Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Abstract

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas.

“…Prior studies have reported STK11 mutations in a similar percentage of IPMNs (9%) [8]. Prior studies have found ATM and CDH1 somatic mutations in a small percentage of pancreatic ductal adenocarcinomas, but these mutations have not yet been reported in IPMNs [33,34]. Somatic mutations in IDH1, PTEN, FGFR3, NRAS and SRC have not been reported in IPMNs or in pancreatic ductal adenocarcinomas [33,34].…”

“…Prior studies have found ATM and CDH1 somatic mutations in a small percentage of pancreatic ductal adenocarcinomas, but these mutations have not yet been reported in IPMNs [33,34]. Somatic mutations in IDH1, PTEN, FGFR3, NRAS and SRC have not been reported in IPMNs or in pancreatic ductal adenocarcinomas [33,34]. CTNNB1 mutations are characteristic of pancreatic solid and pseudopapillary tumours, but nuclear expression of β-catenin has been described in some IPMNs [17].…”

ATM Mutations in Cancer: Therapeutic Implications

“…In prostate cancer, targeted next-generation sequencing has revealed an 8% incidence of ATM mutations (59). ATM is also one of the most commonly mutated genes in pancreatic cancer (60) or lung adenocarcinoma (61). In colorectal cancer, loss of ATM protein expression is associated with worse prognosis, based on immunohistochemical analysis of stage II/III cancers (62), and a high percentage of ATM-mutated cases has been reported by COSMIC (47).…”

Development of bioluminescent chick chorioallantoic membrane (CAM) models from primary pancreatic cancer cells: A platform for drug testing

“…However, previously it has been shown that the long-term maintenance in culture of PDAC cell lines, such as BxPC-3, CFPAC-1 and PANC-1 cells 33,34 , resulted in distinct and irreversible loss of crucial genetic and biologic properties. This included the occurrence of distinct stem cell populations and complex genomic aberrations, affecting critical signaling pathways 35,36 . A more recent study used PDAC primary cell cultures obtained from ascites, demonstrating the establishment of cell masses on the CAM that were consistent with the in vitro studies of tumorigenicity of the PDAC primary cultures 37 .…”