Pancreatic Cancer: Molecular Genetics and Clinical Applications

Abstract

Pancreatic cancer (PC) is a relatively common type of cancer with a dismal prognosis. Recent advances in molecular biology allowed the identification of many of the genes involved in pancreatic carcinogenesis; currently, it is accepted that PC is fundamentally a genetic disease caused by inherited and acquired (somatic) mutations in cancer‐associated genes (oncogenes, tumour‐suppressor genes, genome‐maintenance genes). Other genetic/molecular pathways (such as telomere shortening, upregulation and overexpression of growth factors or their receptors (such as EGFR, TGFβ), tumour angiogenesis and alterations of developmental signalling pathways (such as the Hedgehog signalling pathway)) are also involved in pancreatic carcinogenesis. Pancreatic carcinogenesis is a multistep phenomenon, characterised by the progressive accumulation of multiple genetic alterations, which occur in an ordered sequence rather than a random fashion. Advances in our understanding of molecular biology of PC will improve clinical management of patients with PC by providing better diagnostic, prognostic and therapeutic tools.

Key Concepts:

  • Pancreatic cancer has been associated with inherited and acquired (somatic) mutations in cancer‐related genes.

  • Genes involved in pancreatic carcinogenesis include oncogenes, tumour‐suppressor genes and genome‐maintenance genes.

  • Other genetic/molecular pathways are also involved in pancreatic carcinogenesis, such as telomere shortening, developmental signalling pathways (such as the Hedgehog signalling pathway), and upregulation and overexpression of growth factors or their receptors (such as EGFR, TGFβ, VEGF‐A, VEGFR1, VEGFR2).

  • Pancreatic carcinogenesis is a multistep phenomenon, characterised by the progressive accumulation of multiple genetic/molecular alterations, occurring in an ordered sequence rather than a random fashion.

  • Potential clinical implications include the recognition of groups of individuals with high risk for PC development (in these groups an as yet undefined programme of intensive surveillance may diagnose pancreatic lesions at a pre‐invasive stage) and the development of new and effective diagnostic, prognostic and therapeutic tools.

Keywords: pancreas; cancer; molecular biology; genes; oncogenes; surgery; management; diagnosis; treatment

Figure 1.

Multistep pancreatic carcinogenesis. Note the progression of pancreatic neoplasia from premalignant pancreatic lesions (PanIN, left) to carcinoma (right). (From Maitra et al., .)

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References

Abbruzzese JL (2002) New applications of gemcitabine and future directions in the management of pancreatic cancer. Cancer 95: 941–945.

Bardeesy N and DePinho R (2002) Pancreatic cancer biology and genetics. Nature Reviews Cancer 2: 897–909.

Bashyam MD, Bair R, Kim YH et al. (2005) Array‐based comparative genomic hybridization identifies localized DNA amplifications and homozygous deletions in pancreatic cancer. Neoplasia 7(6): 556–562.

Biankin AV, Kench JG, Morey AL et al. (2001) Overexpression of p21WAF/CIP1 is an early event in the development of pancreatic intraepithelial neoplasia. Cancer Research 61: 8830–8837.

Brune K, Hong S‐M, Li A et al. (2008) Genetic and epigenetic alterations of familial pancreatic cancers. Cancer Epidemiology Biomarkers and Prevention 17: 3536–3542.

Calhoun ES, Jones JB, Ashfaq R et al. (2003) BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets. American Journal of Pathology 163(4): 1255–1260.

Ebert M, Schandl L and Schmid R (2001) Differentiation of chronic pancreatitis from pancreatic cancer: recent advances in molecular diagnosis. Digestive Diseases and Sciences 19: 32–36.

Gao J, Song J, Huang H et al. (2010) Methylation of the SPARC gene promoter and its clinical implications in pancreatic cancer. Journal of Experimental and Clinical Cancer Research 29: 28.

Greer J and Whitcomb D (2007) Role of BRCA 1 and BRCA 2 mutations in pancreatic cancer. Gut 56: 601–605.

Hahn SA, Schutte M, Hoque AT et al. (1996) DPC4, a candidate tumor‐suppressor gene at human chromosome 18q21.1. Science 271: 350–353.

Harada T, Chelala C, Bhakta V et al. (2008) Genome‐wide DNA copy number analysis in pancreatic cancer using high‐density single nucleotide polymorphism arrays. Oncogene 27: 1951–1960.

