Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer, due to both its late stage at diagnosis and its resistance to chemotherapy. However, recent advances in our understanding of the biology of PDAC have revealed new opportunities for early detection and targeted therapy of PDAC. In this review, we discuss the pathogenesis of PDAC, including molecular alterations in tumor cells, cellular alterations in the tumor microenvironment, and population-level risk factors. We review the current status of surveillance and early detection of PDAC, including populations at high risk and screening approaches. We outline the diagnostic approach to PDAC and highlight key treatment considerations, including how therapeutic approaches change with disease stage and targetable subtypes of PDAC. Recent years have seen significant improvements in our approaches to detect and treat PDAC, but large-scale, coordinated efforts will be needed to maximize the clinical impact for patients and improve overall survival. Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer, due to both its late stage at diagnosis and its resistance to chemotherapy. However, recent advances in our understanding of the biology of PDAC have revealed new opportunities for early detection and targeted therapy of PDAC. In this review, we discuss the pathogenesis of PDAC, including molecular alterations in tumor cells, cellular alterations in the tumor microenvironment, and population-level risk factors. We review the current status of surveillance and early detection of PDAC, including populations at high risk and screening approaches. We outline the diagnostic approach to PDAC and highlight key treatment considerations, including how therapeutic approaches change with disease stage and targetable subtypes of PDAC. Recent years have seen significant improvements in our approaches to detect and treat PDAC, but large-scale, coordinated efforts will be needed to maximize the clinical impact for patients and improve overall survival. Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is predicted to be the second leading cause of cancer death in the United States by 2030.1Rahib L. Smith B. Aizenberg R. et al.Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States.Cancer Res. 2014; 74: 2913-2921Crossref PubMed Scopus (3828) Google Scholar One reason for the dismal prognosis of pancreatic cancer is that 90% of tumors are diagnosed at a late stage after they have spread beyond the pancreas, with systemic metastases in >50%.2Siegel R.L. Miller K.D. Fuchs H.E. et al.Cancer Statistics, 2021.CA Cancer J Clin. 2021; 71: 7-33Crossref PubMed Scopus (4997) Google Scholar,3Kommalapati A. Tella S.H. Goyal G. et al.Contemporary management of localized resectable pancreatic cancer.Cancers (Basel). 2018; 10: 24Crossref Scopus (33) Google Scholar This underscores the need for tools to detect PDAC earlier, before it has spread beyond the pancreas, and for therapies that more effectively kill PDAC cells after they have metastasized. In the past decade, basic and translational investigations have significantly improved our understanding of the biological processes that drive pancreatic tumorigenesis, and this understanding is beginning to be leveraged to improve the care of patients with pancreatic cancer. In this review, we discuss the pathogenesis, screening, diagnosis, and treatment of PDAC, focusing on both fundamental concepts and recent advances.Pathogenesis of Pancreatic CancerPathology of Pancreatic NeoplasiaPDAC arises from noninvasive precancerous lesions that are curable if detected and treated early enough (Figure 1). These precancerous lesions are classified by their size and involvement with the pancreatic ductal system. Most PDACs arise from microscopic pancreatic intraepithelial neoplasia (PanIN), a neoplasm involving pancreatic ducts, which is by definition <5 mm.4Basturk O. Hong S.M. Wood L.D. et al.A revised classification system and recommendations from the baltimore consensus meeting for neoplastic precursor lesions in the pancreas.Am J Surg Pathol. 