Primary Tumor‐Associated Loss of the Y Chromosome and Clinical Outcome in Metastatic Colorectal Cancer

BACKGROUND: Alterations of the Y chromosome are frequent events in solid tumors, yet their biological and clinical significance remains incompletely understood. In colorectal cancer (CRC), recent studies have suggested context-dependent roles of Y-linked genes in tumor progression, while the impact of tumor-associated loss of the Y chromosome (LoY) in metastatic disease has not been clearly established. METHODS: We retrospectively analyzed primary tumor samples from 91 male patients with metastatic CRC treated at a single institution. Tumor LoY status was assessed using a droplet digital PCR-based assay. Associations between LoY, clinicopathological characteristics, KRAS/BRAF mutation status, and patient outcomes, including progression-free survival (PFS) and overall survival (OS), were evaluated. Exploratory analyses of TCGA-COAD/READ data were performed using chromosome Y copy-number segment data, mutation data, and survival information. RESULTS: Tumor LoY was detected in 46 cases (50.5%) and was more frequent in rectal cancers (p = 0.038). LoY was not associated with age, microsatellite instability status, KRAS or BRAF mutations. While PFS did not differ according to LoY status, OS was longer in patients with LoY-positive tumors (p = 0.046). In multivariable analysis, LoY showed a non-significant trend toward improved OS (HR = 0.52, 95% CI: 0.25-1.10; p = 0.07). In exploratory TCGA analyses, chromosome Y copy-number signal did not significantly differ between colon and rectal cancers, but lower chromosome Y signal was associated with worse OS, particularly in TCGA-COAD after adjustment for age and KRAS/BRAF status. CONCLUSIONS: LoY is a frequent chromosomal alteration in metastatic CRC and appears enriched in rectal primary tumors in our cohort. Its association with clinical outcome may depend on disease stage, molecular background, and analytical methodology. These findings support further investigation of Y chromosome loss as a context-dependent biomarker in CRC.