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Updated: Sep 29, 2025
Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma
Published on: November 19, 2019
Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma
Philip A Philip1, Ibrahim Azar1, Joanne Xiu2
1Wayne State University, School of Medicine, Karmanos Cancer Center, Detroit, Michigan.
Purpose:
KRAS mutation (MT) is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). A small subset of PDACs harbor KRAS wild-type (WT). We aim to characterize the molecular profiles of KRAS WT PDAC to uncover new pathogenic drivers and offer targeted treatments.
Experimental Design:
Tumor tissue obtained from surgical or biopsy material was subjected to next-generation DNA/RNA sequencing, microsatellite instability (MSI) and mismatch repair status determination.
Results:
Of the 2,483 patients (male 53.7%, median age 66 years) studied, 266 tumors (10.7%) were KRAS WT. The most frequently mutated gene in KRAS WT PDAC was TP53 (44.5%), followed by BRAF (13.0%). Multiple mutations within the DNA-damage repair (BRCA2, ATM, BAP1, RAD50, FANCE, PALB2), chromatin remodeling (ARID1A, PBRM1, ARID2, KMT2D, KMT2C, SMARCA4, SETD2), and cell-cycle control pathways (CDKN2A, CCND1, CCNE1) were detected frequently. There was no statistically significant difference in PD-L1 expression between KRAS WT (15.8%) and MT (17%) tumors. However, KRAS WT PDAC were more likely to be MSI-high (4.7% vs. 0.7%; P < 0.05), tumor mutational burden-high (4.5% vs. 1%; P < 0.05), and exhibit increased infiltration of CD8+ T cells, natural killer cells, and myeloid dendritic cells. KRAS WT PDACs exhibited gene fusions of BRAF (6.6%), FGFR2 (5.2%), ALK (2.6%), RET (1.3%), and NRG1 (1.3%), as well as amplification of FGF3 (3%), ERBB2 (2.2%), FGFR3 (1.8%), NTRK (1.8%), and MET (1.3%). Real-world evidence reveals a survival advantage of KRAS WT patients in overall cohorts as well as in patients treated with gemcitabine/nab-paclitaxel or 5-FU/oxaliplatin.
Conclusions:
KRAS WT PDAC represents 10.7% of PDAC and is enriched with targetable alterations, including immuno-oncologic markers. Identification of KRAS WT patients in clinical practice may expand therapeutic options in a clinically meaningful manner.
Insights
KRAS wild-type (WT) pancreatic ductal adenocarcinoma (PDAC) is enriched with targetable alterations and immune markers. Identifying these patients may expand therapeutic options and improve outcomes.
Area of Science:
- Oncology
- Genomics
- Cancer Research
Background:
- KRAS mutations are key drivers in pancreatic ductal adenocarcinoma (PDAC).
- A small fraction of PDAC cases exhibit wild-type KRAS, suggesting alternative oncogenic pathways.
Purpose of the Study:
- To molecularly characterize KRAS wild-type (WT) PDAC.
- To identify novel pathogenic drivers and potential therapeutic targets in KRAS WT PDAC.
Main Methods:
- Next-generation DNA/RNA sequencing of tumor tissues.
- Microsatellite instability (MSI) and mismatch repair status determination.
- Analysis of gene mutations, fusions, and amplifications.
Main Results:
- KRAS WT PDAC (10.7%) frequently harbors TP53, BRAF mutations, and alterations in DNA-damage repair and chromatin remodeling pathways.
- KRAS WT PDAC shows higher rates of MSI-high, tumor mutational burden-high, and increased immune cell infiltration.
- Gene fusions (BRAF, FGFR2, ALK) and amplifications (FGF3, ERBB2, FGFR3) were identified, alongside a survival advantage for KRAS WT patients.
Conclusions:
- KRAS WT PDAC presents distinct molecular profiles with targetable alterations and immunooncologic markers.
- Identifying KRAS WT PDAC patients can lead to expanded therapeutic strategies and improved clinical outcomes.
