Publication highlights

In this study, researchers at the Crick and UCL investigated how an epigenetic change called DNA methylation cooperates with genetic changes in non-small cell lung cancer (NSCLC) using 217 tumour and normal regions from 59 TRACERx patients. This is the first multiregional lung cancer cohort integrating genomic, transcriptomic, and epigenomic data to map tumour evolution in such detail. They uncovered a novel mechanism, where DNA methylation fine-tunes how oncogenes are switched on together by compacting the DNA. We also identified hypermethylated driver genes emerging early in tumour evolution and developed a new metric, Mr/Mn, to distinguish functional from passenger methylation changes. Our work highlights epigenetic drivers with therapeutic potential.

In a joint effort from the Francis Crick Institute, UCL and the Netherlands Cancer Institute, researchers have demonstrated that lung cancers consist of different subclones that differ intrinsically in their capacity to evade immune attack. Cancers are genetically heterogeneous – consisting of different subclones – but to what extent this affects immune evasion remained largely unclear. Now, using samples from the TRACERx cancer evolution study, the team have established organoids – mini-tumours growing in 3D - from different regions from the same tumour, and further separated these into individual subclones. Challenging these with immune cells from the patient’s tumour showed that different subclones isolated from the same tumour differ profoundly in their ability to trigger an immune response. This provides direct functional evidence that subclonal cancer evolution has important consequences for the ability to evade immune attack.

Researchers at the Crick and the University of York with clinicians from Great Ormond Street and Guy’s and St Thomas’ Hospitals have investigated all the kinase enzymes expressed (the kinome) in children with a disease called Multiple Endocrine Neoplasia Type 2 (MEN2), to identify new therapeutic markers and targets. This autosomal dominant disease leads to several cancers including the development of thyroid cancer and is caused by pathogenic variants in the receptor tyrosine kinase RET. But the development and progression of these tumours are not always predictable, even within families with the same RET pathogenic variant. This study identified MEN2 subtype and RET pathogenic variant-specific alterations in signalling pathways including mTOR, PKA, NF-κB and focal adhesions, each of which were subsequently validated in patient thyroid tissue.

Researchers at the Crick have shown that over 40% of variation in kidney cancer behaviour is due to non-genetic factors. The team analysed the DNA and RNA of 243 samples from 79 people with kidney cancer in the TRACERx Renal study, to understand both genetic and transcriptional variation (when the genes are read in the cell and converted into proteins). They showed that over 40% of transcriptional variation could not be accounted for by major cancer mutations in the DNA. Instead, it was happening when the DNA was being read in the cells and converted into proteins. Their research identified four types of transcriptional variation which give tumours an advantage, which could be targeted by new treatments or help doctors understand the risk of a person’s cancer spreading.

Researchers at the Crick and the UCL Cancer Institute have identified a genetic change which happens early in lung cancer development, that makes cancer cells divide abnormally and become harder to treat. They studied non-small cell lung cancer samples from the Cancer Research UK-funded TRACERx study, to investigate which genetic changes make two hallmarks of cancer, chromosomal instability and whole genome doubling, more likely. They identified that a gene called FAT1 was mutated in lung cancer cells with unstable chromosomes before they doubled their genomes. Cells with a complete loss of FAT1 couldn’t divide properly to produce two new cells. When FAT1 and another gene involved in cell size regulation called YAP1 were removed, the cancer cells no longer doubled their genomes. This suggests that drugs that block YAP1 could be particularly effective against cells with high levels of chromosomal instability.

Researchers from the Francis Crick Institute and UCL, part of the eDyNAmic Cancer Grand Challenges team, have shown that rogue genetic material called extrachromosomal DNA (ecDNA) can drive the survival of some of the most aggressive cancers. The team analysed Genomics England data from nearly 15,000 people with one of 39 different types of cancer, finding that over 17% of the samples contained ecDNA, with the highest rates seen in sarcomas, glioblastoma and a type of breast cancer. They then found that ecDNA was associated with shorter survival across all cancer types. The researchers hope that identifying and targeting vulnerabilities in ecDNA could stop tumours from evolving and becoming resistant to treatment.

An important aspect of cancer research is the model systems that researchers use to test new therapies. Within the TRACERx lung cancer study, researchers from the CRUK Lung Cancer Centre of Excellence have performed a direct comparison of patient tumours and a commonly used laboratory model - ‘patient-derived xenograft’ or ‘PDX’ models - in which patient tumour tissue isgrown within immunocompromised mice.

The researchers found that patient tumours are often genetically complex, with many co-existing subclones (groups of cell populations with different characteristics). However, the PDX models often only represented one of these subclones. This over-simplicity of PDX models might limit their ability to predict patient responses. These findings will shape the future use of PDX models in lung cancer research and clinical studies.