• Emilija Nikolovska Trpchevska University Clinic of Gastroenterohepatology,Faculty of Medicine University“St.Cyril&Methodius”, Skopje, R.of North Macedonia
  • Rozalinda Popova Jovanovska University Clinic of Gastroenterohepatology,Faculty of Medicine University“St.Cyril&Methodius”, Skopje, R.of North Macedonia
  • Gordana Petrushevska Institute of Pathology, Faculty of Medicine, University of ’’St. Cyril and Methodius”, Skopje, R.of North Macedonia
  • Aleksandar Eftimov Institute of Pathlogy, Faculty of Medicine, University of ’’St. Cyril and Methodius”, Skopje, R.of North Macedonia
  • Dafina Nikolova University Clinic of Gastroenterohepatology,Faculty of Medicine University“St.Cyril&Methodius”, Skopje, R.of North Macedonia
  • Ance Volkanovska Nikolovska University Clinic of Gastroenterohepatology,Faculty of Medicine University“St.Cyril&Methodius”, Skopje, R.of North Macedonia


Pancreatic adenocarcinoma is the seventh cause of death of all malignant tumors worldwide and has the worst prognosis of all solid tumors. In Europe, it is the sixth most common cause of cancer related death and in United States it is the fifth cause of death after lung cancer, prostate cancer, breast and colorectal cancer. Numerous molecular studies have analyzed genetic and epigenetic changes as responsible for the histological variants of this cancer, their correlation with family predisposition, and opportunities for better treatment and survival. This study included 42 patients with pancreatic adenocarcinoma. Tumor tissue samples obtained from surgical specimen were histopathologicaly examined and genetic mutations were determinate. Prior to surgery, patients were diagnosed by imaging modalities (abdominal ultrasound and/or CT), clinical and laboratory examinations. Histopathological analyses included: T category, grade of tumor differentiation, vascular invasion, lymph node involvement and metastasis. We obtained the KRAS and EGFR gene mutations on the Randox investigator diagnostic platform.The aim of the study was to determine the frequency of KRAS and EGFR mutations in pancreatic adenocarcinoma and their correlation with multiple tumor characteristics. No one patient had EGFR mutation. The results showed that more of the patients with KRAS genetic mutations are frequently associated with advanced disease stage and worse prognosis, although the difference was not statistically significant in comparison to patients without KRAS mutations.

 Key words:pancreatic adenocarcinoma, KRAS, EGFR.


