Oral Presentation 38th Lorne Cancer Conference 2026

Genomic evolution in preinvasive lung disease in TRACERx (133965)

Clare Puttick 1 , Haoran Zhai 2 , Mihaela Angelova 2 3 , Emma Colliver 2 3 , Katey Enfield 2 3 , Carlos Martínez-Ruiz 2 3 , Ariana Huebner 2 3 , Mark S Hill 2 3 , Piotr Pawlik 3 4 , Maise Al Bakir 2 3 , Alexander M Frankell 2 3 , David A Moore 2 3 , Nicholas McGranahan 3 4 , Charles Swanton 2 3 5 , Mariam Jamal-Hanjani 4 5 6
  1. Garvan Institute, London, LONDON, United Kingdom
  2. Francis Crick Institute, London, LONDON, United Kingdom
  3. Cancer Institute, University College London, London, United Kingdom
  4. Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK
  5. Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK
  6. Department of Oncology, University College London Hospitals, London, UK

Lung cancer remains the leading cause of cancer-related mortality worldwide. Improving early diagnosis and intervention requires a deeper understanding of the earliest steps in tumour evolution, yet these stages remain poorly characterised. To address this, we performed whole-exome sequencing (WES) and imaging mass cytometry (IMC) on multiregional preinvasive (n=62) and invasive (n=127) lesions collected at the same surgery timepoint from 21 patients with lung adenocarcinoma (LUAD) and 13 with lung squamous cell carcinoma (LUSC) from the TRACERx study.

Phylogenetic reconstruction revealed that preinvasive and invasive lesions shared a common ancestral clone in 6/21 patients with LUAD and 13/13 patients with LUSC. LUAD preinvasive lesions that shared an ancestral clone with the invasive disease exhibited significantly higher mutation burden, increased genomic instability, more frequent whole genome doubling and loss of heterozygosity (LOH) at the Human Leukocyte Antigen locus, than those that did not. IMC demonstrated that both LUAD and LUSC preinvasive lesions harboured significantly higher infiltration of CD4, CD8 T cells and myeloid cells compared with their invasive counterparts.

In the LUSC phylogenies where the preinvasive and invasive samples shared a common ancestral clone, we found that significantly more LOH and amplification occurred prior to the preinvasive-invasive divergence than after. This included several chromosomal arm LOH events that occurred more frequently prior to preinvasive-invasive divergence, including 3p, 9p, 9q, 13q and 17p in LUAD, and 3p, 4q, 5q, 13q, 9p, 9q and 17p in LUSC. APOBEC mutagenesis and whole genome doubling were detected both before and after the preinvasive-invasive divergence. Finally, leveraging the smoking-associated mutational signature (SBS4) in six ex-smokers, we estimated the absolute timing of the preinvasive-invasive divergence as occurring 6, 8, 9, 12, 22, and 38 years before primary surgery.