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. 2017 Nov;14(5):5980-5988.
doi: 10.3892/ol.2017.6946. Epub 2017 Sep 14.

Dysregulation of KRAS signaling in pancreatic cancer is not associated with KRAS mutations and outcome

Radmila Lemstrova  1 , Veronika Brynychova  2   3 , David J Hughes  4 , Viktor Hlavac  2   3 , Pavel Dvorak  5 , Joanne E Doherty  6 , Helena A Murray  6 , Martin Crockard  6 , Martin Oliverius  7 , Jan Hlavsa  8 , Eva Honsova  9 , Jan Mazanec  10 , Zdenek Kala  8 , Martin Lovecek  11 , Roman Havlik  11 , Jiri Ehrmann  12   13 , Ondrej Strouhal  1 , Pavel Soucek  2   3 , Bohuslav Melichar  1   13 , Beatrice Mohelnikova-Duchonova  1   2
Affiliations

Dysregulation of KRAS signaling in pancreatic cancer is not associated with KRAS mutations and outcome

Radmila Lemstrova et al. Oncol Lett. 2017 Nov.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a poor prognosis, and no targeted therapy is currently available. The aim of the present study was to investigate the prognostic significance of the expression of V-Ki-ras2 Κirsten rat sarcoma viral oncogene homolog (KRAS), downstream signaling pathway genes and the association with clinical characteristics in PDAC patients undergoing radical surgery. Tumors and adjacent non-neoplastic pancreatic tissues were examined in 45 patients with histologically verified PDAC. KRAS and B-Raf proto-oncogene, serine/threonine kinase (BRAF) gene mutation analysis was performed using the KRAS/BRAF/phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α array. The transcript profile of 52 KRAS downstream signaling pathway genes was assessed using quantitative-polymerase chain reaction. KRAS mutation was detected in 80% of cases. The genes of four signaling pathways downstream of KRAS, including the phosphoinositide 3-kinase/3-phosphoinositide-dependent protein kinase 1/V-akt murine thymoma viral oncogene homolog 1, RAL guanine nucleotide exchange factor, Ras and Rab interactor 1/ABL proto-oncogene-1, non-receptor tyrosine kinase, and RAF proto-oncogene serine/threonine-protein kinase/mitogen-activated protein kinase pathways, exhibited differential expression in PDAC compared with that in the adjacent normal tissues. However, no significant differences in expression were evident between patients with KRAS-mutated and wild-type tumors. The expression of KRAS downstream signaling pathways genes did not correlate with angioinvasion, perineural invasion, grade or presence of lymph node metastasis. Additionally, the presence of KRAS mutations was not associated with overall survival. Among the KRAS downstream effective signaling pathways molecules investigated, only v-raf-1 murine leukemia viral oncogene homolog 1 expression was predictive of prognosis. Overall, KRAS mutation is present in the majority of cases of PDAC, but is not associated with changes in the expression of KRAS downstream signaling pathways and the clinical outcome. This may partly explain the failure of KRAS-targeted therapies in PDAC.

Keywords: KRAS; gene expression; mutation; overall survival; pancreatic ductal adenocarcinoma.

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Figures

Figure 1.
Figure 1.
Dysregulation of KRAS signaling pathway in PDAC tumors compared with that in the paired adjacent non-malignant tissues. KRAS pathway map noting the differentially expressed genes in PDAC tumors compared with those in adjacent non-malignant tissues. Genes overexpressed in tumor tissue are in red, while downregulated genes are in blue. Genes not exhibiting differential expression are in black. KRAS, KRAS proto-oncogene, GTPase; PDAC, pancreatic ductal adenocarcinoma.
Figure 2.
Figure 2.
Heat map of KRAS proto-oncogene, GTPase signaling pathway expression profile of pancreatic ductal adenocarcinoma. Tumor samples are contained within the blue box on the left and the non-malignant pancreatic tissue samples are shown on the right.
Figure 3.
Figure 3.
Heat map of KRAS signaling pathway expression profile of KRAS-mutated pancreatic ductal adenocarcinoma. KRAS wild-type tumors are marked by the blue box on the left and the samples harboring KRAS mutations are on the right. KRAS, KRAS proto-oncogene, GTPase.
Figure 4.
Figure 4.
Kaplan-Meier survival plot presenting the correlation between RAF1 expression and OS. RAF1, V-RAF-1 murine leukemia viral oncogene homolog 1; OS, overall survival; CI, confidence interval.
See this image and copyright information in PMC

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