Cancer-associated Mutations Co-locate with TRPA1 Hinge Formation in the Ankyrin Repeat Region

Abstract

The Transient Receptor Potential Ankyrin1 (TRPA1) ion channel is recurrently mutated in Oesophageal Adenocarcinoma (OAC) patients. A list of point mutations in TPRA1 were obtained from the Catalogue of Somatic Mutations in Cancer (COSMIC) database and mapped on the TRPA1 structure. TRPA1 structures harbouring OAC mutations were simulated in order to inform alterations in structure-function relationships of the channel and propose ways by which mutations promote cancer. Notably, we observe clustering of cancer mutations around dynamic hinges in the intracellular ankyrin repeat region of the structure. We propose that missense mutations observed in OAC promote cancer via TRPA1 activation by altering protein dynamics. Increasing evidence suggests that ion channels are not only responsible for regulating cellular homeostatic mechanisms such as cell volume, membrane potential, and osmolarity but they are also implicated in controlling cell proliferation, migration, apoptosis, and differentiation. Aberrant cell cycle control, cell adhesion, and migration contribute to an invasive phenotype associated with cancer and metastasis. Recent evidence illustrates that disruptions in calcium signalling, secondary to the overactivity of TRPA1, promote Reactive Oxygen Species (ROS) tolerance and apoptosis resistance in cancer cells. We have previously shown that TRPA1 is as a driver gene and is recurrently mutated in 6% of a 551 OAC-patient cohort based on the ratio of non-synonymous to synonymous mutations. Here we confirm this through a detailed analysis of patient data, as well as the behaviour and properties of missense mutations along the protein structure. Kaplan-Meier survival curves from The Cancer Genome Atlas (TCGA) and Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) datasets, reveal that high TRPA1 expression correlates with poor patient prognosis in OAC (p = 0.019), and observe changes in canonical cancer pathways with TRPA1 expression across the cohort.