Cancer is a disease of somatic evolution in our tissues. While a lot is known about the genetic alterations associated with cancers, much remains to be discovered about the evolutionary dynamics of cancer:
- What are the rate-limiting steps in cancer onset and progression?
- What are the relative roles of selection vs drift on mutant clones in the earliest stages of cancer?
- Why do only a small fraction of lesions progress to malignancy and how do we identify these?
Our projects are aimed at interrogating the above questions, by combining experiment, data and theory approaches.
Clonal hematopoiesis and Cancer risk Tracked over 20 years
We make ~5,000,000 new blood cells each second. To achieve this, hematopoietic stem- and progenitor-cells (HSPCs) must constantly divide to replenish the cells we lose. Throughout our lifetimes, therefore, our populations of HSPCs evolve: accumulating genetic alterations, some of which cause clonal expansions and, eventually, cancer. We are studying this by performing deep sequencing on longitudinal blood samples collected over a 20-year period.
Modelling and analysing mutation dynamics in tissues
The fate of a new mutation depends on the evolutionary forces of mutation, genetic drift and selection. In both normal and cancerous tissue evolution, the relative roles of each of these forces remains controversial. How much of the somatic evolution we observe is due to chance or effect? This project aims to address these questions by making quantitative predictions of mutation frequencies under different evolutionary scenarios (e.g. neutral vs selected) and comparing these predictions to available data. These models will provide a rational basis for detecting abnormal clones.
People: Matt Bradley
in-situ DNA barcoding of tissues
DNA barcodes are short (~30bp) sequences of DNA which are stably integrated into a cell’s genome and which serve as “name-tags”, allowing one to track millions of cell lineages through time by counting each tag using next-generation sequencing. In this project we aim to develop an in-situ barcoding technology for mammalian cells based on an existing genetic technology developed in yeast. Because DNA-based lineage tracking is both quantitative and high-throughput, the development of this tool in mammalian cells has the potential to shed light on many questions in cancer and stem cell biology. This project is a collaboration with the lab of Sasha Levy.
People: Emma Wagner
Developing a robust cell-free dna test for breast cancer
Liquid biopsies offer the potential to diagnose cancer early by detecting tumor-derived cell-free DNA (cfDNA) in a blood sample. However, the vast majority of somatic alterations in cfDNA — even those in cancer-associated genes — derive from lesions that will never become malignant, and are present in a large fraction of healthy adults. To develop more robust cfDNA tests we must better understand the somatic variants seen in people who do, and who do not, develop cancer. We will investigate this by creating and analyzing longitudinal cfDNA data from a large cohort of patients who have a high risk of developing breast / ovarian cancers.
People: No one yet! Interested? Email us