Harada T, Chelala C, Crnogorac‐Jurcevic T and Lemoine NR (2009) Genome‐wide analysis of pancreatic cancer using microarray‐based techniques. Pancreatology 9: 13–24.

van der Heijden MS, Brody JR, Gallmeier E et al. (2004) Functional defects in the Fanconi anemia pathway in pancreatic cancer cells. American Journal of Pathology 165(2): 651–657.

Hruban RH, van Mansfeld ADM, Offerhaus GJ et al. (1993) K‐ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant‐enriched polymerase chain reaction analysis and allele‐specific oligonucleotide hybridization. American Journal of Pathology 143(2): 545–554.

Hruban RH, Wilentz RE and Kern SE (2000) Genetic progression in the pancreatic ducts. American Journal of Pathology 156: 1821–1825.

Hustinx SR, Leoni LM, Yeo CJ et al. (2005) Concordant loss of MTAP and p16/CDKN2A expression in pancreatic intraepithelial neoplasia: evidence of homozygous deletion in a noninvasive precursor lesion. Modern Pathology 18(7): 959–963.

Jemal A, Siegel R, Ward E et al. (2009) Cancer statistics, 2009. CA: A Cancer Journal for Clinicians 59: 225–249.

Jones S, Hruban RH, Kamiyama M et al. (2009) Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324(5924): 217.

Kinzler KW and Vogelstein B (1997) Cancer‐susceptibility genes: gate‐keepers and caretakers. Nature 386: 761–763.

Kitada T, Seki S, Sakaguchi H et al. (2003) Clinicopathological significance of hypoxia‐inducible factor‐1a expression in human pancreatic carcinoma. Histopathology 43: 550–555.

Kubo T, Kuroda Y, Kokubu A et al. (2009) Resequencing analysis of the human tyrosine kinase gene family in pancreatic cancer. Pancreas 38: e200–e206.

Kuwahara K, Sasaki T, Kuwada Y et al. (2003) Expression of angiogenic factors in pancreatic ductal carcinoma: a correlative study with clinicopathologic parameters and patient survival. Pancreas 26: 344–349.

Li D, Suzuki H, Liu B et al. (2009) DNA repair gene polymorphisms and risk of pancreatic cancer. Clinical Cancer Research 15(2): 740–746.

Longo R, Cacciamani F, Naso G and Gasparini G (2008) Pancreatic cancer: from molecular signature to target therapy. Critical Reviews in Oncology/Hematology 68: 197–211.

Low S‐K, Kuchiba A, Zembutsu H et al. (2010) Genome‐wide association study of pancreatic cancer in Japanese population. PLoS ONE 5: e11824.

Luttges J, Galehdari H, Brocker V et al. (2001) Allelic loss is often the first hit in the biallelic inactivation of the p53 and DPC4 genes during pancreatic carcinogenesis. American Journal of Pathology 158: 1677–1683.

Maitra A, Adsay NV, Argani P et al. (2003) Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray. Modern Pathology 16: 902–912.

Maitra A, Kern SE and Hruban RH (2006) Molecular pathogenesis of pancreatic cancer. Best Practice and Research Clinical Gastroenterology 20: 211–226.

Malumbres M and Pellicer A (1998) RAS pathways to cell cycle control and cell transformation. Frontiers in Bioscience 3: d887–d912.

Neoptolemos JP, Dunn JA, Stocken DD et al. (2001) Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer. A randomized controlled trial. Lancet 358: 1576–1585.

Oft M, Peli J, Rudaz C et al. (1996) TGF‐beta1 and Ha‐Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells. Genes & Development 10: 2462–2477.

Oliveira‐Cunha M, Siriwardena AK and Byers R (2008) Molecular diagnosis in pancreatic cancer. Diagnostic Histopathology 14: 214–222.

Parker JF, Florell SR, Alexander A et al. (2003) Pancreatic carcinoma surveillance in patients with familial melanoma. Archives of Dermatology 139(8): 1019–1025.

Pogue‐Geile KL, Chen R, Bronner MP et al. (2006) Palladin mutation causes familial pancreatic cancer and suggests a new cancer mechanism. PLoS Medicine 3: e516.

Redston MS, Caldas C, Seymour AB et al. (1994) p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Research 54(11): 3025–3033.