2015; 39: 1730-1741Crossref PubMed Scopus (413) Google Scholar A much smaller proportion of PDACs (<10%) arise from intraductal papillary mucinous neoplasms (IPMNs), macrocystic lesions that involve the pancreatic ductal system.4Basturk O. Hong S.M. Wood L.D. et al.A revised classification system and recommendations from the baltimore consensus meeting for neoplastic precursor lesions in the pancreas.Am J Surg Pathol. 2015; 39: 1730-1741Crossref PubMed Scopus (413) Google Scholar, 5Winter J.M. Cameron J.L. Campbell K.A. et al.1423 pancreaticoduodenectomies for pancreatic cancer: a single-institution experience.J Gastrointest Surg. 2006; 10 (discussion 1210–1191): 1199-1210Crossref PubMed Scopus (1210) Google Scholar, 6Felsenstein M. Noe M. Masica D.L. et al.IPMNs with co-occurring invasive cancers: neighbours but not always relatives.Gut. 2018; 67: 1652-1662Crossref PubMed Scopus (62) Google Scholar The least common precancerous neoplasm, mucinous cystic neoplasm, is clinically and pathologically distinct. Mucinous cystic neoplasms do not involve the ductal system and have a characteristic ovarian-type stroma. They are much more common in women and involve the pancreatic body/tail.7Zamboni G. Scarpa A. Bogina G. et al.Mucinous cystic tumors of the pancreas: clinicopathological features, prognosis, and relationship to other mucinous cystic tumors.Am J Surg Pathol. 1999; 23: 410-422Crossref PubMed Scopus (540) Google Scholar The unique pathological features of each lesion lead to distinct clinical challenges. For example, because of their larger size, IPMNs are commonly detected incidentally on abdominal imaging studies, requiring data-driven approaches to surveillance and intervention for these patients.8Laffan T.A. Horton K.M. Klein A.P. et al.Prevalence of unsuspected pancreatic cysts on MDCT.AJR Am J Roentgenol. 2008; 191: 802-807Crossref PubMed Scopus (615) Google Scholar In contrast, PanINs are rarely detected incidentally. Although the pathological features of these precancers are well characterized, the cell of origin of pancreatic cancer remains controversial. The anatomic location of precancers in the ductal system could support a ductal cell of origin, but numerous studies in murine models have shown that acinar cells can give rise to PanINs following pancreatic injury and metaplasia. However, it is challenging to confirm such findings in human samples. This controversy was recently reviewed in detail elsewhere.9Grimont A. Leach S.D. Chandwani R. Uncertain beginnings: acinar and ductal cell plasticity in the development of pancreatic cancer.Cell Mol Gastroenterol Hepatol. 2021; 13: 369-382Abstract Full Text Full Text PDF PubMed Scopus (4) Google ScholarPrecancerous pancreatic neoplasms are incredibly common and increase in prevalence with age; for example, one autopsy study in older adults identified PanINs in >75% of completely sampled pancreata.10Matsuda Y. Furukawa T. Yachina S. et al.The prevalence and clinicopathological characteristics of high-grade pancreatic intraepithelial neoplasia: autopsy study evaluating the entire pancreatic parenchyma.Pancreas. 2017; 46: 658-664Crossref PubMed Scopus (41) Google Scholar,11Andea A. Sarkar F. Adsay V.N. Clinicopathological correlates of pancreatic intraepithelial neoplasia: a comparative analysis of 82 cases with and 152 cases without pancreatic ductal adenocarcinoma.Mod Pathol. 2003; 16: 996-1006Crossref PubMed Scopus (209) Google Scholar Although these lesions have a risk for progression to PDAC, most will not progress to cancer, and by themselves they have no risk of spread beyond the pancreas.12Rezaee N. Barbon C. Zaki A. et al.Intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia is a risk factor for the subsequent development of pancreatic ductal adenocarcinoma.HPB (Oxford). 2016; 18: 236-246Abstract Full Text Full Text PDF PubMed Google Scholar,13Oyama H. Tada M. Takagi K. et al.Long-term risk of malignancy in branch-duct intraductal papillary mucinous neoplasms.Gastroenterology. 