Mia Petljak, PhD

As we age, our cells accumulate DNA mutations that can drive cell expansion in different tissues, contributing to cancer and non-malignant age-related diseases. Our laboratory investigates the causes of DNA mutations and the mechanisms driving cell expansion in diseases, with the ultimate goal of developing new therapies and preventative strategies that target these underlying causes.

To translate our fundamental discoveries into clinical and preventative applications, our multidisciplinary team - comprising clinical, computational, and basic biology scientists and collaborators - operates at the interface between functional and computational genomics, multi-omics, cell and molecular biology, and genomic epidemiology. By integrating computational analyses of large-scale DNA sequencing datasets with experimental research, we begin by identifying both the environmental and cell-intrinsic factors that cause DNA mutations and/or promote cell evolution. For example, we develop and apply innovative methods to define genome-wide mutational fingerprints, known as mutational signatures, which are imprinted on DNA by specific mutational exposures. Using these signatures, we analyze DNA from experimental systems and clinical samples to pinpoint mutational sources, investigate their roles in cell expansion, tissue physiology, and disease, and quantify exposures for cancer risk prediction.

Our work builds on our landmark characterization of ongoing mutational processes in cancer (Cell, 2019). By leveraging our new models and methods, we subsequently uncovered the mechanisms underlying key mutational processes in cancer and aging tissues (Nature, 2022). Through these discoveries, we identified several mutational processes as potential therapeutic targets and biomarkers for precision cancer medicine. For instance, we provided the first causal evidence that APOBEC3 deaminases - enzymes typically involved in mutating viral DNA and RNA - are prevalent sources of mutations in cancer cells. These mutational processes have since been implicated in therapy resistance and established as actionable targets in patients with cancer, providing a platform for the application of our research in clinical practice.

Current projects in the lab include:

• Identifying biomarkers, mechanisms, impacts and therapeutic exploitability of APOBEC3 mutagenesis in cancer
• Characterization of mutational signatures and carcinogenic risks of emerging environmental exposures
• Development of methods for detection of exposures and related cancer risks using large-scale genome-wide DNA analyses  
• Dissecting the mechanisms and impacts of somatic cell evolution in disease