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

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

New constraints on Saturn's interior from Cassini astrometric data

This work has been supported by the European Community’s Seventh Framework Program (FP7/2007-2013) under grant agreement 263466 for the FP7-ESPaCE project, the International Space Science Institute (ISSI), PNP (INSU/CNES) and AS GRAM (INSU/CNES/INP). The work of R. A. J. was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with NASA. N.C. and C.M. were supported by the UK Science and Technology Facilities Council (Grant No. ST/M001202/1) and are grateful to them for financial assistance. C.M. is also grateful to the Leverhulme Trust for the award of a Research Fellowship. N.C. thanks the Scientific Council of the Paris Observatory for funding. S. Mathis acknowledge funding by the European Research Council through ERC grant SPIRE 647383