2020; 158: 226-237.e225Abstract Full Text Full Text PDF PubMed Google Scholar Morphologically, these lesions are categorized as low-grade or high-grade based on architectural and cytological atypia (Figure 1).4Basturk O. Hong S.M. Wood L.D. et al.A revised classification system and recommendations from the baltimore consensus meeting for neoplastic precursor lesions in the pancreas.Am J Surg Pathol. 2015; 39: 1730-1741Crossref PubMed Scopus (413) Google Scholar This 2-tiered grading system (low-grade vs high-grade) is a relatively recent revision of a previously used 3-tiered grading system for pancreatic precancers; the change to a 2-tiered system was driven by increased interobserver reproducibility as well as clinical impact of the revised system.4Basturk O. Hong S.M. Wood L.D. et al.A revised classification system and recommendations from the baltimore consensus meeting for neoplastic precursor lesions in the pancreas.Am J Surg Pathol. 2015; 39: 1730-1741Crossref PubMed Scopus (413) Google Scholar Low-grade precancers have basally oriented nuclei and mild to moderate cytologic atypia (Figure 1A), and high-grade precancers have marked architectural alterations (cribriforming, micropapillae, budding), loss of nuclear polarity, and severe cytologic atypia (Figure 1B).4Basturk O. Hong S.M. Wood L.D. et al.A revised classification system and recommendations from the baltimore consensus meeting for neoplastic precursor lesions in the pancreas.Am J Surg Pathol. 2015; 39: 1730-1741Crossref PubMed Scopus (413) Google Scholar In IPMNs, the grade of dysplasia is also correlated with the direction of differentiation of the neoplastic cells, with gastric-type IPMNs enriched for low-grade dysplasia and intestinal-type and pancreatobiliary-type more likely to be high-grade.14Furukawa T. Kloppel G. Adsay N.V. et al.Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study.Virchows Archiv. 2005; 447: 794-799Crossref PubMed Scopus (0) Google Scholar When stratified by grade of dysplasia, low-grade precancerous lesions are far more common, whereas high-grade lesions are mostly found in pancreata associated with PDAC, suggesting that high-grade precancers have a higher risk for progression to invasive carcinoma.10Matsuda Y. Furukawa T. Yachina S. et al.The prevalence and clinicopathological characteristics of high-grade pancreatic intraepithelial neoplasia: autopsy study evaluating the entire pancreatic parenchyma.Pancreas. 2017; 46: 658-664Crossref PubMed Scopus (41) Google Scholar,11Andea A. Sarkar F. Adsay V.N. Clinicopathological correlates of pancreatic intraepithelial neoplasia: a comparative analysis of 82 cases with and 152 cases without pancreatic ductal adenocarcinoma.Mod Pathol. 2003; 16: 996-1006Crossref PubMed Scopus (209) Google Scholar Moreover, associated carcinomas are much more frequently associated with high-grade rather than low-grade IPMNs, and recent evolutionary analysis defined high-grade IPMNs as the direct precursor of PDAC.6Felsenstein M. Noe M. Masica D.L. et al.IPMNs with co-occurring invasive cancers: neighbours but not always relatives.Gut. 2018; 67: 1652-1662Crossref PubMed Scopus (62) Google Scholar,15Noë M. Niknafs N. Fischer C.G. et al.Genomic characterization of malignant progression in neoplastic pancreatic cysts.Nat Commun. 2020; 11: 4085Crossref PubMed Scopus (29) Google Scholar This evidence highlights that the morphological grade of dysplasia correlates with risk of transformation to invasive carcinoma.Pathologically, PDAC consists of malignant glands with haphazard architecture embedded in a dense desmoplastic stroma (Figure 1C). This pauci-cellularity significantly complicates the molecular analysis of primary PDAC samples, as most cells in a tissue fragment are likely non-neoplastic; without enrichment for neoplastic cells, often fewer than 10% of cells may be malignant. There are also several morphological variants, including adenosquamous carcinoma and undifferentiated