Publication highlights

Oesophageal adenocarcinoma shows high genetic heterogeneity making the identification of cancer drivers challenging. We developed a machine learning algorithm to identify cancer drivers in 261 oesophageal adenocarcinomas. Although most predicted drivers were rare or patient-specific, they all perturbed well-known cancer pathways. Using the recurrence of the same pathway perturbations rather than individual genes, we stratified patients into six groups different for their clinical features. We validated experimentally the contribution of these genes to disease progression and revealed acquired dependencies exploitable in therapy. This study described a new way to identify cancer drivers that we have recently further developed for application in precision oncology.

Taking advantage of our sgRNA library, we performed a large-scale characterisation of CRISPR-induced in/del patterns and discovered that Cas9-induced double strand breaks are repaired in a predictable or unpredictable way, depending on the target site. These findings provided the broad scientific community with guidelines for a more effective and safer use of CRISPR technology, with important implications for clinical applications. They also revealed a striking influence of DNA sequence in dictating DSB repair outcomes and laid the foundation for future mechanistic studies that can increase our understanding of end-joining processes in human cells.

This study showed that epigenetic mechanisms play an important role in generating functional heterogeneity within tumours, and can override genetic alterations that initiate the disease by inhibiting cell proliferative potential during tumour growth. The finding that heterogeneous patterns of H1.0 are broadly observed in cancer and that H1.0 is an independent predictor of patient survival in multiple types of solid tumours makes a strong case for a general role of epigenetic regulators in cancer. Mechanistic characterisation of how H1.0 controls malignant self-renewing states also provided insights into general mechanisms through which the linker histone regulates gene expression.

Research from the Scaffidi lab has developed a new strategy to identify cancer-specific vulnerabilities. They identified a group of proteins, called the male-specific lethal (MSL) acetyltransferase complex, which could be used to increase chromosomal instability in cancer cells without inducing severe adverse effects in normal tissues.