Genomic landscape of adenosquamous carcinoma of the colorectum reveals actionable therapeutic targets

Colorectal adenosquamous carcinoma (ASC) is an extremely rare and aggressive subtype accounting for merely 0.06% of all colorectal malignancies, with its genomic features and clinical therapeutic targets remaining largely unelucidated. This study aimed to characterize the unique genomic mutational landscape of ASC and identify clinically actionable therapeutic targets via whole-exome sequencing (WES). Tumor tissues and matched adjacent normal tissues from 3 patients with pathologically confirmed ASC were collected with ethical approval and written informed consent. Comprehensive WES and bioinformatics analyses, including strict data quality control, accurate variant detection and systematic annotation, were performed to compare the genomic profiles between ASC and conventional colorectal cancer (CRC). Key findings revealed distinct genomic characteristics of ASC that are markedly different from conventional CRC: 1.No mutations in NRAS/KRAS/BRAF, the most common driver genes in conventional CRC, were detected; instead, recurrent mutations in DNA damage repair genes (e.g., BRCA1, FANCA, WRN) and unique high-frequency mutations in MUC16 and SMYD4 were identified. 2.All ASC samples exhibited a high tumor mutational burden (TMB > 10), a clinically recognized threshold predictive of responsiveness to immune checkpoint inhibitors such as PD-1 monoclonal antibodies. 3.A panel of significantly mutated genes (SMGs) (e.g., AHNAK2, KRT40, ZNF568) and functionally enriched pathways (e.g., ABC Transporter Pathway, Adherens Junction Pathway) closely associated with tumor aggressiveness and metastasis were identified. This study concludes that ASC harbors unique genomic features that render conventional CRC therapeutic regimens ineffective. Immune checkpoint inhibitors and PARP inhibitors targeting DNA repair gene mutations represent promising first-line therapeutic options for ASC patients, while KRT40 may serve as a novel diagnostic biomarker for this rare subtype. These findings fill the critical gap in genomic research on ASC, providing a direct molecular basis for improving clinical diagnosis and formulating personalized precision therapy, though validation in larger multicenter cohort studies is warranted.