carcinoma with osteoclast-like giant cells, some of which have unique clinical and/or molecular features.16Luchini C. Capelli P. Scarpa A. Pancreatic ductal adenocarcinoma and its variants.Surg Pathol Clin. 2016; 9: 547-560Abstract Full Text Full Text PDF PubMed Google Scholar Most PDACs are not localized at diagnosis, and >50% of patients present with distant metastases.2Siegel R.L. Miller K.D. Fuchs H.E. et al.Cancer Statistics, 2021.CA Cancer J Clin. 2021; 71: 7-33Crossref PubMed Scopus (4997) Google Scholar The most common site of metastasis is the liver, and increasing evidence suggests that distinct metastatic sites carry different prognostic features, with lung-only metastases having an improved prognosis compared with other sites.17Groot V.P. Gemenetzis G. Blair A.B. et al.Implications of the pattern of disease recurrence on survival following pancreatectomy for pancreatic ductal adenocarcinoma.Ann Surg Oncol. 2018; 25: 2475-2483Crossref PubMed Scopus (47) Google Scholar,18Wangjam T. Zhang Z. Zhou X.C. et al.Resected pancreatic ductal adenocarcinomas with recurrence limited in lung have a significantly better prognosis than those with other recurrence patterns.Oncotarget. 2015; 6: 36903-36910Crossref PubMed Scopus (42) Google Scholar Moreover, autopsy studies suggest that distinct molecular alterations may increase the likelihood of local vs systemic disease progression, with distant metastases more common in patients with somatic mutations in the gene SMAD4.19Iacobuzio-Donahue C.A. Fu B. Yachida S. et al.DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer.J Clin Oncol. 2009; 27: 1806-1813Crossref PubMed Scopus (797) Google ScholarMolecular Alterations in Neoplastic CellsPDAC is caused, at least in part, by somatic mutations in oncogenes and tumor suppressor genes (Figure 2). The most commonly mutated genes in PDAC, the oncogene KRAS and the tumor suppressor genes CDKN2A, TP53, and SMAD4, were originally discovered in the 1980s and 1990s through targeted molecular biology and sequencing approaches.20Almoguera C. Shibata D. Forrester K. et al.Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes.Cell. 1988; 53: 549-554Abstract Full Text PDF PubMed Scopus (1884) Google Scholar, 21Scarpa A. Capelli P. Mukai K. et al.Pancreatic adenocarcinomas frequently show p53 gene mutations.Am J Pathol. 1993; 142: 1534-1543PubMed Google Scholar, 22Caldas C. Hahn S.A. da Cost L.T. et al.Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma.Nat Genet. 1994; 8: 27-32Crossref PubMed Scopus (1105) Google Scholar, 23Hahn S.A. Schutte M. Hoque A.T. et al.DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.Science. 1996; 271: 350-353Crossref PubMed Google Scholar The first comprehensive look at the PDAC exome came in 2008 with the first whole exome sequencing study of 24 PDACs.24Jones S. Zhang X. Parsons D.W. et al.Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.Science. 2008; 321: 1801-1806Crossref PubMed Scopus (3034) Google Scholar This study revealed that the PDAC genome landscape is composed of these 4 previously described “mountains” (KRAS, CDKN2A, TP53, SMAD4) as well as a larger number of less frequently mutated “hills.”24Jones S. Zhang X. Parsons D.W. et al.Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.Science. 2008; 321: 1801-1806Crossref PubMed Scopus (3034) Google Scholar Subsequent large-scale PDAC sequencing studies have refined this landscape in great detail, including efforts by The Cancer Genome Atlas and The International Cancer Genome Consortium.25Biankin A.V. Waddell N. Kassahn K.S. et al.Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.Nature. 2012; 491: 399-405Crossref PubMed Scopus (1428) Google Scholar, 26Bailey P. Chang D.K. Nones K. et al.Genomic analyses identify molecular subtypes of pancreatic cancer.Nature. 2016; 531: 47-52Crossref PubMed Scopus (1774) Google Scholar, 27Waddell N. Pajic M. Patch A.M. et al.Whole genomes redefine the mutational landscape of pancreatic cancer.Nature. 