Quantitative evaluation of gene dosage effects in the Ras/ERK and PI3K/mTOR pathways on metastatic transformation of oesophageal cancer (360G-Wellcome-215296_Z_19_Z)

Distant metastases account for ~90% of cancer-related deaths, but our understanding of the determinants of this process is limited. I propose to elucidate early genomic mechanisms that enable cells to acquire a metastatic phenotype, with focus on allelic imbalance resulting from copy number changes and the underlying genomic instability. I have previously characterized the implications of genomic amplifications of receptor tyrosine kinases and downstream pathways (MAPK/ERK/PI3K) in the progression of oesophageal adenocarcinoma, a cancer with frequent metastases and prevalent genomic instability. Recent studies have highlighted similar gene dosage effects in KRAS promoting metastasis in pancreatic cancer, and a more general role for genomic instability in accelerating metastatic spread. This study proposes to explore the involvement of such alterations in local invasion in oesophageal adenocarcinoma using whole-genome and RNA sequencing data from primary tumours of this type. I aim to: (1) characterize gene dosage effects and co-dependencies at genomic/transcriptional level in the Ras/MAPK and PI3K/AKT pathways; (2) understand the mutational processes generating such alterations; (3) employ machine learning to identify features in 1) and 2) that are predictive of cellular invasion in this cancer. This integrated framework will highlight pathway vulnerabilities during metastatic onset that may be targetable in the clinic.