Early-Onset Colorectal Cancers Exhibit Distinctive Placental-Like Features

The incidence of early-onset colorectal cancer (EO-CRC, diagnosed earlier than age 50) is rising worldwide. Despite distinctive clinicopathological features, whether EO-CRC represents a biologically distinct entity from standard-onset CRC (SO-CRC) remains unclear. To investigate molecular underpinnings of EO-CRC, we applied high-resolution label-free mass spectrometry coupled with transcriptomic approaches on primary tumours, healthy mucosae, and metastases of EO-CRC and SO-CRC patients. Most EO-CRC displayed reactivation of placental-like programs and HERVH reactivation, a family of retrotransposons maintaining pluripotency. These features were retained in patient-derived organoids (PDOs) showing sensitivity to pharmacological ATR (Ataxia Telangiectasia and Rad3-related) inhibition. While these findings point to specific EO-CRC vulnerabilities, they require further validation in larger geographically distinct series. These findings distinguish most EO-CRC from SO-CRC as they possess specific placental mimicry and HERVH reactivation. The placental mimicry and HERVH reactivation observed may provide a molecular rationale for EO-CRC aggressive behaviour and suggest potential avenues for therapeutic targeting.