2015; 518: 495-501Crossref PubMed Scopus (1558) Google Scholar, 28Cancer Genome Atlas Research NetworkIntegrated genomic characterization of pancreatic ductal adenocarcinoma.Cancer Cell. 2017; 32: 185-203.e113Abstract Full Text Full Text PDF PubMed Scopus (858) Google Scholar Several important groups of “hills” have been characterized in these studies, including genes involved in DNA repair, chromatin remodeling, and axon guidance, some of which delineate clinically important groups that respond to specific therapies. Recent efforts have also identified kataegis, a process leading to clustered nucleotide substitutions, in PDAC; this process is likely associated with the activity of APOBEC enzymes.29ICGC/TCGA Pan-Cancer Analysis of Whole Genomes ConsortiumPan-cancer analysis of whole genomes.Nature. 2020; 578: 82-93Crossref PubMed Scopus (812) Google ScholarFigure 2Mechanisms of pancreatic cancer pathogenesis. Molecular contributions to pathogenesis include somatic mutations in driver genes, chromosomal alterations, epigenetic alterations, and transcriptional reprogramming, all occurring in tumor cells. Cellular contributions from the non-neoplastic tumor microenvironment include alterations in cancer-associated fibroblasts and the immune microenvironment. Population-level contributions include inherited DNA mutations, diabetes, obesity, smoking, and chronic pancreatitis.View Large Image Figure ViewerDownload Hi-res image Download (PPT)In addition to small somatic mutations involving coding regions, the expansion of PDAC genomic analysis to include whole genome sequencing has also catalogued large chromosomal alterations, including copy number alterations, chromosomal rearrangements, and chromothripsis. Chromothripsis, a term derived from the Greek for “shattering,” refers to a phenomenon in which 1 or a few chromosomes contain hundreds of clustered genomic rearrangements.29ICGC/TCGA Pan-Cancer Analysis of Whole Genomes ConsortiumPan-cancer analysis of whole genomes.Nature. 2020; 578: 82-93Crossref PubMed Scopus (812) Google Scholar For the latter, some investigators propose that these alterations are acquired through catastrophic DNA damage events, resulting in punctuated rather than gradual evolution.30Notta F. Chang-Seng-Yue M. Lemire M. et al.A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns.Nature. 2016; 538: 378-382Crossref PubMed Scopus (306) Google Scholar An ongoing challenge in the interpretation of these alterations is the identification of potential driver genes in large altered regions and the distinction of driver alterations from passengers that occur due to PDAC genomic instability. Copy number alterations and chromothripsis have also been reported in precancerous lesions, with a higher prevalence in high-grade lesions, suggesting these chromosomal alterations are a late event in pancreatic tumorigenesis.31Hata T. Suenaga M. Marchionni L. et al.Genome-wide somatic copy number alterations and mutations in high-grade pancreatic intraepithelial neoplasia.Am J Pathol. 2018; 188: 1723-1733Abstract Full Text Full Text PDF PubMed Scopus (17) Google ScholarIn addition to the identification of genetic drivers, DNA sequencing studies have also revealed other important features of pancreatic tumorigenesis. For example, multiregion sequencing of precancerous lesions, primary tumors, and metastases have allowed evolutionary modeling of various steps in pancreatic tumorigenesis. Studies in IPMNs suggest a period of almost 4 years between the development of high-grade dysplasia and invasive carcinoma.15Noë M. Niknafs N. Fischer C.G. et al.Genomic characterization of malignant progression in neoplastic pancreatic cysts.Nat Commun. 2020; 11: 4085Crossref PubMed Scopus (29) Google Scholar Similarly, in PanIN lesions, modeling from sequencing data suggests an interval of approximately 4 years between the common ancestral cell and the founder cell of the associated PDAC.32Makohon-Moore A.P. Matsukuma K. Zhang M. et al.Precancerous neoplastic cells can move through the pancreatic ductal system.Nature. 