Genetic and transcriptomic analyses of early-onset colon cancer (EOCC): a post hoc analysis of 2973 patients from two adjuvant randomized trials

Abstract

Background: Despite decreasing colon cancer (CC) incidence worldwide, an inverse trend is being registered since the late 1990s in people <50 years old, possibly due to an increasing exposure to lifestyle-related risk factors/exposome. Early-onset CC (EOCC) typically manifests in more advanced stages and may harbor a distinct genetic profile. However, its prognosis remains controversial, and disease stratification through gene expression-based subtyping could potentially provide insight. Materials and methods: We collected data from stage III CC patients enrolled in PETACC-8 and IDEA-France and we analyzed them according to a cut-off of 50 years of age, defining EOCC and late-onset CC (LOCC). Molecular analyses were carried out to evaluate mismatch repair deficiency (dMMR) and extended genetic profile. RNA-sequencing analyses were carried out to determine consensus molecular subtypes (CMS). Results: A total of 2607 LOCC and 366 EOCC were included. When compared to LOCC, EOCC were in better general conditions and presented more advanced-stage diseases. EOCC were more often dMMR, CMS1, RAS wild-type, and mutated for PTEN, CTNNB1, ERBB2, and DDR2. Relapse-free survival (RFS) was similar in the two age groups (3-year rate 74% versus 76%), but differences were observed according to CMS. In CMS1, a better RFS was observed in mismatch repair-proficient (pMMR) EOCC versus LOCC (3-year rate 82% versus 63%, P = 0.041), while this was not observed in dMMR CMS1. Conclusions: In conclusion, EOCCs are diagnosed in more advanced stages, are more often dMMR, harbor a specific genetic profile, and have similar RFS when compared to LOCC, even if the age effect on RFS appeared to vary among CMS groups.

Keywords

• colorectal cancer
• early-onset colorectal cancer
• genetic profile
• transcriptomic profile
• CMS