLDN18 and FOXA1. Immunohistochemical analysis of FOXA1 expression in 112 IPMNs, 113 mucinous cystic neoplasms, and 145 pancreatic ductal adenocarcinomas demonstrated statistically significant loss of expression in low-grade IPMNs (p < 0.0016), mucinous cystic neoplasms (p < 0.0001), and pancreatic ductal adenocarcinoma of any histologic grade (p < 0.0001) compared to normal pancreatic ducts. These data indicate that FOXA1 loss of expression occurs early in pancreatic tumorigenesis. Our study highlights the utility of organoid culture to study the genetics and biology of normal pancreatic duct and IPMNs. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer.

To evaluate whether germline variants in genes encoding pancreatic secretory enzymes contribute to pancreatic cancer susceptibility, we sequenced the coding regions of CPB1 and other genes encoding pancreatic secretory enzymes and known pancreatitis susceptibility genes (PRSS1, CPA1, CTRC, and SPINK1) in a hospital series of pancreatic cancer cases and controls. Variants in CPB1, CPA1 (encoding carboxypeptidase B1 and A1), and CTRC were evaluated in a second set of cases with familial pancreatic cancer and controls. More deleterious CPB1 variants, defined as having impaired protein secretion and induction of endoplasmic reticulum (ER) stress in transfected HEK 293T cells, were found in the hospital series of pancreatic cancer cases (5/986, 0.5%) than in controls (0/1,045, P = 0.027). Among familial pancreatic cancer cases, ER stress-inducing CPB1 variants were found in 4 of 593 (0.67%) vs. 0 of 967 additional controls (P = 0.020), with a combined prevalence in pancreatic cancer cases of 9/1,579 vs. 0/2,012 controls (P < 0.01). More ER stress-inducing CPA1 variants were also found in the combined set of hospital and familial cases with pancreatic cancer than in controls [7/1,546 vs. 1/2,012; P = 0.025; odds ratio, 9.36 (95% CI, 1.15-76.02)]. Overall, 16 (1%) of 1,579 pancreatic cancer cases had an ER stress-inducing CPA1 or CPB1 variant, compared with 1 of 2,068 controls (P < 0.00001). No other candidate genes had statistically significant differences in variant prevalence between cases and controls. Our study indicates ER stress-inducing variants in CPB1 and CPA1 are associated with pancreatic cancer susceptibility and implicate ER stress in pancreatic acinar cells in pancreatic cancer development.

Generation and characterization of a cell line from an intraductal tubulopapillary neoplasm of the pancreas.

Intraductal tubulopapillary neoplasm (ITPN) is a distinct precancerous lesion in the pancreas with unique clinical and molecular features. Although in vitro studies in two-dimensional culture have led to numerous important insights in pancreatic cancer, such models are currently lacking for precancerous lesions. In this study, we report the generation and characterization of a cell line from a human pancreatic ITPN. Neoplastic cells were initially cultured in a three-dimensional organoid system, followed by transfer to two-dimensional culture. RNA sequencing revealed a gene expression profile consistent with pancreatic ductal origin, and whole genome sequencing identified many somatic mutations (including in genes involved in DNA repair and Wnt signaling) and structural rearrangements. In vitro characterization of the tumorigenic potential demonstrated a phenotype between that of normal pancreatic ductal cells and cancer cell lines. This cell line represents a valuable resource for interrogation of unique ITPN biology, as well as precancerous pancreatic lesions more generally.

Prevalence of Germline Mutations Associated With Cancer Risk in Patients With Intraductal Papillary Mucinous Neoplasms.

BACKGROUND & AIMS: Many patients with pancreatic adenocarcinoma carry germline mutations associated with increased risk of cancer. It is not clear whether patients with intraductal papillary mucinous neoplasms (IPMNs), which are precursors to some pancreatic cancers, also carry these mutations. We assessed the prevalence of germline mutations associated with cancer risk in patients with histologically confirmed IPMN. METHODS: We obtained nontumor tissue samples from 315 patients with surgically resected IPMNs from 1997 through 2017, and we sequenced 94 genes with variants associated with cancer risk. Mutations associated with increased risk of cancer were identified and compared with individuals from the Exome Aggregation Consortium. RESULTS: We identified 23 patients with a germline mutation associated with cancer risk (7.3%; 95% confidence interval, 4.9-10.8). Nine patients had a germline mutation associated with pancreatic cancer susceptibility (2.9%; 95% confidence interval, 1.4-5.4). More patients with IPMNs carried germline mutations in ATM (P < .0001), PTCH1 (P < .0001), and SUFU (P < .0001) compared with controls. Patients with IPMNs and germline mutations associated with pancreatic cancer were more like to have concurrent invasive pancreatic carcinoma compared with patients with IPMNs without these mutations (P < .0320). CONCLUSIONS: In sequence analyses of 315 patients with surgically resected IPMNs, we found that almost 3% to carry mutations associated with pancreatic cancer risk. More patients with IPMNs and germline mutations associated with pancreatic cancer had concurrent invasive pancreatic carcinoma compared with patients with IPMNs without these mutations. Genetic analysis of patients with IPMNs might identify those at greatest risk for cancer.