• What makes an individual at a high risk of developing cancer?

  • Can we detect pre-cancerous mutations and use this to identify high-risk individuals?

  • How does the germline genetic background of an individual interact with acquired mutations and environmental factors influence cancer risk?

The questions that we care about.

Characterizing the genetic basis of carcinogenesis

 
 

The multistage model of carcinogenesis suggests that the successive acquisition of somatic mutations predates cancer development. Each mutation contributes to a clone’s fitness advantage, resulting in clonal expansions. This evolutionary process results from an interplay between environmental factors, the genetic targets of selection and the contexts in which these mutations contribute to differential clonal fitness. Our understanding of this process is mainly based on retrospective modeling of clonal structures observed at cancer diagnosis and in vitro and animal studies.

Our lab studies this using clonal hematopoiesis (CH). CH is process whereby a stem cell in the bone marrow develops an acquired mutation that imparts a fitness advantage. In some cases this can lead to hematologic malignancy. Studies of CH present a unique opportunity to study the evolutionary process underlying malignant transformation. We leverage large population databases and patient cohorts to understand this process using multi-modal sequencing approaches.

 
 

Ultimately our goal is to develop precision prevention approaches to stop the development of cancer. This means that we need to 1) identify individuals at a sufficiently high risk of developing cancer to warrant intervention and 2) develop molecularly targeted approaches to stop pre-malignant mutations from progressing to cancer. We partner with industry to develop trials for cancer prevention. One example is an ongoing trial where we are using the IDH1 inhibitor, ivosidenib, and the IDH2 inhibitor, enasidenib to treat individuals with CH and abnormal blood counts, a disease entity called CCUS (clonal cytopenia of uncertain significance).