1. Risch HA. Etiology of pancreatic cancer, with a hypothesis concerning the role of N-nitroso compounds and excess gastric acidity. J Natl Cancer Inst. 2003 Jul 2;95(13):948–60.
2.Kim VM, Ahuja N. Early detection of pancreatic cancer. Chin J Cancer Res. 2015
3.Sarnecka AK, Zagozda M, Durlik M. An Overview of Genetic Changes and Risk of Pancreatic Ductal Adenocarcinoma. J Cancer. 2016 Oct 22;7(14):2045–51.
4 Witkiewicz AK, McMillan EA, Balaji U, Baek G, Lin W-C, Mansour J, Mollae M et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat Commun [Internet]. 2015 Apr 9 [cited 2020 Jun 19];6. Available from:
5 Biankin AV, Waddell N, Kassahn KS, Gingras M-C, Muthuswamy LB, Johns AL, Miller D et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012 Nov 15;491(7424):399–405.
6 Waters AM, Der CJ. KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. Cold Spring Harb Perspect Med [Internet]. 2018 Sep 4 [cited 2020 Jun 19];8(9). Available from:
7.Bryant KL, Mancias JD, Kimmelman AC, Der CJ. KRAS: feeding pancreatic cancer proliferation. Trends Biochem Sci. 2014 Feb;39(2):91–100.
8.Di Magliano MP, Logsdon CD. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology. 2013 Jun;144(6):1220–9.
9.Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013 Nov 28;503(7477):548–51.
10.Cicenas J, Kvederaviciute K, Meskinyte I, Meskinyte-Kausiliene E, Skeberdyte A, Cicenas J. KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 Mutations in Pancreatic Cancer. Cancers. 2017 Apr 28;9(5).
11.Cowan RW, Maitra A. Genetic progression of pancreatic cancer. Cancer J Sudbury Mass. 2014 Feb;20(1):80–4.
12.Oliveira-Cunha M, Newman WG, Siriwardena AK. Epidermal growth factor receptor in pancreatic cancer. Cancers. 2011 Mar 24;3(2):1513–26.
13.Lee J, Jang K-T, Ki C-S, Lim T, Park YS, Lim HY, Donk-Wook C et al. Impact of epidermal growth factor receptor (EGFR) kinase mutations, EGFR gene amplifications, and KRAS mutations on survival of pancreatic adenocarcinoma. Cancer. 2007 Apr 15;109(8):1561–9.
14.Tzeng C-WD, Frolov A, Frolova N, Jhala NC, Howard JH, Buchsbaum DJ, Vicher C et al. Epidermal growth factor receptor (EGFR) is highly conserved in pancreatic cancer. Surgery. 2007 Apr;141(4):464–9.
15.Boeck S, Jung A, Laubender RP, Neumann J, Egg R, Goritschan C, Vehling-Keiser U et al. EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104. Br J Cancer. 2013 Feb 5;108(2):469–76.
16.Morgan MA, Parsels LA, Kollar LE, Normolle DP, Maybaum J, Lawrence TS. The combination of epidermal growth factor receptor inhibitors with gemcitabine and radiation in pancreatic cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2008 Aug 15;14(16):5142–9.
17 Burris H, Rocha-Lima C. New therapeutic directions for advanced pancreatic cancer: targeting the epidermal growth factor and vascular endothelial growth factor pathways. The Oncologist. 2008 Mar;13(3):289–98.
18.Czarnecka AM, Korzeń P, Nowak-Dement A, Kukwa W, Korniluk J, Szczylik C. Prolonged complete response following gemcitabine-erlotinib combined therapy in advanced pancreatic cancer. Oncol Lett. 2016 Feb;11(2):1101–4.
19.Rishi A, Goggins M, Wood LD, Hruban RH. Pathological and molecular evaluation of pancreatic neoplasms. Semin Oncol. 2015 Feb;42(1):28–39.
20 Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, Ross S et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003 Dec;4(6):437–50.
21.Shen R, Wang Q, Cheng S, Liu T, Jiang H, Zhu J, Wu Y et al. The biological features of PanIN initiated from oncogenic Kras mutation in genetically engineered mouse models. Cancer Lett. 2013 Oct 1;339(1):135–43.
22.Khan MAA, Azim S, Zubair H, Bhardwaj A, Patel GK, Khushman M, Singh S et al. Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward. Int J Mol Sci. 2017 Apr 6;18(4).
23.Wang JP, Wu C-Y, Yeh Y-C, Shyr Y-M, Wu Y-Y, Kuo C-Y, Hung Y et al. Erlotinib is effective in pancreatic cancer with epidermal growth factor receptor mutations: a randomized, open-label, prospective trial. Oncotarget. 2015 Jul 20;6(20):18162–73.
24.Valsecchi ME, McDonald M, Brody JR, Hyslop T, Freydin B, Yeo CJ, Solomides Ch et al. Epidermal growth factor receptor and insulinlike growth factor 1 receptor expression predict poor survival in pancreatic ductal adenocarcinoma. Cancer. 2012 Jul 15;118(14):3484–93.
25.Guo M, Luo G, Liu C, Cheng H, Lu Y, Jin K, Liu Z et al. The Prognostic and Predictive Role of Epidermal Growth Factor Receptor in Surgical Resected Pancreatic Cancer. Int J Mol Sci. 2016 Jul 8;17(7).
26.Bournet B, Buscail C, Muscari F, Cordelier P, Buscail L. Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities. Eur J Cancer Oxf Engl 1990. 2016 Feb;54:75–83.
27.Lemstrova R, Brynychova V, Hughes DJ, Hlavac V, Dvorak P, Doherty JE, Murray H et al. Dysregulation of KRAS signaling in pancreatic cancer is not associated with KRAS mutations and outcome. Oncol Lett. 2017 Nov;14(5):5980–8.
28.Windon AL, Loaiza-Bonilla A, Jensen CE, Randall M, Morrissette JJD, Shroff SG. A KRAS wild type mutational status confers a survival advantage in pancreatic ductal adenocarcinoma. J Gastrointest Oncol. 2018 Feb;9(1):1–10.
29.Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK, Hruban R et al. Recent progress in pancreatic cancer. CA Cancer J Clin. 2013 Sep;63(5):318–48.
30.Smit VT, Boot AJ, Smits AM, Fleuren GJ, Cornelisse CJ, Bos JL. KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas. Nucleic Acids Res. 1988 Aug 25;16(16):7773–82.
31.Wilentz RE, Chung CH, Sturm PD, Musler A, Sohn TA, Offerhaus GJ, Jeo Ch et al. K-ras mutations in the duodenal fluid of patients with pancreatic carcinoma. Cancer. 1998 Jan 1;82(1):96–103.
32.Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988 May 20;53(4):549–54.
33.H Kondo , K Sugano, N Fukayama, K Hosokawa, H Ohkura, A Ohtsu, K Mukai et al. Detection of K-ras gene mutations at codon 12 in the pancreatic juice of patients with intraductal papillary mucinous tumors of the pancreas - PubMed [Internet]. [cited 2020 Jun 19]. Available from:
34.Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: Mission possible? Nat Rev Drug Discov. 2014 Nov;13(11):828–51.
35.Smith MJ, Neel BG, Ikura M. NMR-based functional profiling of RASopathies and oncogenic RAS mutations. Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4574–9.
36.Ostrem JML, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov. 2016;15(11):771–85.
37. Bournet B, Muscari F, Buscail C, Assenat E, Barthet M, Hammel P, Selves J et al. KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma. Clin Transl Gastroenterol. 2016 Mar 24;7:e157.
38. Barrett MT, Deiotte R, Lenkiewicz E, Malasi S, Holley T, Evers L, Posner R et al. Clinical study of genomic drivers in pancreatic ductal adenocarcinoma. Br J Cancer. 2017 Aug 8;117(4):572–82.
How to Cite
TRPCHEVSKA, Emilija Nikolovska et al. KRAS MUTATIONS IN PANCREATIC ADENOCARCINOMA IN CORRELATION WITH CLINICAL AND PATHOLOGICAL CHARACTERISTCS. Journal of Morphological Sciences, [S.l.], v. 3, n. 1, p. 55-64, july 2020. ISSN 2545-4706. Available at: <>. Date accessed: 21 jan. 2022.