Oncogenes in KRAS Wild Type Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an invasive cancer, ranked the fourth most prevalent cause of cancer related death. Somatic genetic alterations are primary drivers of PDAC. 93% of patients have activating mutations in the master oncogene, KRAS. Several studies have investigated the mutational landscapes of pancreatic cancer. However, comprehensive studies of KRAS wild type pancreatic tumours are limited. Hence the process of initiation and progression of this cancer remains to be discovered and may be associated with genes that have not been identified.

The current project aims to identify oncogenes in KRAS wild type Pancreatic cancer. It also aims to identify whether these oncogenes are from the MAPK pathway or independent of it. The genomic and transcriptomic landscapes of KRAS wild type PDAC were verified. In the absence of KRAS mutation, alternative oncogenes were found. In the genomic data analysis, two cohorts were analysed including 70 samples in the KRAS wild type cohort and 571 in the KRAS mutant cohort. In the absence of KRAS mutation, tumours were found to be rare as were (i) Oncogenic BRAF in-frame deletions, hotspot alterations and oncogenic fusions (known and novel) (frequency of 17%), oncogenic GNAS hotspot mutation (frequency of 12%) and somatic alterations in RET (7% frequency). Recurrent copy number gains (CNV >4) were observed in MYC (23% frequency), CDK6 (16% frequency), AKT2 (16% frequency), KDM6A (14% frequency), EGFR (12% frequency), RICTOR (12% frequency), MET (11% frequency), FGFR1(10% frequency), FGF3 (9% frequency) and FGF4 (9% frequency) in the KRAS wild type cohort. Other low frequency fusion events in the MAPK pathway include: RET-CCDC6; ROS1-SLC4A4; BRAF-SND1; BRAF-SDK1; TRIM24-BRAF; STK4-SLC13A3; ARHGAP24-MAPk10; BRAF-BRAF; STMN1-CDK5RAP3, and; SLC4A4-RASGRF1.

Two independent differential expression analyses were performed on the RNA-seq of KRAS wild type versus KRAS mutant Pancreatic Adenocarcinomas, generated by the Australian and Canadian ICGC- pancreatic cancer Consortium consisting of RNA-seq from 88 and 224 bulk tumour samples respectively. Pathway analysis showed that the Calcium signalling pathway was over-expressed in both the Australian and Canadian wild type.This up-regulation of the Calcium signalling pathway in the whole cohort of KRAS wild type is consistent with GNAS mutation in the genomic analysis of the KRAS wild type cohort. Additionally, the MAPK signalling pathway shows no difference throughout the whole cohort of KRAS wild type. Together, these findings at the genomic level reveal that the MAPK signalling pathway is the dominant pathway in the KRAS wild type cohort. The results of comparing RNA expression in two groups of KRAS wild type and KRAS mutant analysis suggest that one oncogene has been substituted for another oncogene in the MAPK pathway, creating an interruption in the MAPK pathway. The lack of differences between KRAS mutant and KRAS wildtype in the MAPK pathway could suggest that the MAPK pathway is up-regulated in both sets, resulting in a lack of difference in the expression.