2018; 561: 201-205Crossref PubMed Scopus (50) Google Scholar Relatedly, modeling from multiregion sequencing of metastases and primary PDACs suggests that many years elapse between tumor initiation and metastasis.33Yachida S. Jones S. Bozic I. et al.Distant metastasis occurs late during the genetic evolution of pancreatic cancer.Nature. 2010; 467: 1114-1117Crossref PubMed Scopus (1846) Google Scholar Intriguingly, these studies show no differences in driver gene mutations between primary and metastatic tumors, suggesting that alterations other than DNA mutations may promote metastasis.33Yachida S. Jones S. Bozic I. et al.Distant metastasis occurs late during the genetic evolution of pancreatic cancer.Nature. 2010; 467: 1114-1117Crossref PubMed Scopus (1846) Google Scholar,34Makohon-Moore A.P. Zhang M. Reiter J.G. et al.Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer.Nat Genet. 2017; 49: 358-366Crossref PubMed Scopus (222) Google Scholar Recent studies in precancerous lesions have revealed surprising genetic heterogeneity, even with respect to well-characterized driver gene mutations.15Noë M. Niknafs N. Fischer C.G. et al.Genomic characterization of malignant progression in neoplastic pancreatic cysts.Nat Commun. 2020; 11: 4085Crossref PubMed Scopus (29) Google Scholar,35Kuboki Y. Fischer C.G. Beleva Guthrie V. et al.Single-cell sequencing defines genetic heterogeneity in pancreatic cancer precursor lesions.J Pathol. 2019; 247: 347-356Crossref PubMed Scopus (32) Google Scholar, 36Fischer C.G. Beleva Guthrie V. Braxton A.M. et al.Intraductal papillary mucinous neoplasms arise from multiple independent clones, each with distinct mutations.Gastroenterology. 2019; 157: 1123-1137.e1122Abstract Full Text Full Text PDF PubMed Google Scholar, 37Fujikura K. Hosoda W. Felsenstein M. et al.Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic KLF4 mutations predominantly in low-grade regions.Gut. 2020; 70: 928-939Crossref PubMed Scopus (11) Google Scholar These studies suggest a polyclonal origin for at least a subset of precancerous lesions, convergent evolution in later driver gene mutations, and distinct selective forces at different time points in tumorigenesis (Figure 3). In addition, multifocal neoplasia is also quite common in patients with precancerous pancreatic lesions; co-occurring PanINs and IPMNs/carcinomas are frequently genetically independent (ie, sharing no somatic mutations, which suggests initiation from separate cells), as are IPMNs and their recurrences.6Felsenstein M. Noe M. Masica D.L. et al.IPMNs with co-occurring invasive cancers: neighbours but not always relatives.Gut. 2018; 67: 1652-1662Crossref PubMed Scopus (62) Google Scholar,38Hosoda W. Chianchiano P. Griffin J.F. et al.Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4.J Pathol. 2017; 242: 16-23Crossref PubMed Scopus (72) Google Scholar, 39Pea A. Yu J. Rezaee N. et al.Targeted DNA sequencing reveals patterns of local progression in the pancreatic remnant following resection of intraductal papillary mucinous neoplasm (IPMN) of the pancreas.Ann Surg. 2017; 266: 133-141Crossref PubMed Scopus (71) Google Scholar, 40Omori Y. Ono Y. Tanino M. et al.Pathways of progression from intraductal papillary mucinous neoplasm to pancreatic ductal adenocarcinoma based on molecular features.Gastroenterology. 2019; 156: 647-661.e642Abstract Full Text Full Text PDF PubMed Google ScholarFigure 3A refined model of multistep tumorigenesis in premalignant pancreatic tumorigenesis. Low-grade IPMNs are characterized by multiple mutations in the initiating oncogene KRAS, suggesting polyclonal evolution of multiple genetically independent precancers. Selection of a clone leads to the development of a high-grade IPMN, which then undergoes ongoing evolution, at times with distinct alterations in the same gene arising in distinct subclones. Selection of an advanced clone that invades the basement membrane leads to the development of invasive PDAC. While this model has been validated in human IPMN samples, its applicability to microscopic human PanINs requires further investigation.