SMAD4 Protein Alterations in Early-Onset Colorectal Cancer: Implications as a Potential Marker for Aggressive Disease and Prognosis—A Clinicopathological and Molecular Analysis of 18 Cases in Patients < 40 Years of Age

Background/Objectives: Colorectal cancer (CRC) is relatively uncommon in individuals under 40 years of age; however, its rising incidence is a growing concern. This study aimed to investigate clinicopathologic features, genetic alterations, and protein expression patterns in early-onset colorectal cancer (EOCRC) to better understand the underlying mechanisms and prognostic factors. Methods: We retrospectively analyzed 18 patients diagnosed with EOCRC (<40 years) at our institution between 2018 and 2023. Next-generation sequencing (NGS) and immunohistochemistry (IHC) were used to assess genomic alterations and protein expression profiles. Clinicopathologic data were correlated with molecular findings and outcomes. Results: The cohort included ten females and eight males (mean age, 32.7 years; range, 17–38 years). Tumors most frequently arose in the rectum (56%) and were predominantly high stage (T3–T4, 67%) and moderately differentiated (78%). Lymphovascular invasion occurred in 50% of cases, and lymph node metastasis in 39%. Most tumors were microsatellite stable (MSS, 89%) and mismatch repair–proficient; two cases (11%) were MSI-high with germline MMR mutations. Among 17 patients who underwent NGS, the most frequent mutations involved KRAS (35%), APC (24%), TP53 (18%), and SMAD4 (18%). Notably, SMAD4 protein downregulation by IHC was observed in 67% of cases, including 60% of SMAD4 wild-type tumors. Loss of SMAD4 expression was significantly associated with lymph node metastasis (p = 0.037) and poor survival (p = 0.045). Conclusions: SMAD4 alteration—on both the genetic and protein levels—is common in EOCRC and is significantly correlated with aggressive clinicopathologic features and worse prognosis.