A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine.

摘要: Primary adenocarcinoma of the anal canal is a rare and aggressive gastrointestinal disease with unclear pathogenesis. Because its rarity, no clear clinical practice guideline has been defined targeted therapeutic armamentarium yet to be developed. The present article aimed at addressing this information gap by in-depth characterising glandular neoplasms histologic, immunologic, genomic epidemiologic levels. In multi-institutional study, we first examined histological features displayed each collected tumour (n = 74) analysed their etiological relationship human papillomavirus (HPV) infection. intratumoural immune cell subsets (CD4, CD8, Foxp3), expression checkpoints (PD-1, PD-L1), defect in mismatch repair proteins mutation analysis multiple clinically relevant genes cancer setting were also determined. Finally, prognostic significance clinicopathological variable was assessed. Phenotypic revealed two region-specific subtypes adenocarcinoma. significant differences HPV status, density tumour-infiltrating lymphocytes, mutational profile several targetable further supported separation these latter into distinct entities. Importantly, gland/transitional-type cancers, which poorly respond standard treatments, less mutations downstream effectors EGFR signalling pathway (i.e., KRAS NRAS) demonstrated significantly higher inhibitory ligand-receptor pair PD-1/PD-L1 compared counterparts arising from colorectal mucosa. Taken together, findings reported reveal, for time, that arise HPV-dependent or independent pathways. These leads both individual profiles landscapes can benefits.