Mutational signatures of early-onset colorectal cancer.

e15113 Background: Despite a reduction of Colorectal Cancer (CRC) incidence in western countries in the past decades, Early-Onset CRCs (EO-CRC, patients diagnosed with CRC ≤ 40 years old) incidence has increased. Although frequently occurring in the context of familial syndromes, EO-CRCs are mainly sporadic cases and phenotipically enriched for distal localisation and advanced stage at diagnosis. Whether EO-sporadic CRCs pathogenesis differs from that of normal-onset (NO) CRC and how this might impact incidence rates is currently unknown. This had prompted us to ask if, at the genetic level, “traces” of peculiar pathogenic processes could be identified in EO-specific (or -enriched) genetic signatures (GS). Methods: The mutational signatures of 424 TCGA CRC patient samples (19 EO and 405 ≥ 50 years at diagnosis) were analyzed and the similarity between each mutational profile and COSMIC GS was calculated using Bioconductor R package Mutational Patterns (doi: 10.1186/s13073-018-0539-0). Unsupervised hierarchical clustering of the samples according to similarity to GS was performed in single cohort and pooled analysis. Association between age and individual GS was assessed through grouped and linear correlation analysis. Results: EO-CRC patients were grouped in three main clusters: Cluster1 exposing a major similarity with GS10 (associated with defects in polymerase proofreading activity), Cluster2 showing stronger similarities with GS6 (associated with mismatch repair deficiency), and GS1 (associated with 5-MeC deamination) and Cluster3 presenting similarity with multiple GSs, such as 3 (associated with homologous recombination deficiency) and 5 (pathogenesis unknown). Overall this clustering was maintained when EO-CRC samples were pooled with NO CRC. Grouped and correlation analysis revealed no significant association between age and individual GSs, including GS1 (associated with age). Conclusions: These preliminary analyses show that the relative contribution of known GS is similar in EO and NO cohorts of patients. Possible enrichment for EO-CRC in specific signature clusters will be analysed on a wider sample series.