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Although alterations in DNA sequence are the most extensively characterized, other types of molecular alterations also contribute to PDAC pathogenesis. Epigenetic modifications to DNA (such as methylation) and histones (such as acetylation and methylation) can heritably modulate chromatin structure and gene expression. Epigenetic inactivation via DNA methylation has been frequently identified for the tumor suppressor gene CDKN2A, but methylation is not a common inactivation mechanism for other PDAC drivers, such as TP53 and SMAD4.41Schutte M. Hruban R.H. Geradts J. et al.Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas.Cancer Res. 1997; 57: 3126-3130PubMed Google Scholar,42Vincent A. Omura N. Hong S.M. et al.Genome-wide analysis of promoter methylation associated with gene expression profile in pancreatic adenocarcinoma.Clin Cancer Res. 2011; 17: 4341-4354Crossref PubMed Scopus (126) Google Scholar Comprehensive methylation profiling in The Cancer Genome Atlas study identified 2 clusters of PDACs based on the extent of their DNA hypermethylation, and integrated analysis of DNA methylation and messenger RNA expression data identified almost 100 genes that were recurrently silenced by DNA methylation, including ZPF82, PAPR6, and DNAJC15.28Cancer Genome Atlas Research NetworkIntegrated genomic characterization of pancreatic ductal adenocarcinoma.Cancer Cell. 2017; 32: 185-203.e113Abstract Full Text Full Text PDF PubMed Scopus (858) Google Scholar In addition, global epigenomic reprogramming modulates the PDAC genome. Studies in human autopsy samples have shown global alterations in histone states in metastases compared with primary tumors, suggesting that epigenetic alterations may play a role in driving metastasis.43McDonald O.G. Li X. Saunders T. et al.Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis.Nat Genet. 2017; 49: 367-376Crossref PubMed Scopus (234) Google Scholar Such epigenetic alterations also have been reported in precancerous PanIN and IPMN lesions.44Fukushima N. Sato N. Ueki T. et al.Aberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma.Am J Pathol. 2002; 160: 1573-1581Abstract Full Text Full Text PDF PubMed Google Scholar, 45Sato N. Fukushima N. Hruban R.H. et al.CpG island methylation profile of pancreatic intraepithelial neoplasia.Mod Pathol. 2008; 21: 238-244Crossref PubMed Scopus (92) Google Scholar, 46Sato N. Ueki T. Fukushima N. et al.Aberrant methylation of CpG islands in intraductal papillary mucinous neoplasms of the pancreas.Gastroenterology. 2002; 123: 365-372Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 47Fujikura K. Alruwaii Z.I. Haffner M. et al.Downregulation of 5-hydroxymethylcytosine is an early event in pancreatic tumorigenesis.J Pathol. 2021; 254: 279-288Crossref PubMed Scopus (1) Google ScholarMultiple studies have categorized the transcriptomes of human PDACs, with several unique subtyping schemes proposed.26Bailey P. Chang D.K. Nones K. et al.Genomic analyses identify molecular subtypes of pancreatic cancer.Nature. 2016; 531: 47-52Crossref PubMed Scopus (1774) Google Scholar,28Cancer Genome Atlas Research NetworkIntegrated genomic characterization of pancreatic ductal adenocarcinoma.Cancer Cell. 2017; 32: 185-203.e113Abstract Full Text Full Text PDF PubMed Scopus (858) Google Scholar,48Moffitt R.A. Marayati R. 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Wilson G.W. et al.Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution.Nat Genet. 2020; 52: 231-240Crossref PubMed Scopus (157) Google Scholar Integrated analyses of these data suggest that there are likely 2 distinct transcriptional subtypes of PDAC, termed classical and basal, with the basal phenotype enriched in metastases and correlated with a worse prognosis.28Cancer Genome Atlas Research NetworkIntegrated genomic characterization of pancreatic du