Oral Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2026

Identifying the aetiological drivers of early-onset colorectal cancer through the mapping of mutational processes (146808)

Peter D Georgeson 1 2 , Alysha Prisc 1 2 , Jihoon E Joo 1 2 , Khalid Mahmood 1 2 3 , Romy Walker 1 2 , Mark Clendenning 1 2 , Yen Lin Chu 1 2 , Julia Como 1 2 , Natalie Diepenhorst 1 2 , Julie McDonald 1 2 , Liam Skinner 4 5 , Lochlan Fennell 4 5 , Finlay A Macrae 6 7 8 , Christophe Rosty 1 2 9 10 , Ingrid M Winship 7 8 , Mark A Jenkins 11 , Daniel D Buchanan 1 2 8
  1. Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia
  2. Collaborative Centre for Genomic Cancer Medicine, University of Melbourne, Parkville, VIC, Australia
  3. Melbourne Bioinformatics, University of Melbourne, Parkville, VIC, Australia
  4. School of Health, University of the Sunshine Coast, Sunshine Coast, QLD, Australia
  5. Centre for Bioinnovation, University of the Sunshine Coast, Sunshine Coast, QLD, Australia
  6. Colorectal Medicine and Genetics, Royal Melbourne Hospital, Parkville, Victoria, Australia
  7. Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
  8. Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, Australia
  9. Envoi Specialists Pathologists, Brisbane, Queensland, Australia
  10. Department of Medicine, University of Queensland, Brisbane, QLD, Australia
  11. Centre for Epidemiology and Biostatistics, University of Melbourne, Parkville, Victoria, Australia

Background: The causes of the increasing incidence of early-onset colorectal cancer (EOCRC) in Australia and globally are unknown. To elucidate the biology and aetiology of contemporary EOCRC, we aimed to understand the mutational processes driving EOCRC development.

 

Methods: Non-hereditary, DNA mismatch repair (MMR)-proficient EOCRCs (n=275) and early-onset polyps (n=95) underwent tumour and matched germline whole exome sequencing. Single base substitution (SBS), indel (ID) and doublet (DBS) signatures from COSMIC v3.4 definitions were calculated. Dimensionality reduction with UMAP was applied using all calculated signatures as input features to identify clusters of EOCRC with similar mutational processes.

 

Results: Of the 275 EOCRCs (60.0% females), 37.1% were diagnosed from 18-35yrs, 46.5% from 36-45yrs and 16.4% from 46-55yrs with 26.2% located in the proximal colon, 37.5% in the distal and 34.5% in the rectum. Dimensionality reduction revealed distinct EOCRC clusters with known aetiologies including 1.8% of EOCRCs with Homologous Recombination Deficiency-associated signatures SBS3 and ID6, 2.2% with SBS10a and SBS10b which were related to POLE somatic mutations, and 5.8% had pks+ E.coli colibactin genotoxin related signatures. A unique cluster representing 14.9% of EOCRCs had both SBS89 and DBS8 signatures which do not currently have a known aetiology. EOCRCs with both SBS89 and DBS8 were more common in the proximal colon compared with distal and rectal EOCRCs (23% vs 11% p=0.027), were more prevalent in the youngest age at diagnosis group (18-35years 26% vs 7%, p=6x10-5) and were more likely to be born after 1980 (p=9.5x10-5). SBS89/DBS8 signatures tended to be more common in serrated polyps (32%) compared with adenomatous polyps (15%; p=0.08).

 

Discussion: Tumour mutational signature profiling identified clusters of EOCRCs with distinct aetiologies providing novel insights into the causes of EOCRC. Individuals, with SBS89 and DBS8 mutational processes, had the youngest age at diagnosis and displayed evidence of a birth cohort effect.