Publication highlights

This TRACERx work shows that bespoke patient-specific panels to analyse ctDNA can be used to monitor MRD recurrence and tumour branched evolution in the adjuvant setting in the absence of macroscopic disease, and that tumour Ki67 index, necrosis, squamous histology and FDG-PET avidity are closely associated with ctDNA release. We further demonstrate the limitations of ctDNA approaches for early detection as a function of tumour volume and cancer cell number, and show that the subclone identified in ctDNA prior to disease recurrence is identical to the tumour subclone identified at metastatic sites, permitting adjuvant MRD studies to prevent recurrence.

This work evaluates the relationship between intratumour heterogeneity of single nucleotide variants and somatic copy number aberrations and recurrence free survival in non-small cell lung cancer. Diversity of chromosome number or structure rather than single nucleotide variants is associated with poorer recurrence free survival, independent of tumour stage in multivariable analyses. Through subclonal copy number analyses, mirrored subclonal allelic imbalance is found, driving parallel evolution of chromosome copy number gains or losses on either the maternal or paternal chromosome in different regions of the same tumour.

Through an analysis of TRACERx, extended from our haplotyping analysis, we developed an algorithm called LOHHLA which infers allele specific copy number aberrations in HLA. We find HLA loss occurs in 40% of early stage lung cancers, usually as a subclonal event, and is permissive for branched evolution associated with expansion of mutations predicted to bind the lost HLA allele.

We analysed the first 100 TRACERx patients to unravel how escape from adaptive immunity occurs in non-small cell lung cancer. Immune ‘hot’ tumours, characterised by a brisk lymphoid infiltrate, had been selected for HLA LOH or deleterious mutations in the antigen presentation machinery. In contrast immune ‘cold’ tumours with an absent lymphoid infiltrate had lost clonal neoantigens through DNA copy number loss events. We found evidence for negative selection of subclones early in tumour evolution harbouring neoantigens in genes essential for non-small cell lung cancer viability. Patient outcome was worse for tumours with evidence of an immune evasion event.

A new study from the Swanton lab identified genetic changes in tumours which could be used to predict if immunotherapy drugs would be effective in individual patients.

This is the largest genomic study ever to be conducted in renal cell cancer and the first to show how evolutionary features of the tumour impact the clinical phenotype. Patent arising.

This study leverages molecular archaeology of cancer approaches in a large-scale pan-cancer setting to construct timelines of tumour evolution, showing when in a tumour’s evolutionary history key events typically happen. It demonstrates that tumours typically develop over multiple years to sometimes decades, highlighting opportunities for early detection.