Bioinformatics Seminar
Time: 11AM
Venue: Davis Auditorium and Teams
11 October 2022
Fishing for resistance mutations in PARP1
Matthew WakefieldWEHI Bioinformatics
Poly ADP-ribose polymerase inhibitor (PARP) inhibitors are a highly effective therapy in widespread clinical use for breast and ovarian cancer. We are characterising all possible mutations in PARP1 for their impact on inhibitor resistance using a Deep Mutational Scan (DMS). This will provide clinical annotation for making patient care decisions and improve our fundamental understanding of PARP inhibitor function and resistance.Using MAVEDB and its integration into the SHARIANT database this data will be rapidly available to directly support clinical decision making. By testing multiple different PARP inhibitors, we are determining the mutations that are specific to an individual drug, allowing potential substitution with a PARP inhibitor that overcomes the resistance.I will discuss how we are undertaking this screen, and some of the wet lab approaches we are using to maximise the power of this screen in a cost-effective manner. This has included using a new method of barcode association with Oxford Nanopore sequencing and developing an analysis tool called Scissortail, that applies a consensus amplicon sequencing approach using barcodes as unique molecular identifiers. Its application to a dataset of Promethion sequencing of 30M 3kb amplicons will be presented.This method aims to minimise the barriers to conducting MAVE assays and put this technique within the reach of more research groups.