Poster Presentation 38th Lorne Cancer Conference 2026

Characterising genomic heterogeneity in KRAS-mutant lung adenocarcinoma (#240)

Siddharth Pruthi 1 2 , Lauren Ashwood 1 2 , Sharon Hoyte 1 , Rebecca Johnston 1 , Dean Basic 1 , Scott Wood 1 , John Pearson 1 , Nicola Waddell 1 2 , Kate Sutherland 3 4 , Olga Kondrashova 1 2
  1. QIMR Berghofer, Brisbane, QLD, Australia
  2. Centre for Clinical Research, Faculty of Health, Medicine, and Behavioural Sciences; University of Queensland, Brisbane, Queensland, Australia
  3. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  4. University of Melbourne, Melbourne, Victoria, Australia

The proto-oncogene KRAS is a member of the RTK/RAS/RAF proliferative pathway and plays a key signalling role mediated through several downstream targets. KRAS is the most frequently mutated driver gene in lung adenocarcinoma (LUAD), accounting for more than 30% of cases, and current therapies demonstrate limited clinical efficacy in patients with KRAS-mutant LUAD. Previous exome studies have identified molecular features associated with KRAS-mutated LUAD. These include allele-specific phenotypes [1] and recurrent co-occurring alterations associated with distinct transcriptomic signatures and immune microenvironment characteristics that may influence treatment response [2] [3]. However, a lack of large-scale whole-genome-sequencing (WGS) datasets in lung cancer, until recently, has precluded analysis to variants and mutation events within exons, which only account for approximately 1% of the human genome.

Our analysis of over 300 primary tumour-normal cases has revealed a higher prevalence of KRAS mutations than detected by exome-analysis, and identified tumours with high gains (copy number>10) of wild-type KRAS mediated by complex chromosomal rearrangements. We have also found evidence for stronger selection of mutant KRAS compared to other oncogenic driver mutations in both DNA and RNA readouts, and heterogeneity of this measure at the KRAS allele-specific level. Wider chromosomal instability and genome-doubling (approx. 65%) is prevalent in the KRAS-mutant subtype, however timing analysis suggests it occur later in mutation time-scale compared to wild-type cases. Functional analysis of structural variants (SVs) in LUAD has identified potential promoter-hijacking events in TERT, loss-of-function events in KRAS subtype defining genes, and approximately 15% of cases with proximal SVs driving aberrant up-regulation of a canonical P53-pathway gene. Complex genomic rearrangements, classes of inter-leaved large-scale variants originating through catastrophic shattering events [4], are observed in approximately 30% of KRAS cases- and most commonly drive large amplifications of putative oncogenes MYC and NKX2-1. We will also characterise the genomic distinctions between primary and metastatic LUAD tumours using data from the Hartwig Medical Foundation (N=609) [5], to elucidate mutational events that may drive metastases and identify features that may be reflective of tumour evolution.

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  2. Skoulidis, F., et al., Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer discovery, 2015. 5(8): p. 860-877.
  3. Jeanson, A., et al., Efficacy of Immune Checkpoint Inhibitors in KRAS-Mutant Non-Small Cell Lung Cancer (NSCLC). Journal of Thoracic Oncology, 2019. 14(6): p. 1095-1101.
  4. Bao, L., et al., Starfish infers signatures of complex genomic rearrangements across human cancers. Nature cancer, 2022. 3(10): p. 1247-1259.
  5. Priestley, P., et al., Pan-cancer whole-genome analyses of metastatic solid tumours. Nature, 2019. 575(7781): p. 210-216.