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Review
. 2021 Sep 3;13(17):4451.
doi: 10.3390/cancers13174451.

Genomic Heterogeneity of Pancreatic Ductal Adenocarcinoma and Its Clinical Impact

María Laura Gutiérrez  1   2   3   4 , Luis Muñoz-Bellvís  2   3   4   5 , Alberto Orfao  1   2   3   4
Affiliations
Review

Genomic Heterogeneity of Pancreatic Ductal Adenocarcinoma and Its Clinical Impact

María Laura Gutiérrez et al. Cancers (Basel). .

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death due to limited advances in recent years in early diagnosis and personalized therapy capable of overcoming tumor resistance to chemotherapy. In the last decades, significant advances have been achieved in the identification of recurrent genetic and molecular alterations of PDAC including those involving the KRAS, CDKN2A, SMAD4, and TP53 driver genes. Despite these common genetic traits, PDAC are highly heterogeneous tumors at both the inter- and intra-tumoral genomic level, which might contribute to distinct tumor behavior and response to therapy, with variable patient outcomes. Despite this, genetic and genomic data on PDAC has had a limited impact on the clinical management of patients. Integration of genomic data for classification of PDAC into clinically defined entities-i.e., classical vs. squamous subtypes of PDAC-leading to different treatment approaches has the potential for significantly improving patient outcomes. In this review, we summarize current knowledge about the most relevant genomic subtypes of PDAC including the impact of distinct patterns of intra-tumoral genomic heterogeneity on the classification and clinical and therapeutic management of PDAC.

Keywords: chemoresistance; genetic heterogeneity; genomic subtypes; pancreatic ductal adenocarcinoma; prognosis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Key molecular, histopathological, and immunological features of the major molecular subtypes of PDAC defined based on the GEP of individual tumors. Classical, exocrine, and endocrine differentiated and immune-related PDAC harbor pancreatic epithelial cell differentiation driven by increased expression of endodermal identity genes (depicted in red), that are frequently associated with both low cellular collagen-rich (mature) stroma and variable profiles of tumor infiltrating immune cells. In contrast, squamous PDAC cells display histological dedifferentiation driven by the downregulation of pancreatic endodermal cell-fate determining genes and activation of EMT program (depicted in purple) to further acquisition of mesenchymal features, and are usually embedded in a highly cellular stroma enriched in activated CAFs (immature). EMT: epithelial-to-mesenchymal transition; PSC: pancreatic stellate cells; Treg: regulatory T lymphocytes; NK: natural killer cells; TAM: tumor-associated macrophages; CAF: cancer associated fibroblast; AI: allelic imbalance. (↓): decrease; (↑): increase. Created with BioRender.com.
Figure 2
Figure 2
Schematic overview of the most relevant clinico-pathological features that have been recurrently associated with distinct molecular subtypes of PDAC. Dotted lines indicate non-well-defined clear-cut features between different molecular subtypes of PDAC. d-DSBR: double-strand break repair deficient; d-MMR: mismatch repair-deficient; GEM: gemcitabine; i: inhibitor; AI: allelic imbalance; amp: gene amplification; (↓): decrease; (↑): increase; (+): positive expression; (−): negative expression.
Figure 3
Figure 3
Detection of GATA6, HNF1A, CFTR, KRT81, and KRT17 PDAC molecular subtype-associated biomarker expression by immunohistochemistry of paraffin-embedded primary PDAC sections. Representative images of well/moderately differentiated tumor tissues displaying overexpression of GATA6 and lack of expression of KRT81 and KRT17, associated (i.e., exo/endocrine PDAC) or not (i.e., classical) with higher levels of HNF1A and CFTR proteins altogether are typically seen in tumors with non-squamous PDAC subtypes (A); whereas poorly-differentiated tissues with high expression levels of KRT81 and KRT17 showing no stain of GATA6, HNF1A, CFTR are frequently present in the squamous PDAC tumors (B). HE: hematoxylin and eosin staining; (+): positive expression; (−): negative expression. Images of GATA6 and HNF1A, and CFTR and KRT81 were obtained with permission from the Human Protein Atlas (v20.proteinatlas.org) and Henning et al., respectively [92].
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References

    1. Ferlay J., Partensky C., Bray F. More deaths from pancreatic cancer than breast cancer in the EU by 2017. Acta Oncol. 2016;55:1158–1160. doi: 10.1080/0284186X.2016.1197419. - DOI - PubMed
    1. Rahib L., Smith B.D., Aizenberg R., Rosenzweig A.B., Fleshman J.M., Matrisian L.M. Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–2921. doi: 10.1158/0008-5472.CAN-14-0155. - DOI - PubMed
    1. De Wilde R.F., Hruban R.H., Maitra A., Offerhaus G.J. Reporting precursors to invasive pancreatic cancer: Pancreatic intraepithelial neoplasia, intraductal neoplasms and mucinous cystic neoplasm. Diagn. Histopathol. 2012;18:17–30. doi: 10.1016/j.mpdhp.2011.10.012. - DOI
    1. Samuel N., Hudson T.J. The molecular and cellular heterogeneity of pancreatic ductal adenocarcinoma. Nat. Rev. Gastroenterol. Hepatol. 2012;9:77–87. doi: 10.1038/nrgastro.2011.215. - DOI - PubMed
    1. Jones S., Zhang X., Parsons D.W., Lin J.C., Leary R.J., Angenendt P., Mankoo P., Carter H., Kamiyama H., Jimeno A., et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801–1806. doi: 10.1126/science.1164368. - DOI - PMC - PubMed
-