1. What is aneuploidy?
Aneuploidy refers to the presence of an abnormal number of chromosomes in the genome.
At the organismal level aneuploidy is almost always incompatible with life. At the cellular level, aneuploidy is very rare in healthy tissues (<1%) but extremely frequent in cancer (>90%). Despite its frequency, we still have a poor understanding of how aneuploidy originates in cancer and how it affects cell physiology and tumor development.
Relevant publications:
- Davoli and de Lange, 2011
- Knouse, Davoli et al, 2017
2. Specific patterns of aneuploidy in cancer
If we look at the frequency of chromosome or arm-level amplifications and deletions in cancer, what we see is that not all chromosomes are gained or lost at the same frequency, but there are specific chromosomes that tend to be frequently amplified or deleted in human cancer. Why is that? Is this due to the frequency of occurrence of each event or to selection during tumorigenesis? We are interested in answering this question using bioinformatics and experimental tools. Within this research line, we recently showed that the density of cancer driver genes on each chromosome predicts the frequency of deletion or amplification, suggesting that specific aneuploidy is a driver event in human cancer.
Relevant publications:
- Davoli et al., 2013
- Sack, Davoli et al., 2018
3. Prediction of cancer driver genes based on point mutations
Cancer is a genetic disease driven by the clonal expansion of cellular clones that during tumorigenesis accumulate a high number of point mutations. A current challenge in cancer biology is to discriminate between genes that are mutated in cancer but do not play an active role during tumorigenesis (passengers) and genes that are mutated in cancer and drive tumor progression (drivers). There are two main classes of cancer driver genes: tumor suppressor genes (TSG) and oncogenes (OG). We are developing tools to predict whether a gene behaves as a driver or passenger in human cancer by studying its pattern of somatic point mutations (see TUSON Explorer tool; Davoli et al 2013)
Relevant publications:
- Davoli et al., 2013
- Sack, Davoli et al., 2018
4. Impact of aneuploidy on response to immunotherapy
Immunotherapy represents one of the most exciting new avenues of cancer treatment. However, despite its strong curative potential, only a fraction of patients benefit from current immunotherapy approaches. We have recently shown that high levels of tumor aneuploidy is a predictor of poor response to immunotherapy (Davoli et al 2017). We are very much interested in understanding the mechanism by which high levels of aneuploidy promote cancer immune evasion. In addition, we are also investigating potential new strategies to effectively target high aneuploid tumors for cancer therapy.
Relevant publications:
- Davoli et al., 2017
- Knouse, Davoli et al., 2017
