Marsha Wallace

I am a Research Fellow in Bioinformatics at the University of Oxford and the Royal Veterinary College, working at the interface of molecular biology, genomics, and computational analysis to understand how genetic variation shapes disease risk in humans and animals. I trained as a geneticist at Cornell University, where my doctoral research used tumor models with defects in DNA replication and DNA repair to investigate how replication stress leads to genome instability, altered development, and cancer susceptibility. This work revealed unexpected consequences of genomic instability beyond cancer and has been published in Nature. In parallel, applying a comparative oncogenomic approach, I identified hemizygous loss of NF1 as a dominant driver of mammary tumorigenesis, challenging the prevailing two-hit model for tumour suppressor genes by demonstrating that loss of a single NF1 allele is sufficient to promote cancer. Given the association between NF1 loss and resistance to tamoxifen, this discovery has direct implications for treatment stratification affecting hundreds of thousands of patients globally each year. My postdoctoral research at Oxford in the Ludwig Institute for Cancer Research expanded this foundation into human cancer predisposition, focusing on inherited modifiers of cancer risk and onset in Li-Fraumeni syndrome (LFS). I worked with cohorts of Brazilian LFS carriers, where a founder TP53 mutation occurs in 1 in 300 individuals, necessitating population-wide genetic screening and posing a major clinical challenge due to highly variable cancer penetrance. In this context, I identified a germline variant in the retinoic acid pathway that reproducibly modifies the age of onset of adrenocortical carcinoma, a childhood cancer with poor survival if not detected early. This work demonstrated how inherited genetic modifiers can stratify cancer risk within a high-risk population. More recently, at the Wellcome Centre for Human Genetics, Royal Veterinary College, and DPAG, I have driven computational genomics studies spanning rare disease, cancer, and translational veterinary medicine, developing evidence-scoring frameworks to prioritise candidate variants from genomic data. This has delivered world-first insights (e.g. scRNA-seq of insulinoma, WGS of canine stomatocytosis) and patentable translational outputs. Across my work, I am particularly interested in how genetic differences accumulate to influence disease susceptibility, and in developing integrative genomic approaches that translate complex data into biological and clinical insight. My long-term vision is to open new avenues for disease prevention.