Rozenblum E, Schutte M, Goggins M et al. (1997) Tumor‐suppressive pathways in pancreatic carcinoma. Cancer Research 57: 1731–1734.

Schutte M, Hruban RH, Geradts J et al. (1997) Abrogation of the Rb/p16 tumor‐suppressive pathway in virtually all pancreatic carcinomas. Cancer Research 57: 3126–3130.

Schwarte‐Waldhoff I, Volpert OV, Bouck NP et al. (2000) Smad4/DPC4‐mediated tumor suppression through suppression of angiogenesis. Proceedings of the National Academy of Sciences of the USA 97: 9624–9629.

Su GH, Bansal R, Murphy KM et al. (2001) ACVR1B (ALK4, activin receptor type 1B) gene mutations in pancreatic carcinoma. Proceedings of the National Academy of Sciences of the USA 98(6): 3254–3257.

Subramanian G, Schwarz RE, Higgins L et al. (2004) Targeting endogenous transforming growth factor beta receptor signaling in SMAD4‐deficient human pancreatic carcinoma cells inhibits their invasive phenotype1. Cancer Research 64: 5200–5211.

Talar‐Wojnarowska T and Malecka‐Panas E (2006) Molecular pathogenesis of pancreatic adenocarcinoma potential clinical implications. Medical Science Monitor 12: 186–193.

Thayer SP, di Magliano MP, Heiser PW et al. (2003) Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425: 851–856.

Tjarda van Heek N, Meeker AK, Kern SE et al. (2002) Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia. American Journal of Pathology 161: 1541–1547.

Uehara H, Miyamoto M, Kato K et al. (2004) Expression of pigment epithelium‐derived factor decreases liver metastasis and correlates with favorable prognosis for patients with ductal pancreatic adenocarcinoma. Cancer Research 64: 3533–3537.

Vitone LJ, Greenhalf W, McFaul CD and Neoptolemos JP (2006) The inherited genetics of pancreatic cancer and prospects for secondary screening. Best Practice and Research Clinical Gastroenterology 20: 253–283.

Welsh J, Sapinoso L, Kern S et al. (2003) Large‐scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum. Proceedings of the National Academy of Sciences of the USA 100: 3410–3415.

Wong HH and Lemoine NR (2008) Biologic approaches to therapy of pancreatic cancer. Pancreatology 8: 431–461.

Xiong HQ and Abbruzzese JL (2002) Epidermal growth factor receptor targeted therapy for pancreatic cancer. Seminars in Oncology 29(suppl. 14): 31–37.

Yamamoto H, Itoh F, Nakamura H et al. (2001) Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability. Cancer Research 61(7): 3139–3144.

Further Reading

Belda‐Iniesta C, Ibanez de Caceres I, Barriuso J et al. (2008) Molecular biology of pancreatic cancer. Clinical and Translational Oncology 10: 530–537.

Feldmann G, Beaty R, Hruban RH and Maitra A (2007) Molecular genetics of pancreatic intraepithelial neoplasia. Journal of Hepato‐Biliary‐Pancreatic Surgery 14: 224–232.

Feldmann G and Maitra A (2009) Molecular genetics of pancreatic ductal adenocarcinomas and recent implications for translational efforts. Journal of Molecular Diagnostics 10: 111–122.

Furukawa T (2009) Molecular pathology of pancreatic cancer: implications for molecular targeting therapy. Clinical Gastroenterology and Hepatology 7: S35–S39.

Grote T and Lonsdon CD (2007) Progress on molecular markers of pancreatic cancer. Current Opinion in Gastroenterology 23: 508–514.

Mihaljevic AL, Michalski CW, Friess H and Kleeff J (2010) Molecular mechanisms of pancreatic cancer. Langenbeck's Archives of Surgery 395: 295–308.

Rachagani S, Kumar S and Batra SK (2010) MicroRNA in pancreatic cancer: pathological, diagnostic, and therapeutic implications. Cancer Letters 292: 8–16.

Schneider G, Hamacher R, Eser S et al. (2008) Molecular biology of pancreatic cancer – new aspects and targets. Anticancer Research 28(3A): 1541–1550.

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Sakorafas, George H, Pappa, Irene, and Smyrniotis, Vasileios(Dec 2010) Pancreatic Cancer: Molecular Genetics and Clinical Applications. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006057.pub2]